Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals. Supporting Evidence: file:human/EGFR/EGFR-deep-research-falcon.md model: Edison Scientific Literature
GO:0043410 positive regulation of MAPK cascade	IBA GO_REF:0000033	ACCEPT	Summary: EGFR positively regulates the MAPK cascade through recruitment of GRB2-SOS and activation of RAS-RAF-MEK-ERK signaling. Reason: MAPK/ERK pathway activation is a core downstream signaling output of EGFR. This is well-established.
GO:0004714 transmembrane receptor protein tyrosine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that phosphorylates tyrosine residues on substrate proteins following ligand-induced dimerization. This is a core molecular function. Reason: Transmembrane receptor protein tyrosine kinase activity is the defining enzymatic function of EGFR. The kinase domain catalyzes ATP-dependent phosphorylation of tyrosine residues.
GO:0030182 neuron differentiation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: EGFR signaling influences neuron differentiation, a downstream developmental effect. Reason: Neuron differentiation is a downstream developmental process influenced by EGFR signaling, not a core molecular function.
GO:0043066 negative regulation of apoptotic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: EGFR signaling promotes cell survival by activating anti-apoptotic pathways including PI3K-AKT. Reason: Anti-apoptotic effects are downstream consequences of EGFR-PI3K-AKT signaling, not a core function.
GO:0007173 epidermal growth factor receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway.
GO:0050679 positive regulation of epithelial cell proliferation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: EGFR signaling promotes epithelial cell proliferation, a key downstream effect in epithelial tissues. Reason: Epithelial cell proliferation is a major physiological outcome of EGFR signaling but represents a downstream effect.
GO:0043235 receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: EGFR forms homo- and heterodimeric receptor complexes upon ligand binding, which is required for kinase activation. Reason: EGFR dimerization into receptor complexes is essential for signal transduction. EGFR forms homodimers and heterodimers with ERBB2, ERBB3, ERBB4.
GO:0009925 basal plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: EGFR localizes to the basal plasma membrane in polarized cells. Reason: Basal plasma membrane localization is consistent with EGFR function in polarized cells.
GO:0048408 epidermal growth factor binding	IBA GO_REF:0000033	ACCEPT	Summary: EGFR binds EGF through its extracellular domain (subdomains I and III), which induces receptor dimerization and activation. Reason: EGF binding is the canonical ligand-binding function of EGFR. Crystal structures confirm EGF binds domains I and III of the extracellular region.
GO:0000165 MAPK cascade	IEA GO_REF:0000108	ACCEPT	Summary: EGFR participates in the MAPK cascade by activating RAS-RAF-MEK-ERK signaling upon ligand binding. Reason: MAPK cascade activation is a principal downstream effect of EGFR signaling.
GO:0004714 transmembrane receptor protein tyrosine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that phosphorylates tyrosine residues on substrate proteins following ligand-induced dimerization. This is a core molecular function. Reason: Transmembrane receptor protein tyrosine kinase activity is the defining enzymatic function of EGFR. The kinase domain catalyzes ATP-dependent phosphorylation of tyrosine residues.
GO:0046718 symbiont entry into host cell	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: EGFR can serve as a receptor for viral entry, including some herpesviruses. Reason: Viral receptor function is not a normal physiological function of EGFR.
GO:0000139 Golgi membrane	IEA GO_REF:0000044	ACCEPT	Summary: EGFR localizes to Golgi membranes during biosynthesis. Reason: Part of normal EGFR trafficking through the secretory pathway.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: EGFR binds nucleotides (ATP) for its kinase activity. Reason: General parent term for ATP binding, accurate for EGFR.
GO:0001618 virus receptor activity	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: EGFR can act as a receptor for certain viruses. Reason: Virus receptor activity is not a core physiological function.
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: EGFR has protein kinase activity, phosphorylating protein substrates on tyrosine residues. Reason: Accurate parent term for the protein tyrosine kinase activity of EGFR.
GO:0004713 protein tyrosine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: EGFR binds ATP in its kinase domain active site to catalyze phosphorylation reactions. Reason: ATP binding is essential for EGFR kinase activity. The ATP-binding pocket in the kinase domain is the target of many therapeutic inhibitors.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: The EGFR extracellular domain is exposed to the extracellular region. Reason: The ligand-binding ectodomain of EGFR is in the extracellular region.
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Nuclear EGFR has been described in certain contexts and may have transcriptional roles. Reason: Nuclear EGFR is documented but represents a minor, context-dependent localization rather than core EGFR function.
GO:0005768 endosome	IEA GO_REF:0000044	ACCEPT	Summary: EGFR localizes to endosomes following ligand-induced internalization. EGFR continues signaling from early endosomes and is subsequently sorted for recycling or lysosomal degradation. Reason: Endosomal localization is part of normal EGFR trafficking and signaling. EGFR signals from endosomes and trafficking modulates signal duration.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: EGFR is synthesized and processed in the ER membrane. Reason: Part of normal EGFR biosynthesis in the secretory pathway.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway	IEA GO_REF:0000002	ACCEPT	Summary: EGFR is a cell surface receptor protein tyrosine kinase that initiates signaling upon ligand binding. Reason: This is the parent pathway term that accurately describes EGFR function.
GO:0010008 endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: EGFR localizes to endosome membranes during receptor trafficking after internalization. Reason: After ligand-induced endocytosis, EGFR is found on endosome membranes where it continues to signal.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: EGFR is a single-pass transmembrane protein with extracellular, transmembrane, and intracellular domains. The membrane localization is fundamental to its structure and function. Reason: As a transmembrane receptor, EGFR requires membrane localization for proper protein topology, with the extracellular domain for ligand binding and the intracellular kinase domain for signal transduction.
GO:0016301 kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: EGFR has kinase activity, a parent term of protein tyrosine kinase activity. Reason: This is a general parent term that accurately describes EGFR function, though more specific terms are preferred.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: EGFR has transferase activity as it transfers phosphate groups from ATP to protein substrates. Reason: Very general parent term but accurate for EGFR kinase function.
GO:0031965 nuclear membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: EGFR has been reported at the nuclear membrane in certain contexts. Reason: Nuclear membrane localization is not a primary EGFR localization.
GO:0043235 receptor complex	IEA GO_REF:0000117	ACCEPT	Summary: EGFR forms homo- and heterodimeric receptor complexes upon ligand binding, which is required for kinase activation. Reason: EGFR dimerization into receptor complexes is essential for signal transduction. EGFR forms homodimers and heterodimers with ERBB2, ERBB3, ERBB4.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IEA GO_REF:0000117	ACCEPT	Summary: EGFR positively regulates ERK1/2 cascade through RAS-RAF-MEK-ERK signaling axis. Reason: ERK1/2 activation is a core readout of EGFR signaling through the MAPK pathway.
GO:0005515 protein binding	IPI PMID:10229072 Association of Nck with tyrosine-phosphorylated SLP-76 in ac...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:10229072 Association of Nck with tyrosine-phosphorylated SLP-76 in activated T lymphocytes.
GO:0005515 protein binding	IPI PMID:10572067 Dominance of ErbB-1 heterodimers in lung epithelial cells ov...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:10572067 Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2.
GO:0005515 protein binding	IPI PMID:10805725 Class II phosphoinositide 3-kinases are downstream targets o...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:10805725 Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors.
GO:0005515 protein binding	IPI PMID:11896612 Use of signal specific receptor tyrosine kinase oncoproteins...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:11896612 Use of signal specific receptor tyrosine kinase oncoproteins reveals that pathways downstream from Grb2 or Shc are sufficient for cell transformation and metastasis.
GO:0005515 protein binding	IPI PMID:12070153 Identification of both positive and negative domains within ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:12070153 2002 Jun 17. Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation.
GO:0005515 protein binding	IPI PMID:12297049 Crystal structure of a truncated epidermal growth factor rec...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:12297049 Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha.
GO:0005515 protein binding	IPI PMID:12297050 Crystal structure of the complex of human epidermal growth f...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:12297050 Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains.
GO:0005515 protein binding	IPI PMID:12577067 A proteomics strategy to elucidate functional protein-protei...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:12577067 A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling.
GO:0005515 protein binding	IPI PMID:12620237 EGF activates its receptor by removing interactions that aut...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:12620237 EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization.
GO:0005515 protein binding	IPI PMID:14568990 Role of the pleckstrin homology domain of PLCgamma1 in its i...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:14568990 Oct 20. Role of the pleckstrin homology domain of PLCgamma1 in its interaction with the insulin receptor.
GO:0005515 protein binding	IPI PMID:14679214 A novel proteomic screen for peptide-protein interactions.	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:14679214 2003 Dec 16. A novel proteomic screen for peptide-protein interactions.
GO:0005515 protein binding	IPI PMID:14966128 Structural requirements for signal transducer and activator ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:14966128 2004 Feb 13. Structural requirements for signal transducer and activator of transcription 3 binding to phosphotyrosine ligands containing the YXXQ motif.
GO:0005515 protein binding	IPI PMID:15225635 Identification of 14-3-3zeta as an EGF receptor interacting ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:15225635 Identification of 14-3-3zeta as an EGF receptor interacting protein.
GO:0005515 protein binding	IPI PMID:15282549 LRIG1 restricts growth factor signaling by enhancing recepto...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:15282549 Jul 29. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation.
GO:0005515 protein binding	IPI PMID:15345710 The leucine-rich repeat protein LRIG1 is a negative regulato...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:15345710 2004 Sep 1. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases.
GO:0005515 protein binding	IPI PMID:15657067 Phosphotyrosine signaling networks in epidermal growth facto...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:15657067 Epub 2005 Jan 17. Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells.
GO:0005515 protein binding	IPI PMID:15962011 Sprouty2 acts at the Cbl/CIN85 interface to inhibit epiderma...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:15962011 Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation.
GO:0005515 protein binding	IPI PMID:16253990 Increased proliferation and altered growth factor dependence...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16253990 Oct 27. Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein.
GO:0005515 protein binding	IPI PMID:16273093 A quantitative protein interaction network for the ErbB rece...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16273093 A quantitative protein interaction network for the ErbB receptors using protein microarrays.
GO:0005515 protein binding	IPI PMID:16499958 Crystal structure of the ubiquitin binding domains of rabex-...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16499958 Feb 23. Crystal structure of the ubiquitin binding domains of rabex-5 reveals two modes of interaction with ubiquitin.
GO:0005515 protein binding	IPI PMID:16516204 Activation of ErbB2 by 2-methyl-1,4-naphthoquinone (menadion...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16516204 Epub 2006 Feb 28. Activation of ErbB2 by 2-methyl-1,4-naphthoquinone (menadione) in human keratinocytes: role of EGFR and protein tyrosine phosphatases.
GO:0005515 protein binding	IPI PMID:16799092 Dynamic profiling of the post-translational modifications an...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16799092 Epub 2006 Jun 23. Dynamic profiling of the post-translational modifications and interaction partners of epidermal growth factor receptor signaling after stimulation by epidermal growth factor using Extended Range Proteomic Analysis (ERPA).
GO:0005515 protein binding	IPI PMID:16843263 HER2 kinase domain mutation results in constitutive phosphor...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16843263 HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors.
GO:0005515 protein binding	IPI PMID:16914641 Intersectin regulates epidermal growth factor receptor endoc...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16914641 Aug 16. Intersectin regulates epidermal growth factor receptor endocytosis, ubiquitylation, and signaling.
GO:0005515 protein binding	IPI PMID:16954185 Advanced glycation end product (AGE) receptor 1 suppresses c...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:16954185 Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor.
GO:0005515 protein binding	IPI PMID:17126326 Extracellular heat shock protein 70 mediates heat stress-ind...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17126326 Epub 2006 Nov 20. Extracellular heat shock protein 70 mediates heat stress-induced epidermal growth factor receptor transactivation in A431 carcinoma cells.
GO:0005515 protein binding	IPI PMID:17148612 A system for quantifying dynamic protein interactions define...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17148612 A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions.
GO:0005515 protein binding	IPI PMID:17284441 Epidermal growth factor directs sex-specific steroid signali...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17284441 2007 Feb 5. Epidermal growth factor directs sex-specific steroid signaling through Src activation.
GO:0005515 protein binding	IPI PMID:17403676 Rin1 interacts with signal-transducing adaptor molecule (STA...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17403676 2007 Apr 2. Rin1 interacts with signal-transducing adaptor molecule (STAM) and mediates epidermal growth factor receptor trafficking and degradation.
GO:0005515 protein binding	IPI PMID:17697999 Ligand-induced structural transitions in ErbB receptor extra...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17697999 Ligand-induced structural transitions in ErbB receptor extracellular domains.
GO:0005515 protein binding	IPI PMID:17726113 Inhibition of the leucine-rich repeat protein LINGO-1 enhanc...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17726113 Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models.
GO:0005515 protein binding	IPI PMID:18046415 Inhibition of the EGF receptor by binding of MIG6 to an acti...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18046415 Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.
GO:0005515 protein binding	IPI PMID:18273061 Structural basis for a novel intrapeptidyl H-bond and revers...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18273061 Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.
GO:0005515 protein binding	IPI PMID:18455122 Survival of cancer cells is maintained by EGFR independent o...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18455122 Survival of cancer cells is maintained by EGFR independent of its kinase activity.
GO:0005515 protein binding	IPI PMID:18542056 LRIG1 negatively regulates the oncogenic EGF receptor mutant...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18542056 LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII.
GO:0005515 protein binding	IPI PMID:18776048 Comparisons of tyrosine phosphorylated proteins in cells exp...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18776048 Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS.
GO:0005515 protein binding	IPI PMID:18824549 Acidic mammalian chitinase is secreted via an ADAM17/epiderm...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18824549 2008 Sep 29. Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells.
GO:0005515 protein binding	IPI PMID:19167335 Large-scale structural analysis of the classical human prote...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:19167335 Large-scale structural analysis of the classical human protein tyrosine phosphatome.
GO:0005515 protein binding	IPI PMID:19172738 Phosphorylation-dependent binding of 14-3-3 terminates signa...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:19172738 Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein.
GO:0005515 protein binding	IPI PMID:19650109 Flow cytometric in situ proximity ligation analyses of prote...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:19650109 Flow cytometric in situ proximity ligation analyses of protein interactions and post-translational modification of the epidermal growth factor receptor family.
GO:0005515 protein binding	IPI PMID:19798056 Participation of Tom1L1 in EGF-stimulated endocytosis of EGF...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:19798056 Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor.
GO:0005515 protein binding	IPI PMID:20029029 Regulation of epidermal growth factor receptor trafficking b...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20029029 Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
GO:0005515 protein binding	IPI PMID:20153921 EGFR and EGFRvIII interact with PUMA to inhibit mitochondria...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20153921 2010 Feb 13. EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity.
GO:0005515 protein binding	IPI PMID:20308550 The phosphatase and tensin homolog regulates epidermal growt...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20308550 The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation.
GO:0005515 protein binding	IPI PMID:20403327 TRP channel regulates EGFR signaling in hair morphogenesis a...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20403327 TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.
GO:0005515 protein binding	IPI PMID:20473329 SIRPalpha1 receptors interfere with the EGFRvIII signalosome...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20473329 SIRPalpha1 receptors interfere with the EGFRvIII signalosome to inhibit glioblastoma cell transformation and migration.
GO:0005515 protein binding	IPI PMID:20562913 Differential roles of ERK and Akt pathways in regulation of ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20562913 Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells.
GO:0005515 protein binding	IPI PMID:20624308 EGFR/Met association regulates EGFR TKI resistance in breast...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20624308 EGFR/Met association regulates EGFR TKI resistance in breast cancer.
GO:0005515 protein binding	IPI PMID:20935677 A positive feedback loop of ER-α36/EGFR promotes malignant g...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20935677 A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells.
GO:0005515 protein binding	IPI PMID:21203579 HER2 phosphorylation is maintained by a PKB negative feedbac...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21203579 HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer.
GO:0005515 protein binding	IPI PMID:21258405 Galectin-3 regulates MUC1 and EGFR cellular distribution and...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21258405 Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells.
GO:0005515 protein binding	IPI PMID:21266349 EGFR nuclear translocation modulates DNA repair following ci...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21266349 2011 Jan 25. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment.
GO:0005515 protein binding	IPI PMID:21278786 PI3K inhibition results in enhanced HER signaling and acquir...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21278786 PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer.
GO:0005515 protein binding	IPI PMID:21278788 Translationally controlled tumor protein induces human breas...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21278788 Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src.
GO:0005515 protein binding	IPI PMID:21349850 MAPK scaffold IQGAP1 binds the EGF receptor and modulates it...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21349850 2011 Feb 24. MAPK scaffold IQGAP1 binds the EGF receptor and modulates its activation.
GO:0005515 protein binding	IPI PMID:21376233 Activation of multiple proto-oncogenic tyrosine kinases in b...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21376233 Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.
GO:0005515 protein binding	IPI PMID:21439278 Engineered epidermal growth factor mutants with faster bindi...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21439278 2011 Mar 23. Engineered epidermal growth factor mutants with faster binding on-rates correlate with enhanced receptor activation.
GO:0005515 protein binding	IPI PMID:21706016 Selected reaction monitoring mass spectrometry reveals the d...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21706016 Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor.
GO:0005515 protein binding	IPI PMID:21822280 Simultaneous visualization of the extracellular and cytoplas...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21822280 Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor.
GO:0005515 protein binding	IPI PMID:21951318 Ligand-dependent differences in estrogen receptor beta-inter...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:21951318 Ligand-dependent differences in estrogen receptor beta-interacting proteins identified in lung adenocarcinoma cells corresponds to estrogenic responses.
GO:0005515 protein binding	IPI PMID:22411794 Hypoxia promotes ligand-independent EGF receptor signaling v...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:22411794 Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1.
GO:0005515 protein binding	IPI PMID:22439932 NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:22439932 NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma.
GO:0005515 protein binding	IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:22939624 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
GO:0005515 protein binding	IPI PMID:23178489 The role of insulin-like growth factor binding protein-3 in ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23178489 The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents.
GO:0005515 protein binding	IPI PMID:23178716 SnoN/SkiL expression is modulated via arsenic trioxide-induc...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23178716 2012 Nov 21. SnoN/SkiL expression is modulated via arsenic trioxide-induced activation of the PI3K/AKT pathway in ovarian cancer cells.
GO:0005515 protein binding	IPI PMID:23273428 Insights into the aberrant activity of mutant EGFR kinase do...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23273428 Dec 27. Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition.
GO:0005515 protein binding	IPI PMID:23397142 Analysis of protein-protein interactions in cross-talk pathw...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23397142 Epub 2013 Feb 8. Analysis of protein-protein interactions in cross-talk pathways reveals CRKL protein as a novel prognostic marker in hepatocellular carcinoma.
GO:0005515 protein binding	IPI PMID:23436906 Parallel visualization of multiple protein complexes in indi...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23436906 Epub 2013 Feb 22. Parallel visualization of multiple protein complexes in individual cells in tumor tissue.
GO:0005515 protein binding	IPI PMID:23520446 Protein phosphorylation profiling using an in situ proximity...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23520446 Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells.
GO:0005515 protein binding	IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.
GO:0005515 protein binding	IPI PMID:23636329 EGFR modulates microRNA maturation in response to hypoxia th...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23636329 EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2.
GO:0005515 protein binding	IPI PMID:23764002 Epidermal growth factor receptor potentiates MCM7-mediated D...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23764002 Epidermal growth factor receptor potentiates MCM7-mediated DNA replication through tyrosine phosphorylation of Lyn kinase in human cancers.
GO:0005515 protein binding	IPI PMID:23799367 Threshold-controlled ubiquitination of the EGFR directs rece...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23799367 Threshold-controlled ubiquitination of the EGFR directs receptor fate.
GO:0005515 protein binding	IPI PMID:23866081 Lyn, a Src family kinase, regulates activation of epidermal ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23866081 Lyn, a Src family kinase, regulates activation of epidermal growth factor receptors in lung adenocarcinoma cells.
GO:0005515 protein binding	IPI PMID:24034250 EGFR-mediated Beclin 1 phosphorylation in autophagy suppress...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24034250 EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance.
GO:0005515 protein binding	IPI PMID:24076656 Endophilin, Lamellipodin, and Mena cooperate to regulate F-a...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24076656 Endophilin, Lamellipodin, and Mena cooperate to regulate F-actin-dependent EGF-receptor endocytosis.
GO:0005515 protein binding	IPI PMID:24135280 EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 a...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24135280 EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma.
GO:0005515 protein binding	IPI PMID:24189400 Perturbation of the mutated EGFR interactome identifies vuln...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24189400 Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.
GO:0005515 protein binding	IPI PMID:24557338 Characterisation of HER heterodimers in breast cancer using ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24557338 Characterisation of HER heterodimers in breast cancer using in situ proximity ligation assay.
GO:0005515 protein binding	IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells.
GO:0005515 protein binding	IPI PMID:24780295 Importance of EGFR/ERCC1 interaction following radiation-ind...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24780295 Importance of EGFR/ERCC1 interaction following radiation-induced DNA damage.
GO:0005515 protein binding	IPI PMID:24947832 Differential protein-protein interactions of LRRK1 and LRRK2...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24947832 Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25036637 A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
GO:0005515 protein binding	IPI PMID:25136068 Mycoplasma hyorhinis infection promotes NF-κB-dependent migr...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25136068 Epub 2014 Aug 18. Mycoplasma hyorhinis infection promotes NF-κB-dependent migration of gastric cancer cells.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25241761 Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
GO:0005515 protein binding	IPI PMID:25353163 Soluble LRIG2 ectodomain is released from glioblastoma cells...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25353163 eCollection 2014. Soluble LRIG2 ectodomain is released from glioblastoma cells and promotes the proliferation and inhibits the apoptosis of glioblastoma cells in vitro and in vivo in a similar manner to the full-length LRIG2.
GO:0005515 protein binding	IPI PMID:25594178 A kinase-independent role for EGF receptor in autophagy init...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25594178 A kinase-independent role for EGF receptor in autophagy initiation.
GO:0005515 protein binding	IPI PMID:25796184 PEA-15 facilitates EGFR dephosphorylation via ERK sequestrat...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25796184 2015 Mar 18. PEA-15 facilitates EGFR dephosphorylation via ERK sequestration at increased ER-PM contacts in TNBC cells.
GO:0005515 protein binding	IPI PMID:25873175 AXL mediates resistance to PI3Kα inhibition by activating th...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25873175 AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.
GO:0005515 protein binding	IPI PMID:25970784 PTPRG suppresses tumor growth and invasion via inhibition of...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25970784 PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma.
GO:0005515 protein binding	IPI PMID:26005835 RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and rest...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:26005835 RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth.
GO:0005515 protein binding	IPI PMID:26280537 Secreted and O-GlcNAcylated MIF binds to the human EGF recep...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:26280537 Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation.
GO:0005515 protein binding	IPI PMID:26551075 EGF-receptor specificity for phosphotyrosine-primed substrat...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:26551075 Nov 9. EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src.
GO:0005515 protein binding	IPI PMID:26751287 The LINK-A lncRNA activates normoxic HIF1α signalling in tri...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:26751287 The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.
GO:0005515 protein binding	IPI PMID:27059931 Weak binding to E3 ubiquitin ligase c-Cbl increases EGFRvA p...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:27059931 Apr 16. Weak binding to E3 ubiquitin ligase c-Cbl increases EGFRvA protein stability.
GO:0005515 protein binding	IPI PMID:27569582 GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hep...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:27569582 2016 Aug 25. GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis.
GO:0005515 protein binding	IPI PMID:2790960 Functional independence of the epidermal growth factor recep...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:2790960 Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation.
GO:0005515 protein binding	IPI PMID:27956147 Systematic Identification of Oncogenic EGFR Interaction Part...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:27956147 2016 Dec 9. Systematic Identification of Oncogenic EGFR Interaction Partners.
GO:0005515 protein binding	IPI PMID:28065597 A Global Analysis of the Receptor Tyrosine Kinase-Protein Ph...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:28065597 2017 Jan 5. A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.
GO:0005515 protein binding	IPI PMID:28988771 EGFR Ligands Differentially Stabilize Receptor Dimers to Spe...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:28988771 2017 Oct 5. EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics.
GO:0005515 protein binding	IPI PMID:29455656 The E3 ubiquitin ligase NEDD4 mediates cell migration signal...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:29455656 The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells.
GO:0005515 protein binding	IPI PMID:29844572 RANK-c attenuates aggressive properties of ER-negative breas...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:29844572 May 29. RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.
GO:0005515 protein binding	IPI PMID:30083275 The S100A4 Protein Signals through the ErbB4 Receptor to Pro...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:30083275 The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival.
GO:0005515 protein binding	IPI PMID:30662352 COPI-Mediated Nuclear Translocation of EGFRvIII Promotes STA...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:30662352 COPI-Mediated Nuclear Translocation of EGFRvIII Promotes STAT3 Phosphorylation and PKM2 Nuclear Localization.
GO:0005515 protein binding	IPI PMID:31585087 Oncogenic Mutations Rewire Signaling Pathways by Switching P...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:31585087 Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites.
GO:0005515 protein binding	IPI PMID:31862538 Neuropeptide bombesin receptor activation stimulates growth ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:31862538 Neuropeptide bombesin receptor activation stimulates growth of lung cancer cells through HER3 with a MAPK-dependent mechanism.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
GO:0005515 protein binding	IPI PMID:33420426 AXL is a candidate receptor for SARS-CoV-2 that promotes inf...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:33420426 Jan 8. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells.
GO:0005515 protein binding	IPI PMID:34591612 A protein interaction landscape of breast cancer.	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:34591612 Oct 1. A protein interaction landscape of breast cancer.
GO:0005515 protein binding	IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:34591642 Oct 1. A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
GO:0005515 protein binding	IPI PMID:35384245 Physical and functional interactome atlas of human receptor ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:35384245 Physical and functional interactome atlas of human receptor tyrosine kinases.
GO:0005515 protein binding	IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:35512704 2022 May 4. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
GO:0005515 protein binding	IPI PMID:37100772 Large-scale phage-based screening reveals extensive pan-vira...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:37100772 Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs.
GO:0005515 protein binding	IPI PMID:7518560 Hierarchy of binding sites for Grb2 and Shc on the epidermal...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:7518560 Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor.
GO:0005515 protein binding	IPI PMID:7542744 The phosphotyrosine interaction domain of Shc binds an LXNPX...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:7542744 The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor.
GO:0005515 protein binding	IPI PMID:7657591 Tyrosine phosphorylation of the c-cbl proto-oncogene protein...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:7657591 Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation.
GO:0005515 protein binding	IPI PMID:7685104 Substrate specificity of the protein tyrosine phosphatases.	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:7685104 Substrate specificity of the protein tyrosine phosphatases.
GO:0005515 protein binding	IPI PMID:7693694 Sequence specificity in recognition of the epidermal growth ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:7693694 Sequence specificity in recognition of the epidermal growth factor receptor by protein tyrosine phosphatase 1B.
GO:0005515 protein binding	IPI PMID:7797556 Src phosphorylation of the epidermal growth factor receptor ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:7797556 Src phosphorylation of the epidermal growth factor receptor at novel sites mediates receptor interaction with Src and P85 alpha.
GO:0005515 protein binding	IPI PMID:7993895 Identification of amino acids in the N-terminal SH2 domain o...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:7993895 Identification of amino acids in the N-terminal SH2 domain of phospholipase C gamma 1 important in the interaction with epidermal growth factor receptor.
GO:0005515 protein binding	IPI PMID:8034616 Tyrosines 1148 and 1173 of activated human epidermal growth ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:8034616 Tyrosines 1148 and 1173 of activated human epidermal growth factor receptors are binding sites of Shc in intact cells.
GO:0005515 protein binding	IPI PMID:8621392 Determinants of substrate recognition in the protein-tyrosin...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:8621392 Determinants of substrate recognition in the protein-tyrosine phosphatase, PTP1.
GO:0005515 protein binding	IPI PMID:8887653 The phosphotyrosine interaction domains of X11 and FE65 bind...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:8887653 The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:8940013 The Grb2-mSos1 complex binds phosphopeptides with higher aff...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:8940013 The Grb2-mSos1 complex binds phosphopeptides with higher affinity than Grb2.
GO:0005515 protein binding	IPI PMID:9020117 Subsets of epidermal growth factor receptors during activati...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9020117 Subsets of epidermal growth factor receptors during activation and endocytosis.
GO:0005515 protein binding	IPI PMID:9050838 Development of "substrate-trapping" mutants to identify phys...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9050838 Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases.
GO:0005515 protein binding	IPI PMID:9135143 Activation of HER4 by heparin-binding EGF-like growth factor...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9135143 Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation.
GO:0005515 protein binding	IPI PMID:9355745 Protein tyrosine phosphatase 1B interacts with and is tyrosi...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9355745 Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor.
GO:0005515 protein binding	IPI PMID:9506989 Grb10 interacts differentially with the insulin receptor, in...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9506989 Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains.
GO:0005515 protein binding	IPI PMID:9544989 Shc phosphotyrosine-binding domain dominantly interacts with...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9544989 Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells.
GO:0042802 identical protein binding	IPI PMID:16777603 An allosteric mechanism for activation of the kinase domain ...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:16777603 An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.
GO:0042802 identical protein binding	IPI PMID:17148612 A system for quantifying dynamic protein interactions define...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:17148612 A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions.
GO:0042802 identical protein binding	IPI PMID:18042729 Epidermal growth factor receptor juxtamembrane region regula...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:18042729 Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation.
GO:0042802 identical protein binding	IPI PMID:19563760 Mechanism for activation of the EGF receptor catalytic domai...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:19563760 Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.
GO:0042802 identical protein binding	IPI PMID:19650109 Flow cytometric in situ proximity ligation analyses of prote...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:19650109 Flow cytometric in situ proximity ligation analyses of protein interactions and post-translational modification of the epidermal growth factor receptor family.
GO:0042802 identical protein binding	IPI PMID:20007378 Structural analysis of the catalytically inactive kinase dom...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:20007378 Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.
GO:0042802 identical protein binding	IPI PMID:20029029 Regulation of epidermal growth factor receptor trafficking b...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:20029029 Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
GO:0042802 identical protein binding	IPI PMID:20359299 A proximity ligation assay using transiently transfected, ep...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:20359299 A proximity ligation assay using transiently transfected, epitope-tagged proteins: application for in situ detection of dimerized receptor tyrosine kinases.
GO:0042802 identical protein binding	IPI PMID:21278786 PI3K inhibition results in enhanced HER signaling and acquir...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:21278786 PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer.
GO:0042802 identical protein binding	IPI PMID:21480528 Comparative analysis of fluorescence resonance energy transf...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:21480528 Apr 8. Comparative analysis of fluorescence resonance energy transfer (FRET) and proximity ligation assay (PLA).
GO:0042802 identical protein binding	IPI PMID:21482778 Quantification of receptor tyrosine kinase transactivation t...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:21482778 Quantification of receptor tyrosine kinase transactivation through direct dimerization and surface density measurements in single cells.
GO:0042802 identical protein binding	IPI PMID:22232519 In situ analysis of mutant EGFRs prevalent in glioblastoma m...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:22232519 Epub 2012 Jan 9. In situ analysis of mutant EGFRs prevalent in glioblastoma multiforme reveals aberrant dimerization, activation, and differential response to anti-EGFR targeted therapy.
GO:0042802 identical protein binding	IPI PMID:22579287 Oncogenic mutations counteract intrinsic disorder in the EGF...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:22579287 Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.
GO:0042802 identical protein binding	IPI PMID:23273428 Insights into the aberrant activity of mutant EGFR kinase do...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:23273428 Dec 27. Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition.
GO:0042802 identical protein binding	IPI PMID:23374349 Conformational coupling across the plasma membrane in activa...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:23374349 Conformational coupling across the plasma membrane in activation of the EGF receptor.
GO:0042802 identical protein binding	IPI PMID:23436906 Parallel visualization of multiple protein complexes in indi...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:23436906 Epub 2013 Feb 22. Parallel visualization of multiple protein complexes in individual cells in tumor tissue.
GO:0042802 identical protein binding	IPI PMID:23636329 EGFR modulates microRNA maturation in response to hypoxia th...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:23636329 EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2.
GO:0042802 identical protein binding	IPI PMID:24135280 EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 a...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:24135280 EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma.
GO:0042802 identical protein binding	IPI PMID:28988771 EGFR Ligands Differentially Stabilize Receptor Dimers to Spe...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:28988771 2017 Oct 5. EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics.
GO:0042802 identical protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
GO:0042802 identical protein binding	IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:35512704 2022 May 4. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
GO:0042802 identical protein binding	IPI PMID:38572507 DRD1 suppresses cell proliferation and reduces EGFR activati...	ACCEPT	Summary: EGFR undergoes homodimerization, binding to itself as part of the activation mechanism. Reason: EGFR homodimerization is essential for kinase activation. Ligand binding promotes EGFR-EGFR homodimer formation. Supporting Evidence: PMID:38572507 Apr 4. DRD1 suppresses cell proliferation and reduces EGFR activation and PD-L1 expression in NSCLC.
GO:0007165 signal transduction	TAS Reactome:R-HSA-212718	ACCEPT	Summary: EGFR mediates signal transduction from extracellular growth factors to intracellular signaling cascades. Reason: Signal transduction is a core function of EGFR as a receptor tyrosine kinase.
GO:0007173 epidermal growth factor receptor signaling pathway	TAS Reactome:R-HSA-177929	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway.
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway	TAS Reactome:R-HSA-182971	ACCEPT	Summary: EGFR participates in negative regulation of its own signaling through internalization and degradation mechanisms. Reason: EGFR signaling is subject to negative feedback through receptor internalization, ubiquitination by CBL, and lysosomal degradation.
GO:0000902 cell morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling influences cell morphogenesis. Reason: Cell morphogenesis is a downstream developmental effect.
GO:0001892 embryonic placenta development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling contributes to embryonic placenta development. Reason: Developmental process downstream of EGFR signaling in specific tissues.
GO:0001942 hair follicle development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling is required for hair follicle development. Reason: Tissue-specific developmental process regulated by EGFR.
GO:0005006 epidermal growth factor receptor activity	IEA GO_REF:0000120	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct.
GO:0006511 ubiquitin-dependent protein catabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR undergoes ubiquitin-dependent degradation. Reason: EGFR is ubiquitinated and degraded, but this describes its regulation rather than function.
GO:0007165 signal transduction	IEA GO_REF:0000107	ACCEPT	Summary: EGFR mediates signal transduction from extracellular growth factors to intracellular signaling cascades. Reason: Signal transduction is a core function of EGFR as a receptor tyrosine kinase.
GO:0007173 epidermal growth factor receptor signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway.
GO:0007435 salivary gland morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling contributes to salivary gland development. Reason: Tissue-specific developmental process.
GO:0008283 cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling influences cell proliferation. Reason: Cell proliferation is a downstream effect of EGFR activation.
GO:0008284 positive regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling promotes cell proliferation through MAPK and PI3K pathways. Reason: Cell proliferation is a downstream phenotypic effect of EGFR signaling.
GO:0008544 epidermis development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling is critical for epidermis development. Reason: Developmental process in EGFR's namesake tissue, but represents downstream effects.
GO:0009986 cell surface	IEA GO_REF:0000120	ACCEPT	Summary: EGFR localizes to the cell surface where it is accessible for ligand binding. Reason: Cell surface localization is consistent with EGFR function as a receptor for extracellular growth factors.
GO:0010467 gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling regulates gene expression. Reason: Gene expression regulation is a downstream effect of EGFR signaling.
GO:0016323 basolateral plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: In polarized epithelial cells, EGFR localizes to the basolateral plasma membrane. Reason: EGFR shows polarized distribution in epithelial cells, localizing to basolateral membranes.
GO:0016567 protein ubiquitination	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR is ubiquitinated by CBL for endocytosis and degradation. Reason: Describes EGFR regulation, not its enzymatic function.
GO:0021795 cerebral cortex cell migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling influences cortical cell migration during development. Reason: Developmental process in the nervous system.
GO:0030139 endocytic vesicle	IEA GO_REF:0000120	ACCEPT	Summary: EGFR is internalized via endocytic vesicles following ligand binding. Reason: Endocytic vesicle localization is part of normal EGFR internalization.
GO:0038134 ERBB2-EGFR signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: EGFR heterodimerizes with ERBB2 to form signaling complexes with distinct downstream effects. Reason: EGFR-ERBB2 heterodimers are an important signaling unit with enhanced signaling capacity.
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: EGFR participates in negative regulation of its own signaling through internalization and degradation mechanisms. Reason: EGFR signaling is subject to negative feedback through receptor internalization, ubiquitination by CBL, and lysosomal degradation.
GO:0042127 regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR regulates cell proliferation through downstream signaling. Reason: General cell proliferation regulation is a downstream effect.
GO:0042908 xenobiotic transport	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: EGFR involvement in xenobiotic transport is not well-established. Reason: This annotation is likely over-interpretation; EGFR is not a transporter.
GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: EGFR itself positively regulates the EGF receptor signaling pathway as the initiating receptor. Reason: EGFR activation initiates and sustains EGF receptor signaling.
GO:0048146 positive regulation of fibroblast proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling promotes fibroblast proliferation. Reason: Cell type-specific downstream effect.
GO:0048408 epidermal growth factor binding	IEA GO_REF:0000107	ACCEPT	Summary: EGFR binds EGF through its extracellular domain (subdomains I and III), which induces receptor dimerization and activation. Reason: EGF binding is the canonical ligand-binding function of EGFR. Crystal structures confirm EGF binds domains I and III of the extracellular region.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: EGFR may localize to perinuclear regions during trafficking. Reason: Perinuclear localization may occur during endocytic trafficking.
GO:0048546 digestive tract morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling influences digestive tract development. Reason: Developmental process downstream of EGFR signaling.
GO:0050673 epithelial cell proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR promotes epithelial cell proliferation. Reason: Cell type-specific proliferation effect.
GO:0050679 positive regulation of epithelial cell proliferation	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: EGFR signaling promotes epithelial cell proliferation, a key downstream effect in epithelial tissues. Reason: Epithelial cell proliferation is a major physiological outcome of EGFR signaling but represents a downstream effect.
GO:0060571 morphogenesis of an epithelial fold	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling contributes to epithelial fold morphogenesis. Reason: Developmental morphogenesis process.
GO:0061029 eyelid development in camera-type eye	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling is involved in eyelid development. Reason: Tissue-specific developmental process.
GO:0070086 ubiquitin-dependent endocytosis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR undergoes ubiquitin-dependent endocytosis. Reason: Describes EGFR trafficking/regulation.
GO:0071230 cellular response to amino acid stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR signaling responds to amino acid availability. Reason: Amino acid response is a contextual regulatory effect.
GO:0071363 cellular response to growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGFR mediates cellular responses to growth factors. Reason: General growth factor response is downstream of receptor activation.
GO:0004714 transmembrane receptor protein tyrosine kinase activity	TAS Reactome:R-HSA-177930	ACCEPT	Summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that phosphorylates tyrosine residues on substrate proteins following ligand-induced dimerization. This is a core molecular function. Reason: Transmembrane receptor protein tyrosine kinase activity is the defining enzymatic function of EGFR. The kinase domain catalyzes ATP-dependent phosphorylation of tyrosine residues.
GO:0004714 transmembrane receptor protein tyrosine kinase activity	TAS Reactome:R-HSA-177933	ACCEPT	Summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that phosphorylates tyrosine residues on substrate proteins following ligand-induced dimerization. This is a core molecular function. Reason: Transmembrane receptor protein tyrosine kinase activity is the defining enzymatic function of EGFR. The kinase domain catalyzes ATP-dependent phosphorylation of tyrosine residues.
GO:0005515 protein binding	IPI PMID:39073202 SNX32 Regulates Sorting and Trafficking of Activated EGFR to...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:39073202 SNX32 Regulates Sorting and Trafficking of Activated EGFR to the Lysosomal Degradation Pathway.
GO:0005006 epidermal growth factor receptor activity	IDA PMID:12828935 Activation of epidermal growth factor receptor signals induc...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:12828935 Activation of epidermal growth factor receptor signals induction of nitric oxide synthase-2 in human optic nerve head astrocytes in glaucomatous optic neuropathy.
GO:0005886 plasma membrane	IDA PMID:20462955 A G{alpha}i-GIV molecular complex binds epidermal growth fac...	ACCEPT	Summary: EGFR is a transmembrane receptor tyrosine kinase that localizes to the plasma membrane where it binds EGF ligands and undergoes dimerization and autophosphorylation to initiate downstream signaling cascades. Reason: Plasma membrane localization is essential for EGFR function as a transmembrane receptor that needs to be at the cell surface to bind extracellular EGF ligands and interact with other membrane-bound signaling components. Supporting Evidence: PMID:20462955 2010 May 12. A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate.
GO:0007173 epidermal growth factor receptor signaling pathway	IDA PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0005768 endosome	IDA PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediate...	ACCEPT	Summary: EGFR localizes to endosomes following ligand-induced internalization. EGFR continues signaling from early endosomes and is subsequently sorted for recycling or lysosomal degradation. Reason: Endosomal localization is part of normal EGFR trafficking and signaling. EGFR signals from endosomes and trafficking modulates signal duration. Supporting Evidence: PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediated inactivation of the EGF receptor.
GO:0019900 kinase binding	IPI PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediate...	ACCEPT	Summary: EGFR binds to kinases including SRC family kinases and downstream signaling kinases. Reason: EGFR interacts with multiple kinases in signaling complexes. Supporting Evidence: PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediated inactivation of the EGF receptor.
GO:0090037 positive regulation of protein kinase C signaling	IDA PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediate...	KEEP AS NON CORE	Summary: EGFR activates PKC signaling through PLC-gamma activation. Reason: PKC signaling regulation is downstream of EGFR-PLC-gamma activation. Supporting Evidence: PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediated inactivation of the EGF receptor.
GO:0007173 epidermal growth factor receptor signaling pathway	IMP PMID:18483258 UVA-induced cell cycle progression is mediated by a disinteg...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:18483258 UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes.
GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:18483258 UVA-induced cell cycle progression is mediated by a disinteg...	KEEP AS NON CORE	Summary: EGFR activates PI3K-AKT signaling through recruitment of PI3K to phosphotyrosine docking sites. Reason: PI3K-AKT pathway activation is a major downstream signaling axis of EGFR, but is not the core function. Supporting Evidence: PMID:18483258 UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes.
GO:1900087 positive regulation of G1/S transition of mitotic cell cycle	IMP PMID:18483258 UVA-induced cell cycle progression is mediated by a disinteg...	KEEP AS NON CORE	Summary: EGFR signaling promotes G1/S cell cycle transition. Reason: Cell cycle regulation is a downstream effect of EGFR proliferative signaling. Supporting Evidence: PMID:18483258 UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes.
GO:0007173 epidermal growth factor receptor signaling pathway	IDA PMID:24854121 Endophilin-1 regulates blood-brain barrier permeability by c...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:24854121 2014 May 20. Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway.
GO:0043410 positive regulation of MAPK cascade	IDA PMID:24854121 Endophilin-1 regulates blood-brain barrier permeability by c...	ACCEPT	Summary: EGFR positively regulates the MAPK cascade through recruitment of GRB2-SOS and activation of RAS-RAF-MEK-ERK signaling. Reason: MAPK/ERK pathway activation is a core downstream signaling output of EGFR. This is well-established. Supporting Evidence: PMID:24854121 2014 May 20. Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway.
GO:0005794 Golgi apparatus	IDA GO_REF:0000052	ACCEPT	Summary: EGFR transits through the Golgi during biosynthesis and trafficking. Reason: EGFR is processed through the secretory pathway including the Golgi.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: EGFR cytoplasmic domain resides in the cytosol and signals to cytosolic proteins. Reason: The intracellular kinase domain of EGFR is in the cytosol.
GO:0005886 plasma membrane	IDA GO_REF:0000052	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005929 cilium	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: EGFR has been detected in cilia. Reason: Ciliary localization is context-specific.
GO:0030054 cell junction	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: EGFR may localize to cell junctions. Reason: Cell junction localization is context-dependent.
GO:0036064 ciliary basal body	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: EGFR has been detected at ciliary basal bodies. Reason: Ciliary localization is context-specific.
GO:0097225 sperm midpiece	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: EGFR has been detected in sperm midpiece. Reason: Sperm-specific localization.
GO:0097228 sperm principal piece	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: EGFR has been detected in sperm principal piece. Reason: Sperm-specific localization.
GO:0097229 sperm end piece	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: EGFR has been detected in sperm end piece. Reason: Sperm-specific localization.
GO:0004713 protein tyrosine kinase activity	TAS Reactome:R-HSA-177934	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function.
GO:0004713 protein tyrosine kinase activity	TAS Reactome:R-HSA-182969	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function.
GO:0004713 protein tyrosine kinase activity	TAS Reactome:R-HSA-183058	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function.
GO:0004713 protein tyrosine kinase activity	TAS Reactome:R-HSA-212710	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function.
GO:0004713 protein tyrosine kinase activity	TAS Reactome:R-HSA-8867041	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function.
GO:0005515 protein binding	IPI PMID:15611079 Epigen, the last ligand of ErbB receptors, reveals intricate...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:15611079 Dec 17. Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity.
GO:0007173 epidermal growth factor receptor signaling pathway	IDA PMID:12828935 Activation of epidermal growth factor receptor signals induc...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:12828935 Activation of epidermal growth factor receptor signals induction of nitric oxide synthase-2 in human optic nerve head astrocytes in glaucomatous optic neuropathy.
GO:0007173 epidermal growth factor receptor signaling pathway	IMP PMID:17655843 EGF receptor transactivation and PI3-kinase mediate stimulat...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:17655843 EGF receptor transactivation and PI3-kinase mediate stimulation of ERK by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role in wound healing.
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:17655843 EGF receptor transactivation and PI3-kinase mediate stimulat...	KEEP AS NON CORE	Summary: EGFR positively regulates PI3K-AKT signaling. Reason: PI3K-AKT regulation is downstream of EGFR activation. Supporting Evidence: PMID:17655843 EGF receptor transactivation and PI3-kinase mediate stimulation of ERK by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role in wound healing.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177935	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8863804	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8864029	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:1902895 positive regulation of miRNA transcription	IMP PMID:21673316 TRPS1 targeting by miR-221/222 promotes the epithelial-to-me...	KEEP AS NON CORE	Summary: EGFR signaling regulates miRNA transcription. Reason: miRNA regulation is a downstream transcriptional effect. Supporting Evidence: PMID:21673316 TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer.
GO:0005886 plasma membrane	IDA PMID:15611079 Epigen, the last ligand of ErbB receptors, reveals intricate...	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals. Supporting Evidence: PMID:15611079 Dec 17. Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity.
GO:0004713 protein tyrosine kinase activity	IDA PMID:2472218 EGF induces tyrosine phosphorylation of phospholipase C-II: ...	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function. Supporting Evidence: PMID:2472218 EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling.
GO:0005006 epidermal growth factor receptor activity	IDA PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) rece...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) receptor and ErbB2 and the affinity of EGF binding are regulated by different mechanisms.
GO:0005006 epidermal growth factor receptor activity	IDA PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF recep...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma.
GO:0005886 plasma membrane	IDA PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) rece...	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals. Supporting Evidence: PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) receptor and ErbB2 and the affinity of EGF binding are regulated by different mechanisms.
GO:0007173 epidermal growth factor receptor signaling pathway	IDA PMID:9890893 Identification of tyrosine phosphorylation sites in human Ga...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:9890893 Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro.
GO:0038134 ERBB2-EGFR signaling pathway	IDA PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) rece...	ACCEPT	Summary: EGFR heterodimerizes with ERBB2 to form signaling complexes with distinct downstream effects. Reason: EGFR-ERBB2 heterodimers are an important signaling unit with enhanced signaling capacity. Supporting Evidence: PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) receptor and ErbB2 and the affinity of EGF binding are regulated by different mechanisms.
GO:0005515 protein binding	IPI PMID:27872189 Biophysical Evidence for Intrinsic Disorder in the C-termina...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:27872189 2016 Nov 21. Biophysical Evidence for Intrinsic Disorder in the C-terminal Tails of the Epidermal Growth Factor Receptor (EGFR) and HER3 Receptor Tyrosine Kinases.
GO:0004713 protein tyrosine kinase activity	IDA PMID:9890893 Identification of tyrosine phosphorylation sites in human Ga...	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function. Supporting Evidence: PMID:9890893 Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro.
GO:0030296 protein tyrosine kinase activator activity	IDA PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF recep...	ACCEPT	Summary: EGFR can activate other tyrosine kinases through heterodimerization (especially ERBB2). Reason: EGFR activates ERBB2 kinase activity through heterodimer formation. Supporting Evidence: PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma.
GO:0030296 protein tyrosine kinase activator activity	IDA PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) rece...	ACCEPT	Summary: EGFR can activate other tyrosine kinases through heterodimerization (especially ERBB2). Reason: EGFR activates ERBB2 kinase activity through heterodimer formation. Supporting Evidence: PMID:11336639 Heterodimerization of the epidermal-growth-factor (EGF) receptor and ErbB2 and the affinity of EGF binding are regulated by different mechanisms.
GO:0005886 plasma membrane	IDA PMID:11331309 Real time fluorescence imaging of PLC gamma translocation an...	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals. Supporting Evidence: PMID:11331309 Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.
GO:0032587 ruffle membrane	IDA PMID:11331309 Real time fluorescence imaging of PLC gamma translocation an...	KEEP AS NON CORE	Summary: EGFR localizes to membrane ruffles during cell migration. Reason: Ruffle localization is associated with EGFR-induced cell migration. Supporting Evidence: PMID:11331309 Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.
GO:0097708 intracellular vesicle	IDA PMID:11331309 Real time fluorescence imaging of PLC gamma translocation an...	ACCEPT	Summary: EGFR is found in intracellular vesicles during trafficking. Reason: Part of EGFR endocytic trafficking. Supporting Evidence: PMID:11331309 Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.
GO:0005515 protein binding	IPI PMID:17334392 A crucial role of plasma membrane-associated sialidase in th...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17334392 Mar 5. A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells.
GO:0019900 kinase binding	IPI PMID:18722344 BCAR3 regulates EGF-induced DNA synthesis in normal human br...	ACCEPT	Summary: EGFR binds to kinases including SRC family kinases and downstream signaling kinases. Reason: EGFR interacts with multiple kinases in signaling complexes. Supporting Evidence: PMID:18722344 BCAR3 regulates EGF-induced DNA synthesis in normal human breast MCF-12A cells.
GO:0005515 protein binding	IPI PMID:26988023 Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facil...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:26988023 Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance.
GO:0005515 protein binding	IPI PMID:25187647 Structural basis for activation of trimeric Gi proteins by m...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25187647 2014 Sep 3. Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin.
GO:0005515 protein binding	IPI PMID:18722344 BCAR3 regulates EGF-induced DNA synthesis in normal human br...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18722344 BCAR3 regulates EGF-induced DNA synthesis in normal human breast MCF-12A cells.
GO:0005515 protein binding	IPI PMID:20462955 A G{alpha}i-GIV molecular complex binds epidermal growth fac...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20462955 2010 May 12. A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate.
GO:0005515 protein binding	IPI PMID:24854121 Endophilin-1 regulates blood-brain barrier permeability by c...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:24854121 2014 May 20. Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway.
GO:0048471 perinuclear region of cytoplasm	IMP PMID:24854121 Endophilin-1 regulates blood-brain barrier permeability by c...	KEEP AS NON CORE	Summary: EGFR may localize to perinuclear regions during trafficking. Reason: Perinuclear localization may occur during endocytic trafficking. Supporting Evidence: PMID:24854121 2014 May 20. Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway.
GO:0045121 membrane raft	ISS GO_REF:0000024	ACCEPT	Summary: EGFR localizes to membrane rafts/lipid rafts in the plasma membrane. Reason: EGFR partitioning into membrane rafts affects its signaling.
GO:0051117 ATPase binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: EGFR may bind to ATPases. Reason: ATPase binding is not a primary EGFR function.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868658	ACCEPT	Summary: EGFR undergoes clathrin-mediated endocytosis and localizes to clathrin-coated vesicles. Reason: Clathrin-mediated endocytosis is a major route for EGFR internalization.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868659	ACCEPT	Summary: EGFR undergoes clathrin-mediated endocytosis and localizes to clathrin-coated vesicles. Reason: Clathrin-mediated endocytosis is a major route for EGFR internalization.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868660	ACCEPT	Summary: EGFR undergoes clathrin-mediated endocytosis and localizes to clathrin-coated vesicles. Reason: Clathrin-mediated endocytosis is a major route for EGFR internalization.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8868661	ACCEPT	Summary: EGFR undergoes clathrin-mediated endocytosis and localizes to clathrin-coated vesicles. Reason: Clathrin-mediated endocytosis is a major route for EGFR internalization.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8869438	ACCEPT	Summary: EGFR undergoes clathrin-mediated endocytosis and localizes to clathrin-coated vesicles. Reason: Clathrin-mediated endocytosis is a major route for EGFR internalization.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8871193	ACCEPT	Summary: EGFR undergoes clathrin-mediated endocytosis and localizes to clathrin-coated vesicles. Reason: Clathrin-mediated endocytosis is a major route for EGFR internalization.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-8871194	ACCEPT	Summary: EGFR undergoes clathrin-mediated endocytosis and localizes to clathrin-coated vesicles. Reason: Clathrin-mediated endocytosis is a major route for EGFR internalization.
GO:0005737 cytoplasm	IDA PMID:22298428 The Ankrd 13 family of UIM-bearing proteins regulates EGF re...	ACCEPT	Summary: EGFR intracellular domain localizes to the cytoplasm. Reason: The cytoplasmic portion of EGFR containing the kinase domain is localized in the cytoplasm. Supporting Evidence: PMID:22298428 Feb 1. The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane.
GO:0005886 plasma membrane	IDA PMID:22298428 The Ankrd 13 family of UIM-bearing proteins regulates EGF re...	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals. Supporting Evidence: PMID:22298428 Feb 1. The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane.
GO:0005515 protein binding	IPI PMID:22298428 The Ankrd 13 family of UIM-bearing proteins regulates EGF re...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:22298428 Feb 1. The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1169421	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1218833	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1220610	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1220612	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1220613	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1220614	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225947	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225949	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225950	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225951	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225952	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225956	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225957	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225960	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225961	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1226012	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1226014	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1226016	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1247841	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1247842	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1247844	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1220611	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0019903 protein phosphatase binding	IPI PMID:28759036 Deficiency in VHR/DUSP3, a suppressor of focal adhesion kina...	ACCEPT	Summary: EGFR binds to protein phosphatases that regulate its phosphorylation state. Reason: EGFR is regulated by phosphatases including PTPN1, PTPN2, and PTPN12. Supporting Evidence: PMID:28759036 Jul 31. Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-9611147	ACCEPT	Summary: EGFR localizes to endosome membranes during receptor trafficking after internalization. Reason: After ligand-induced endocytosis, EGFR is found on endosome membranes where it continues to signal.
GO:0045296 cadherin binding	HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	KEEP AS NON CORE	Summary: EGFR binds to cadherins, linking to cell adhesion regulation. Reason: Cadherin binding represents crosstalk between EGFR and cell adhesion. Supporting Evidence: PMID:25468996 E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
GO:0030335 positive regulation of cell migration	IMP PMID:25678558 Navigator-3, a modulator of cell migration, may act as a sup...	KEEP AS NON CORE	Summary: EGFR signaling promotes cell migration through various downstream effectors. Reason: Cell migration is a downstream cellular behavior influenced by EGFR signaling. Supporting Evidence: PMID:25678558 Navigator-3, a modulator of cell migration, may act as a suppressor of breast cancer progression.
GO:0005515 protein binding	IPI PMID:28479384 Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in ...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:28479384 Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in gastric cancer cells.
GO:0004713 protein tyrosine kinase activity	IMP PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mam...	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
GO:0005515 protein binding	IPI PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mam...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
GO:0007173 epidermal growth factor receptor signaling pathway	IMP PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mam...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
GO:0032991 protein-containing complex	IDA PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mam...	ACCEPT	Summary: EGFR forms protein complexes with signaling partners. Reason: EGFR exists in multiprotein signaling complexes. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
GO:0033138 positive regulation of peptidyl-serine phosphorylation	IMP PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mam...	KEEP AS NON CORE	Summary: EGFR signaling leads to downstream serine phosphorylation events. Reason: Serine phosphorylation regulation is a downstream effect of EGFR signaling cascades. Supporting Evidence: PMID:20878056 Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.
GO:0005006 epidermal growth factor receptor activity	IMP PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediate...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediated inactivation of the EGF receptor.
GO:1903078 positive regulation of protein localization to plasma membrane	IDA PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediate...	KEEP AS NON CORE	Summary: EGFR signaling can regulate protein localization to plasma membrane. Reason: Downstream cellular effect. Supporting Evidence: PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediated inactivation of the EGF receptor.
GO:0005886 plasma membrane	IDA PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediate...	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals. Supporting Evidence: PMID:22732145 Diacylglycerol kinase θ counteracts protein kinase C-mediated inactivation of the EGF receptor.
GO:1905208 negative regulation of cardiocyte differentiation	IMP PMID:23069713 The promotion of cardiogenic differentiation of hMSCs by tar...	KEEP AS NON CORE	Summary: EGFR signaling negatively regulates cardiocyte differentiation. Reason: Cell type-specific developmental effect. Supporting Evidence: PMID:23069713 Epub 2012 Oct 13. The promotion of cardiogenic differentiation of hMSCs by targeting epidermal growth factor receptor using microRNA-133a.
GO:0005768 endosome	IDA PMID:16554368 The ESCRT-III subunit hVps24 is required for degradation but...	ACCEPT	Summary: EGFR localizes to endosomes following ligand-induced internalization. EGFR continues signaling from early endosomes and is subsequently sorted for recycling or lysosomal degradation. Reason: Endosomal localization is part of normal EGFR trafficking and signaling. EGFR signals from endosomes and trafficking modulates signal duration. Supporting Evidence: PMID:16554368 Mar 22. The ESCRT-III subunit hVps24 is required for degradation but not silencing of the epidermal growth factor receptor.
GO:0008284 positive regulation of cell population proliferation	IMP PMID:27057632 Tumor-suppressive miR-218-5p inhibits cancer cell proliferat...	KEEP AS NON CORE	Summary: EGFR signaling promotes cell proliferation through MAPK and PI3K pathways. Reason: Cell proliferation is a downstream phenotypic effect of EGFR signaling. Supporting Evidence: PMID:27057632 Tumor-suppressive miR-218-5p inhibits cancer cell proliferation and migration via EGFR in non-small cell lung cancer.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IMP PMID:21673316 TRPS1 targeting by miR-221/222 promotes the epithelial-to-me...	ACCEPT	Summary: EGFR positively regulates ERK1/2 cascade through RAS-RAF-MEK-ERK signaling axis. Reason: ERK1/2 activation is a core readout of EGFR signaling through the MAPK pathway. Supporting Evidence: PMID:21673316 TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer.
GO:0030307 positive regulation of cell growth	IDA PMID:15467833 CEACAM1 modulates epidermal growth factor receptor--mediated...	KEEP AS NON CORE	Summary: EGFR signaling promotes cell growth. Reason: Cell growth regulation is a downstream effect of EGFR activation. Supporting Evidence: PMID:15467833 CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation.
GO:0005515 protein binding	IPI PMID:23912460 Hyperactivation of EGFR and downstream effector phospholipas...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:23912460 Aug 5. Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B.
GO:0005515 protein binding	IPI PMID:25311788 EGFR phosphorylates and inhibits lung tumor suppressor GPRC5...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25311788 EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.
GO:0005515 protein binding	IPI PMID:25666625 Epidermal growth factor receptor (EGFR) signaling requires a...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:25666625 2015 Feb 9. Epidermal growth factor receptor (EGFR) signaling requires a specific endoplasmic reticulum thioredoxin for the post-translational control of receptor presentation to the cell surface.
GO:0009986 cell surface	IDA PMID:25666625 Epidermal growth factor receptor (EGFR) signaling requires a...	ACCEPT	Summary: EGFR localizes to the cell surface where it is accessible for ligand binding. Reason: Cell surface localization is consistent with EGFR function as a receptor for extracellular growth factors. Supporting Evidence: PMID:25666625 2015 Feb 9. Epidermal growth factor receptor (EGFR) signaling requires a specific endoplasmic reticulum thioredoxin for the post-translational control of receptor presentation to the cell surface.
GO:0031901 early endosome membrane	IDA PMID:17714434 Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth...	ACCEPT	Summary: EGFR localizes to early endosome membranes following internalization, where it continues to signal. Reason: Early endosome membrane localization is well-documented for EGFR trafficking. Supporting Evidence: PMID:17714434 2007 Aug 20. Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation.
GO:0097489 multivesicular body, internal vesicle lumen	IDA PMID:17714434 Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth...	ACCEPT	Summary: EGFR is sorted into multivesicular bodies for lysosomal degradation. Reason: MVB sorting is part of EGFR downregulation pathway. Supporting Evidence: PMID:17714434 2007 Aug 20. Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation.
GO:0005515 protein binding	IPI PMID:8305738 The human GRB2 and Drosophila Drk genes can functionally rep...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:8305738 The human GRB2 and Drosophila Drk genes can functionally replace the Caenorhabditis elegans cell signaling gene sem-5.
GO:0031625 ubiquitin protein ligase binding	IPI PMID:23418353 The E3 ubiquitin ligases RNF126 and Rabring7 regulate endoso...	ACCEPT	Summary: EGFR binds to CBL E3 ubiquitin ligase, which ubiquitinates EGFR for endocytosis and degradation. Reason: CBL binding to EGFR is critical for receptor downregulation. Supporting Evidence: PMID:23418353 Feb 15. The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor.
GO:0010008 endosome membrane	IDA PMID:22719997 SNX12 role in endosome membrane transport.	ACCEPT	Summary: EGFR localizes to endosome membranes during receptor trafficking after internalization. Reason: After ligand-induced endocytosis, EGFR is found on endosome membranes where it continues to signal. Supporting Evidence: PMID:22719997 SNX12 role in endosome membrane transport.
GO:0005925 focal adhesion	HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome...	KEEP AS NON CORE	Summary: EGFR localizes to focal adhesions during cell migration. Reason: Focal adhesion localization is associated with EGFR-mediated migration. Supporting Evidence: PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.
GO:0005515 protein binding	IPI PMID:9852145 Interaction of ZPR1 with translation elongation factor-1alph...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9852145 Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells.
GO:0043235 receptor complex	IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm...	ACCEPT	Summary: EGFR forms homo- and heterodimeric receptor complexes upon ligand binding, which is required for kinase activation. Reason: EGFR dimerization into receptor complexes is essential for signal transduction. EGFR forms homodimers and heterodimers with ERBB2, ERBB3, ERBB4. Supporting Evidence: PMID:23382219 Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
GO:0007611 learning or memory	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: EGFR signaling may influence learning and memory processes. Reason: High-level behavioral phenotype, represents very downstream effects.
GO:0071364 cellular response to epidermal growth factor stimulus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: EGFR mediates cellular responses to EGF. Reason: This describes the cellular response, not the core receptor function.
GO:0001934 positive regulation of protein phosphorylation	IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es...	KEEP AS NON CORE	Summary: EGFR promotes protein phosphorylation through its kinase activity and downstream signaling. Reason: This is a general downstream effect of EGFR signaling. Supporting Evidence: PMID:20551055 Epub 2010 Jun 15. Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.
GO:0003682 chromatin binding	IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es...	KEEP AS NON CORE	Summary: Nuclear EGFR has been reported to bind chromatin and regulate transcription. Reason: Nuclear EGFR has been described in some contexts, but this is not a core function of EGFR. Supporting Evidence: PMID:20551055 Epub 2010 Jun 15. Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.
GO:0005515 protein binding	IPI PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:20551055 Epub 2010 Jun 15. Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.
GO:0005634 nucleus	IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es...	KEEP AS NON CORE	Summary: Nuclear EGFR has been described in certain contexts and may have transcriptional roles. Reason: Nuclear EGFR is documented but represents a minor, context-dependent localization rather than core EGFR function. Supporting Evidence: PMID:20551055 Epub 2010 Jun 15. Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es...	KEEP AS NON CORE	Summary: EGFR signaling leads to transcriptional activation of target genes. Reason: Transcriptional regulation is a downstream effect of EGFR signaling pathways. Supporting Evidence: PMID:20551055 Epub 2010 Jun 15. Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es...	ACCEPT	Summary: EGFR positively regulates ERK1/2 cascade through RAS-RAF-MEK-ERK signaling axis. Reason: ERK1/2 activation is a core readout of EGFR signaling through the MAPK pathway. Supporting Evidence: PMID:20551055 Epub 2010 Jun 15. Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.
GO:0071392 cellular response to estradiol stimulus	IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es...	KEEP AS NON CORE	Summary: EGFR can be activated in response to estradiol through crosstalk mechanisms. Reason: Estradiol response represents crosstalk/secondary activation, not core function. Supporting Evidence: PMID:20551055 Epub 2010 Jun 15. Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1247999	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1248002	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1248655	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637764	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637765	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637766	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637770	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637792	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637794	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637795	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637796	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637798	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637800	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637801	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637806	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5637808	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5638137	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1250195	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1306957	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1306963	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1306965	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177923	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177924	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177925	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177926	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177927	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177930	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177933	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177934	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177936	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177937	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177938	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177939	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177941	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177943	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177944	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177945	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-182969	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-182986	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-182990	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-182993	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-182994	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183002	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183036	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183051	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183055	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183058	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183067	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183072	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183084	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-183089	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1963563	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1963581	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1963582	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-212706	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-212710	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-212713	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2179387	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2179407	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2179415	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2316434	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2400009	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5672965	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6785636	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6785648	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8847995	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8848005	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8864105	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8864125	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8866279	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8867041	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8867044	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8867047	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8867754	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8867756	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868071	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868072	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868230	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868236	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868648	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868651	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8868661	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8951490	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9018572	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9018573	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9625482	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9625487	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664588	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664918	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664933	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664940	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664950	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664976	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664983	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664991	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665000	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665009	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665032	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665034	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665389	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665404	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665406	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665407	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665408	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665409	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665410	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665411	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665413	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665415	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665416	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665417	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665698	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665699	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665700	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665701	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665704	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665705	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665706	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665707	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665709	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-NUL-1248744	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-NUL-1251923	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-NUL-1251929	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005515 protein binding	IPI PMID:19509291 GAREM, a novel adaptor protein for growth factor receptor-bo...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:19509291 2009 Jun 9. GAREM, a novel adaptor protein for growth factor receptor-bound protein 2, contributes to cellular transformation through the activation of extracellular signal-regulated kinase signaling.
GO:0005515 protein binding	IPI PMID:18602463 Ataxin-2 associates with the endocytosis complex and affects...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:18602463 2008 Jun 15. Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking.
GO:0005515 protein binding	IPI PMID:10026169 Identification of Grb4/Nckbeta, a src homology 2 and 3 domai...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:10026169 Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck.
GO:0005515 protein binding	IPI PMID:15590694 Suppressors of cytokine signaling 4 and 5 regulate epidermal...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:15590694 2004 Dec 7. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling.
GO:0004713 protein tyrosine kinase activity	IDA PMID:17115032 Tyrosine phosphorylation controls PCNA function through prot...	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function. Supporting Evidence: PMID:17115032 Tyrosine phosphorylation controls PCNA function through protein stability.
GO:0005006 epidermal growth factor receptor activity	IDA PMID:17115032 Tyrosine phosphorylation controls PCNA function through prot...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:17115032 Tyrosine phosphorylation controls PCNA function through protein stability.
GO:0005515 protein binding	IPI PMID:17115032 Tyrosine phosphorylation controls PCNA function through prot...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17115032 Tyrosine phosphorylation controls PCNA function through protein stability.
GO:0005634 nucleus	IDA PMID:17115032 Tyrosine phosphorylation controls PCNA function through prot...	KEEP AS NON CORE	Summary: Nuclear EGFR has been described in certain contexts and may have transcriptional roles. Reason: Nuclear EGFR is documented but represents a minor, context-dependent localization rather than core EGFR function. Supporting Evidence: PMID:17115032 Tyrosine phosphorylation controls PCNA function through protein stability.
GO:0042177 negative regulation of protein catabolic process	IDA PMID:17115032 Tyrosine phosphorylation controls PCNA function through prot...	KEEP AS NON CORE	Summary: EGFR signaling can inhibit protein catabolism. Reason: Downstream effect of EGFR survival signaling. Supporting Evidence: PMID:17115032 Tyrosine phosphorylation controls PCNA function through protein stability.
GO:0045739 positive regulation of DNA repair	IDA PMID:17115032 Tyrosine phosphorylation controls PCNA function through prot...	KEEP AS NON CORE	Summary: Nuclear EGFR has been implicated in DNA repair regulation. Reason: DNA repair regulation is a non-canonical nuclear EGFR function. Supporting Evidence: PMID:17115032 Tyrosine phosphorylation controls PCNA function through protein stability.
GO:0045740 positive regulation of DNA replication	IDA PMID:17115032 Tyrosine phosphorylation controls PCNA function through prot...	KEEP AS NON CORE	Summary: EGFR signaling promotes DNA replication through proliferative signaling. Reason: DNA replication regulation is downstream of EGFR proliferative signaling. Supporting Evidence: PMID:17115032 Tyrosine phosphorylation controls PCNA function through protein stability.
GO:0019899 enzyme binding	IPI PMID:12009895 Plasma membrane phospholipid scramblase 1 is enriched in lip...	ACCEPT	Summary: EGFR binds to downstream enzymes including kinases and phosphatases. Reason: EGFR interacts with various enzymes as part of signaling. Supporting Evidence: PMID:12009895 Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor.
GO:0045121 membrane raft	IDA PMID:12009895 Plasma membrane phospholipid scramblase 1 is enriched in lip...	ACCEPT	Summary: EGFR localizes to membrane rafts/lipid rafts in the plasma membrane. Reason: EGFR partitioning into membrane rafts affects its signaling. Supporting Evidence: PMID:12009895 Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor.
GO:0043066 negative regulation of apoptotic process	IMP PMID:18070883 A novel role of Sprouty 2 in regulating cellular apoptosis.	KEEP AS NON CORE	Summary: EGFR signaling promotes cell survival by activating anti-apoptotic pathways including PI3K-AKT. Reason: Anti-apoptotic effects are downstream consequences of EGFR-PI3K-AKT signaling, not a core function. Supporting Evidence: PMID:18070883 2007 Dec 10. A novel role of Sprouty 2 in regulating cellular apoptosis.
GO:0005515 protein binding	IPI PMID:17182860 Activated Cdc42-associated kinase 1 is a component of EGF re...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17182860 Dec 20. Activated Cdc42-associated kinase 1 is a component of EGF receptor signaling complex and regulates EGF receptor degradation.
GO:0005768 endosome	IDA PMID:17182860 Activated Cdc42-associated kinase 1 is a component of EGF re...	ACCEPT	Summary: EGFR localizes to endosomes following ligand-induced internalization. EGFR continues signaling from early endosomes and is subsequently sorted for recycling or lysosomal degradation. Reason: Endosomal localization is part of normal EGFR trafficking and signaling. EGFR signals from endosomes and trafficking modulates signal duration. Supporting Evidence: PMID:17182860 Dec 20. Activated Cdc42-associated kinase 1 is a component of EGF receptor signaling complex and regulates EGF receptor degradation.
GO:0004888 transmembrane signaling receptor activity	IDA PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-...	ACCEPT	Summary: EGFR is a transmembrane signaling receptor. Reason: This accurately describes EGFR as a transmembrane receptor. Supporting Evidence: PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
GO:0007166 cell surface receptor signaling pathway	IDA PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-...	KEEP AS NON CORE	Summary: EGFR participates in cell surface receptor signaling. Reason: This general term is accurate but less specific than EGFR signaling pathway terms. Supporting Evidence: PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
GO:0007173 epidermal growth factor receptor signaling pathway	IDA PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-...	ACCEPT	Summary: EGFR is the initiating receptor of the EGF receptor signaling pathway, binding EGF family ligands and activating downstream signaling cascades. Reason: This is the defining biological process for EGFR - it is the primary receptor that initiates this pathway. Supporting Evidence: PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
GO:0008284 positive regulation of cell population proliferation	IDA PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-...	KEEP AS NON CORE	Summary: EGFR signaling promotes cell proliferation through MAPK and PI3K pathways. Reason: Cell proliferation is a downstream phenotypic effect of EGFR signaling. Supporting Evidence: PMID:7736574 Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
GO:0090263 positive regulation of canonical Wnt signaling pathway	IMP PMID:20302655 Epidermal growth factor receptor regulates beta-catenin loca...	KEEP AS NON CORE	Summary: EGFR signaling can crosstalk with and regulate Wnt signaling. Reason: Wnt pathway crosstalk is a secondary/downstream effect of EGFR. Supporting Evidence: PMID:20302655 Epidermal growth factor receptor regulates beta-catenin location, stability, and transcriptional activity in oral cancer.
GO:0004713 protein tyrosine kinase activity	IDA PMID:17599051 The evolutionarily conserved EBR module of RALT/MIG6 mediate...	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function. Supporting Evidence: PMID:17599051 Jun 18. The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity.
GO:0005515 protein binding	IPI PMID:17599051 The evolutionarily conserved EBR module of RALT/MIG6 mediate...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17599051 Jun 18. The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity.
GO:0005737 cytoplasm	IDA PMID:7588596 WT1 suppresses synthesis of the epidermal growth factor rece...	ACCEPT	Summary: EGFR intracellular domain localizes to the cytoplasm. Reason: The cytoplasmic portion of EGFR containing the kinase domain is localized in the cytoplasm. Supporting Evidence: PMID:7588596 WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis.
GO:0005515 protein binding	IPI PMID:19602593 Cetuximab/C225-induced intracellular trafficking of epiderma...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:19602593 Epub 2009 Jul 14. Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor.
GO:0070435 Shc-EGFR complex	ISS GO_REF:0000024	ACCEPT	Summary: EGFR forms a complex with SHC adaptor protein. Reason: SHC binding to phosphorylated EGFR is a key signaling event.
GO:0019903 protein phosphatase binding	IPI PMID:15899872 Transforming growth factor {beta} (TGF-{beta})-Smad target g...	ACCEPT	Summary: EGFR binds to protein phosphatases that regulate its phosphorylation state. Reason: EGFR is regulated by phosphatases including PTPN1, PTPN2, and PTPN12. Supporting Evidence: PMID:15899872 Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function.
GO:0070141 response to UV-A	IDA PMID:18483258 UVA-induced cell cycle progression is mediated by a disinteg...	KEEP AS NON CORE	Summary: EGFR can be activated by UV-A exposure. Reason: UV-A activation is a stress response, not normal physiological activation. Supporting Evidence: PMID:18483258 UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes.
GO:0005515 protein binding	IPI PMID:17909029 The phosphoinositide kinase PIKfyve mediates epidermal growt...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:17909029 The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus.
GO:0016323 basolateral plasma membrane	IDA PMID:12646923 Segregation of receptor and ligand regulates activation of e...	ACCEPT	Summary: In polarized epithelial cells, EGFR localizes to the basolateral plasma membrane. Reason: EGFR shows polarized distribution in epithelial cells, localizing to basolateral membranes. Supporting Evidence: PMID:12646923 Segregation of receptor and ligand regulates activation of epithelial growth factor receptor.
GO:0005515 protein binding	IPI PMID:11279102 Sorting nexin 6, a novel SNX, interacts with the transformin...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:11279102 2001 Mar 8. Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1225978	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1248677	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177922	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-177942	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1963586	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1963589	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1977959	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-445069	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8857549	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8857555	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8857565	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8857577	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8857583	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8874797	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9609689	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9610867	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9611147	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9611158	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9634702	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9664567	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665388	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9665697	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9674531	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9851407	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals.
GO:0007165 signal transduction	IDA PMID:10572067 Dominance of ErbB-1 heterodimers in lung epithelial cells ov...	ACCEPT	Summary: EGFR mediates signal transduction from extracellular growth factors to intracellular signaling cascades. Reason: Signal transduction is a core function of EGFR as a receptor tyrosine kinase. Supporting Evidence: PMID:10572067 Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2.
GO:0050679 positive regulation of epithelial cell proliferation	IDA PMID:10572067 Dominance of ErbB-1 heterodimers in lung epithelial cells ov...	KEEP AS NON CORE	Summary: EGFR signaling promotes epithelial cell proliferation, a key downstream effect in epithelial tissues. Reason: Epithelial cell proliferation is a major physiological outcome of EGFR signaling but represents a downstream effect. Supporting Evidence: PMID:10572067 Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2.
GO:0005515 protein binding	IPI PMID:9419975 Epiregulin binds to epidermal growth factor receptor and Erb...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:9419975 Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4.
GO:0005515 protein binding	IPI PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF recep...	REMOVE	Summary: Generic 'protein binding' term provides no specific information about EGFR molecular function. Reason: Per GO curation guidelines, 'protein binding' is uninformative and should be replaced with more specific binding terms. EGFR interacts with many proteins including ligands (EGF), dimerization partners (ERBB2-4), adaptors (GRB2, SHC), and signaling molecules, but this generic term does not capture any specific binding activity. Supporting Evidence: PMID:2176151 The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma.
GO:0004709 MAP kinase kinase kinase activity	NAS PMID:15542601 Activation of the epidermal growth factor receptor by respir...	MARK AS OVER ANNOTATED	Summary: EGFR is not a direct MAP3K. EGFR activates the MAPK cascade but acts upstream of RAF (the actual MAP3K). Reason: EGFR is a receptor tyrosine kinase that activates RAS, which then activates RAF (the MAP3K). EGFR itself does not have MAP3K activity. Supporting Evidence: PMID:15542601 2004 Nov 12. Activation of the epidermal growth factor receptor by respiratory syncytial virus results in increased inflammation and delayed apoptosis.
GO:0004713 protein tyrosine kinase activity	IMP PMID:14702346 Sorting of ligand-activated epidermal growth factor receptor...	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function. Supporting Evidence: PMID:14702346 2003 Dec 31. Sorting of ligand-activated epidermal growth factor receptor to lysosomes requires its actin-binding domain.
GO:0005006 epidermal growth factor receptor activity	IDA PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0005634 nucleus	IDA PMID:12828935 Activation of epidermal growth factor receptor signals induc...	KEEP AS NON CORE	Summary: Nuclear EGFR has been described in certain contexts and may have transcriptional roles. Reason: Nuclear EGFR is documented but represents a minor, context-dependent localization rather than core EGFR function. Supporting Evidence: PMID:12828935 Activation of epidermal growth factor receptor signals induction of nitric oxide synthase-2 in human optic nerve head astrocytes in glaucomatous optic neuropathy.
GO:0005737 cytoplasm	IDA PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	ACCEPT	Summary: EGFR intracellular domain localizes to the cytoplasm. Reason: The cytoplasmic portion of EGFR containing the kinase domain is localized in the cytoplasm. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0005768 endosome	IDA PMID:14702346 Sorting of ligand-activated epidermal growth factor receptor...	ACCEPT	Summary: EGFR localizes to endosomes following ligand-induced internalization. EGFR continues signaling from early endosomes and is subsequently sorted for recycling or lysosomal degradation. Reason: Endosomal localization is part of normal EGFR trafficking and signaling. EGFR signals from endosomes and trafficking modulates signal duration. Supporting Evidence: PMID:14702346 2003 Dec 31. Sorting of ligand-activated epidermal growth factor receptor to lysosomes requires its actin-binding domain.
GO:0016020 membrane	IDA PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	ACCEPT	Summary: EGFR is an integral membrane protein spanning the plasma membrane with extracellular ligand-binding and intracellular kinase domains. Reason: EGFR is a type I transmembrane protein; membrane localization is fundamental to its structure and function. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0030335 positive regulation of cell migration	IMP PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	KEEP AS NON CORE	Summary: EGFR signaling promotes cell migration through various downstream effectors. Reason: Cell migration is a downstream cellular behavior influenced by EGFR signaling. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0050730 regulation of peptidyl-tyrosine phosphorylation	IMP PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	KEEP AS NON CORE	Summary: EGFR regulates tyrosine phosphorylation of substrates. Reason: While related to EGFR kinase activity, this describes regulatory outcomes. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0051015 actin filament binding	IDA PMID:14702346 Sorting of ligand-activated epidermal growth factor receptor...	KEEP AS NON CORE	Summary: EGFR has been reported to bind actin filaments. Reason: Actin binding may be involved in EGFR trafficking/localization. Supporting Evidence: PMID:14702346 2003 Dec 31. Sorting of ligand-activated epidermal growth factor receptor to lysosomes requires its actin-binding domain.
GO:0051205 protein insertion into membrane	TAS PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	KEEP AS NON CORE	Summary: EGFR is inserted into the membrane during biosynthesis. Reason: Describes EGFR biogenesis rather than function. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0098609 cell-cell adhesion	IMP PMID:12435727 Epidermal growth factor receptor mediates increased cell pro...	KEEP AS NON CORE	Summary: EGFR signaling influences cell-cell adhesion. Reason: Downstream cellular behavior. Supporting Evidence: PMID:12435727 2002 Nov 14. Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
GO:0001503 ossification	NAS PMID:12925580 Mice humanised for the EGF receptor display hypomorphic phen...	KEEP AS NON CORE	Summary: EGFR signaling may influence bone formation. Reason: Developmental process in bone tissue. Supporting Evidence: PMID:12925580 Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart.
GO:0005615 extracellular space	NAS PMID:9103388 Expression of a truncated epidermal growth factor receptor-l...	KEEP AS NON CORE	Summary: Soluble EGFR ectodomain isoforms may be released to extracellular space. Reason: Truncated soluble EGFR isoforms exist but this is not the primary EGFR form. Supporting Evidence: PMID:9103388 Expression of a truncated epidermal growth factor receptor-like protein (TEGFR) in ovarian cancer.
GO:0042327 positive regulation of phosphorylation	IDA PMID:15082764 Epidermal growth factor receptor stimulation activates the R...	KEEP AS NON CORE	Summary: EGFR promotes phosphorylation through its kinase activity. Reason: General phosphorylation regulation is downstream of EGFR kinase activity. Supporting Evidence: PMID:15082764 Epidermal growth factor receptor stimulation activates the RNA binding protein CUG-BP1 and increases expression of C/EBPbeta-LIP in mammary epithelial cells.
GO:0003690 double-stranded DNA binding	NAS PMID:6325948 ATP-stimulated interaction between epidermal growth factor r...	MARK AS OVER ANNOTATED	Summary: Nuclear EGFR has been reported to associate with chromatin, but direct DNA binding is controversial. Reason: While nuclear EGFR has been described, its direct DNA binding role is not well-established and may be indirect through transcription factor interactions. Supporting Evidence: PMID:6325948 ATP-stimulated interaction between epidermal growth factor receptor and supercoiled DNA.
GO:0004713 protein tyrosine kinase activity	TAS PMID:16076471 The epidermal growth factor receptors and their family of li...	ACCEPT	Summary: EGFR possesses protein tyrosine kinase activity, phosphorylating itself and downstream substrates upon activation. Reason: Protein tyrosine kinase activity is fundamental to EGFR signaling. This is the parent term of transmembrane receptor protein tyrosine kinase activity and accurately describes EGFR function. Supporting Evidence: PMID:16076471 The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis.
GO:0005006 epidermal growth factor receptor activity	NAS PMID:2790960 Functional independence of the epidermal growth factor recep...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:2790960 Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation.
GO:0005006 epidermal growth factor receptor activity	NAS PMID:6325948 ATP-stimulated interaction between epidermal growth factor r...	ACCEPT	Summary: EGFR is the prototypical EGF receptor, binding EGF and related ligands to initiate signaling cascades controlling proliferation, survival, and differentiation. Reason: This is the most specific molecular function term for EGFR and is definitionally correct. Supporting Evidence: PMID:6325948 ATP-stimulated interaction between epidermal growth factor receptor and supercoiled DNA.
GO:0005886 plasma membrane	IDA PMID:15465819 Ubiquitin ligase activity of c-Cbl guides the epidermal grow...	ACCEPT	Summary: EGFR is a transmembrane receptor that localizes to the plasma membrane where it binds extracellular ligands and initiates intracellular signaling. Reason: Plasma membrane localization is essential for EGFR function as a cell surface receptor. EGFR resides at the plasma membrane to receive extracellular growth factor signals. Supporting Evidence: PMID:15465819 2004 Oct 1. Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment.
GO:0018108 peptidyl-tyrosine phosphorylation	IEA	NEW	Summary: Core catalytic function of EGFR as a receptor tyrosine kinase that phosphorylates substrate proteins on tyrosine residues Reason: EGFR is a receptor tyrosine kinase that catalyzes the phosphorylation of tyrosine residues on target substrate proteins. Upon ligand binding and receptor dimerization, EGFR undergoes autophosphorylation of its C-terminal tyrosine residues, which then serve as docking sites for adaptor proteins. EGFR also phosphorylates numerous downstream substrate proteins on tyrosine residues to propagate growth factor signaling. This peptidyl-tyrosine phosphorylation activity is fundamental to EGFR's mechanism of signal transduction. Supporting Evidence: file:human/EGFR/EGFR-uniprot.txt Receptor tyrosine-protein kinase that binds ligands of the EGF family and activates several signaling cascades
GO:0046777 protein autophosphorylation	IEA	NEW	Summary: Essential mechanism of EGFR activation through trans-autophosphorylation of C-terminal tyrosine residues upon ligand-induced dimerization Reason: Protein autophosphorylation is the fundamental mechanism by which EGFR activates its signaling cascade. Upon EGF or other ligand binding, EGFR undergoes dimerization, which brings two kinase domains into proximity for trans-autophosphorylation. EGFR phosphorylates multiple tyrosine residues in its own C-terminal tail (including Y1068, Y1086, Y1148, Y1173), creating docking sites for SH2 and PTB domain-containing signaling proteins. This autophosphorylation is essential for EGFR signal transduction and downstream pathway activation. Supporting Evidence: file:human/EGFR/EGFR-uniprot.txt Receptor tyrosine-protein kinase that binds ligands of the EGF family and activates several signaling cascades

Core Functions

epidermal growth factor binding and signal transduction through transmembrane receptor protein tyrosine kinase activity

Molecular Function:

transmembrane receptor protein tyrosine kinase activity

Directly Involved In:

epidermal growth factor receptor signaling pathway positive regulation of MAPK cascade MAPK cascade

Cellular Locations:

plasma membrane membrane

Substrates:

epidermal growth factor binding

Supporting Evidence:

PMID:12297050
Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains
PMID:12297049
Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha
PMID:18042729
Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation
PMID:19563760
Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment

autophosphorylation activity mediating receptor dimerization and downstream signaling activation

Molecular Function:

transmembrane receptor protein tyrosine kinase activity

Directly Involved In:

peptidyl-tyrosine phosphorylation protein autophosphorylation

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:18042729
Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation
PMID:19563760
Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms.

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links.

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods.

PMID:10026169

Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck.

Grb4 and Nck adaptor proteins associate with receptor tyrosine kinases and SOS1.

"Both Nck and Grb4 proteins could associate with receptor tyrosine kinases and the SH3-binding proteins PAK, Sos1, and PRK2,"

PMID:10229072

Association of Nck with tyrosine-phosphorylated SLP-76 in activated T lymphocytes.

Nck SH2 domain binds tyrosine-phosphorylated SLP-76.

"In vitro experiments show that the interaction between Nck and SLP-76 is mediated via the Nck SH2 domain."

PMID:10572067

Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2. Both ErbB-1 and ErbB-2 contribute significantly to tumorigenicity.

EGFR (ErbB-1) forms heterodimers with ErbB-2 that drive tumorigenic signaling in HBECs.

"These data demonstrate the importance of TGF-alpha-mediated signaling through the ErbB-1/-2 heterodimer in development of the tumorigenic phenotype."

PMID:10805725

Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors.

PI3K-C2alpha and PI3K-C2beta are recruited to activated EGFR signaling complexes.

"We demonstrate that PI3K-C2alpha and PI3K-C2beta represent two downstream targets of the activated epidermal growth factor (EGF) receptor in human carcinoma-derived A431 cells. Stimulation of quiescent cultures with EGF resulted in the rapid recruitment of both enzymes to a phosphotyrosine signaling complex that contained the EGF receptor and Erb-B2."

PMID:11279102

Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases.

SNX1-4 interact with receptor tyrosine kinases including EGFR, and SNX6 shows similar behavior.

"have been shown to bind to several receptor tyrosine kinases, including receptors for epidermal growth factor"

PMID:11331309

Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.

PLC gamma translocates to the plasma membrane and colocalizes with EGFR after EGF stimulation.

"Colocalization with the receptor was observed in the plasma membrane and in membrane ruffles where PI 4,5-P(2) substrate could also be visualized."

PMID:11336639

Heterodimerization of the epidermal-growth-factor (EGF) receptor and ErbB2 and the affinity of EGF binding are regulated by different mechanisms.

EGFR-ErbB2 heterodimer formation is ligand-independent and regulated separately from high-affinity EGF binding.

"ErbB2-EGFR heterodimer formation was found to be ligand-independent, and the number of heterodimers was not altered by overexpression of [K44A]dynamin."

PMID:11896612

Use of signal specific receptor tyrosine kinase oncoproteins reveals that pathways downstream from Grb2 or Shc are sufficient for cell transformation and metastasis.

Recruitment of Grb2 or Shc downstream of a RTK is sufficient to drive transformation and metastasis.

"Variants that recruit the Shc or Grb2 adaptor proteins generated foci of morphologically transformed fibroblast cells and induced anchorage-independent growth, scattering of epithelial cells and experimental metastasis."

PMID:12009895

Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor.

EGFR physically associates with PLSCR1 in lipid rafts and EGF stimulates PLSCR1 tyrosine phosphorylation.

"physical and functional interactions between the epidermal growth factor (EGF) receptor and phospholipid scramblase 1 (PLSCR1)"

PMID:12070153

Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation.

EGFR C-terminal tail regions regulate STAT activation, with truncations causing constitutive STAT signaling.

"Transient transfection of 293 cells with EGFR lacking the C-tail, i.e. Y974DeltaEGFR or Y992DeltaEGFR, led to EGF-independent or constitutive STAT activation"

PMID:12297049

Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha.

The EGFR ectodomain binds TGFalpha via L1 and L2 domains in the ligand-receptor crystal structure.

"We report the crystal structure, at 2.5 A resolution, of a truncated human EGFR ectodomain bound to TGFalpha."

PMID:12297050

Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains.

EGF binds between EGFR domains I and III and promotes receptor-mediated dimerization.

"EGFR domains I-III are arranged in a C shape, and EGF is docked between domains I and III."

PMID:12435727

Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.

EGFR overexpression activates Akt and STAT pathways and promotes migration and aggregation in esophageal keratinocytes.

"EGFR overexpression in primary esophageal keratinocytes resulted in the biochemical activation of Akt and STAT pathways and induced enhanced cell migration and cell aggregation."

PMID:12577067

A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling.

The Grb2 SH2 domain binds phosphorylated EGFR and Shc in EGF-stimulated cells.

"Combined cell lysates were affinity-purified over the SH2 domain of the adapter protein Grb2 (GST-SH2 fusion protein) that specifically binds phosphorylated EGFR and Src homologous and collagen (Shc) protein."

PMID:12620237

EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization.

EGF binding relieves autoinhibition of the EGFR ectodomain to expose the dimerization interface.

"The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions. To activate the receptor, EGF binding must promote a large domain rearrangement that exposes this dimerization interface."

PMID:12646923

Segregation of receptor and ligand regulates activation of epithelial growth factor receptor.

Heregulin-alpha activates erbB2 when epithelial polarity is disrupted, indicating ligand-receptor segregation controls activation.

"Here we show that in differentiated human airway epithelia, heregulin-alpha is present exclusively in the apical membrane"

PMID:12828935

Activation of epidermal growth factor receptor signals induction of nitric oxide synthase-2 in human optic nerve head astrocytes in glaucomatous optic neuropathy.

EGFR activation induces NOS-2 in human optic nerve head astrocytes.

"We have now found that activation of the epidermal growth factor receptor (EGFR) induces NOS-2 in astrocytes of the human optic nerve head (ONH) in vitro"

PMID:12925580

Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart.

Humanized EGFR mice show tissue-specific hypomorphic phenotypes and reveal an EGFR role in bone development.

"These results demonstrate that mice humanised for EGFR display tissue-specific hypomorphic phenotypes and describe a novel function for EGFR in bone development."

PMID:14568990

Role of the pleckstrin homology domain of PLCgamma1 in its interaction with the insulin receptor.

PLCgamma1 associates with the insulin receptor via its PH-EF-hand domain.

"This association was found to be independent of PLCgamma1 Src homology 2 domains, and instead required the pleckstrin homology (PH)-EF-hand domain."

PMID:14679214

A novel proteomic screen for peptide-protein interactions.

A tyrosine-phosphorylated EGFR peptide specifically binds the adaptor protein Grb2.

"A tyrosine-phosphorylated peptide of the epidermal growth factor receptor specifically retrieved the Src homology domain (SH) 2- and SH3 domain-containing adapter protein Grb2."

PMID:14702346

Sorting of ligand-activated epidermal growth factor receptor to lysosomes requires its actin-binding domain.

EGFR residues 985-996 are required for lysosomal sorting and degradation after ligand activation.

"Here we demonstrate that the second transport step requires a domain of the EGFR that encompasses residues 985-996 and was previously found to interact with actin. Deletion of domain 989-994 (Delta989-994 EGFR) did not interfere with EGFR uptake but completely abrogated its degradation."

PMID:14966128

Structural requirements for signal transducer and activator of transcription 3 binding to phosphotyrosine ligands containing the YXXQ motif.

STAT3 SH2 binds phosphotyrosine peptides containing a YXXQ motif.

"Only phosphotyrosine (Tyr(P)) peptides containing +3 Gln (not Leu, Met, Glu, or Arg) bound to wild type Stat3."

PMID:15082764

Epidermal growth factor receptor stimulation activates the RNA binding protein CUG-BP1 and increases expression of C/EBPbeta-LIP in mammary epithelial cells.

EGFR signaling phosphorylates CUG-BP1 and increases C/EBPbeta-LIP expression.

"Our data demonstrate that EGFR signaling results in the phosphorylation of CUG-BP1 and this leads to an increase in the binding of CUG-BP1 to C/EBP beta mRNA and elevated expression of the LIP isoform."

PMID:15225635

Identification of 14-3-3zeta as an EGF receptor interacting protein.

EGF rapidly induces association of 14-3-3zeta with EGFR.

"Here, we describe an association of 14-3-3zeta with the epidermal growth factor receptor (EGFR) that is rapidly induced by EGF."

PMID:15282549

LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation.

LRIG1 upregulation enhances EGFR ubiquitylation and degradation via c-Cbl recruitment.

"Upregulation of LRIG1 is followed by enhanced ubiquitylation and degradation of EGFR. The underlying mechanism involves recruitment of c-Cbl, an E3 ubiquitin ligase that simultaneously ubiquitylates EGFR and LRIG1 and sorts them for degradation."

PMID:15345710

The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases.

LRIG1 associates with ErbB receptors and promotes EGFR ubiquitination and degradation.

"We observed that in co-transfected 293T cells, LRIG1 forms a complex with each of the ErbB receptors independent of growth factor binding. We further observed that co-expression of LRIG1 with EGF receptor suppresses cellular receptor levels, shortens receptor half-life, and enhances ligand-stimulated receptor ubiquitination."

PMID:15465819

Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment.

c-Cbl ubiquitin ligase activity and the Eps15 UIM are required for EGFR entry into clathrin-coated pits.

"Both the ubiquitin ligase activity of c-Cbl and the UIM of Eps15 were necessary for plasma membrane recruitment of Eps15 and entry of ligand-bound EGFR into coated pits and vesicles containing Eps15."

PMID:15467833

CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation.

CEACAM1 is phosphorylated by EGFR and suppresses EGFR-mediated proliferation by sequestering Shc.

"CEACAM1 is a substrate of the EGFR and that upon being phosphorylated, CEACAM1 reduces EGFR-mediated growth of transfected Cos-7 and MCF-7 cells"

PMID:15542601

Activation of the epidermal growth factor receptor by respiratory syncytial virus results in increased inflammation and delayed apoptosis.

RSV activates EGFR in lung epithelial cells, increasing ERK activity and IL-8 release while prolonging cell survival.

"We demonstrate for the first time that RSV activates EGFR in lung epithelial cells. Activation of EGFR results in increased ERK activity, contributing to both the inflammatory response (IL-8 release) and prolonging the survival of RSV-infected cells."

PMID:15590694

Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling.

SOCS5 expression promotes EGFR degradation and reduces EGFR signaling.

"The expression of SOCS5 led to a marked reduction in EGFR expression levels by promoting EGFR degradation."

PMID:15611079

Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity.

Epigen (EPG) is more mitogenic than EGF despite lower affinity, likely due to inefficient receptor ubiquitylation and down-regulation.

"Interestingly, soluble EPG is more mitogenic than EGF, although its binding affinity is 100-fold lower. Our results attribute the anomalous mitogenic power of EPG to evasion of receptor-mediated depletion of ligand molecules, as well as to inefficient receptor ubiquitylation and down-regulation."

PMID:15657067

Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells.

Erlotinib inhibition of EGFR reduces phosphorylation of downstream targets including PLCgamma, PI-3 kinase, and STAT3/5.

"Pharmacological inhibition of EGF receptor kinase activity by erlotinib resulted in reduced phosphorylation of downstream signaling, for example through Cbl/Cbl-B, phospholipase Cgamma (PLCgamma), Erk1/2, PI-3 kinase, and STAT3/5."

PMID:15899872

Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function.

RPTPkappa associates with EGFR and HER2, suppressing basal and ligand-induced receptor phosphorylation and proliferation.

"Endogenous RPTPkappa associated with EGF receptor and HER2, resulting in suppression of basal and ErbB ligand-induced proliferation and receptor phosphorylation."

PMID:15962011

Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation.

Sprouty2 inhibits EGFR downregulation by acting at the Cbl/CIN85 interface.

"Here, we show that Sprouty2 associates with CIN85 and acts at the interface between Cbl and CIN85 to inhibit EGFR downregulation."

PMID:16076471

The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis.

EGFR is a tyrosine kinase receptor activated by multiple ligands and is detected on intimal smooth muscle cells in atherosclerotic plaques.

"The epidermal growth factor receptor is a member of type-I growth factor receptor family with tyrosine kinase activity"

PMID:16253990

Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein.

Gab2 overexpression enhances EGF-induced signaling and cell cycle progression.

"expression of Gab2 at levels comparable with those detected in human breast cancer cells accelerated epidermal growth factor (EGF)-induced cell cycle progression and was associated with increased basal Stat5 tyrosine phosphorylation and enhanced and/or more sustained EGF-induced Erk and Akt activation."

PMID:16273093

A quantitative protein interaction network for the ErbB receptors using protein microarrays.

EGFR phosphotyrosine sites recruit many SH2/PTB domains, with increased promiscuity at lower affinity thresholds.

"Most notably, EGFR and ErbB2 become markedly more promiscuous as the threshold is lowered, whereas ErbB3 does not."

PMID:16499958

Crystal structure of the ubiquitin binding domains of rabex-5 reveals two modes of interaction with ubiquitin.

Rabex-5 ubiquitin-binding domains enable interaction with ubiquitinated EGFR in vivo.

"These UBDs determine a number of properties of Rabex-5, including its coupled monoubiquitination and interaction in vivo with ubiquitinated EGFRs."

PMID:16516204

Activation of ErbB2 by 2-methyl-1,4-naphthoquinone (menadione) in human keratinocytes: role of EGFR and protein tyrosine phosphatases.

Menadione activates ErbB2 via EGFR in keratinocytes.

"ErbB2 is activated via the epidermal growth factor receptor (EGFR) upon exposure of cultured human keratinocytes to 2-methyl-1,4-naphthoquinone (menadione)."

PMID:16554368

The ESCRT-III subunit hVps24 is required for degradation but not silencing of the epidermal growth factor receptor.

hVps24 is required for EGFR degradation and transport to lysosomes.

"Depletion of hVps24 by siRNA showed that this ESCRT subunit, like Tsg101, is important for degradation of the epidermal growth factor (EGF) receptor (EGFR) and for transport of the receptor from early endosomes to lysosomes."

PMID:16777603

An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.

EGFR activation is driven by asymmetric kinase domain dimerization rather than activation loop phosphorylation.

"EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes."

PMID:16799092

Dynamic profiling of the post-translational modifications and interaction partners of epidermal growth factor receptor signaling after stimulation by epidermal growth factor using Extended Range Proteomic Analysis (ERPA).

ERPA profiling of EGFR identified 13 phosphorylation sites and quantified their dynamics after EGF stimulation.

"A total of 13 phosphorylation sites were identified, and the estimated stoichiometry was determined over the stimulation time points, including Thr(P) and Ser(P) sites in addition to Tyr(P) sites."

PMID:16843263

HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors.

HER2(YVMA) transphosphorylates EGFR even in the presence of EGFR TKIs.

"HER2(YVMA) transphosphorylated kinase-dead EGFR(K721R) and EGFR(WT) in the presence of EGFR tyrosine kinase inhibitors (TKIs)."

PMID:16914641

Intersectin regulates epidermal growth factor receptor endocytosis, ubiquitylation, and signaling.

Intersectin scaffolds Cbl to promote EGFR ubiquitylation and degradation, supporting EGFR internalization and ERK activation.

"This interaction stimulates the ubiquitylation and degradation of the activated EGFR."

PMID:16954185

Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor.

AGER1 suppresses AGE-induced EGFR phosphorylation and downstream signaling.

"AGE responses also included EGF receptor (EGFR) phosphorylation in MCs or HEK293 cells, but this link was blocked in both MC-R1 and HEK293-R1 cells."

PMID:17115032

Tyrosine phosphorylation controls PCNA function through protein stability.

Nuclear EGFR phosphorylates PCNA Tyr211 to stabilize chromatin-bound PCNA.

"the chromatin-bound PCNA protein is phosphorylated on Tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of EGF receptor (EGFR) in the nucleus."

PMID:17126326

Extracellular heat shock protein 70 mediates heat stress-induced epidermal growth factor receptor transactivation in A431 carcinoma cells.

Secreted Hsp70 mediates ligand-independent EGFR transactivation during heat stress.

"the depletion of Hsp70 from the conditioned medium of heated cells abolishes EGFR transactivation indicating that secreted Hsp70 is essential for EGFR transactivation during heat shock."

PMID:17148612

A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions.

ErbB2 interacts stably with EGFR, and Herceptin inhibits this interaction, promoting EGFR internalization.

"The widely used anti-cancer antibody Herceptin was found to effectively inhibit the interaction of the EGFR and ErbB2"

PMID:17182860

Activated Cdc42-associated kinase 1 is a component of EGF receptor signaling complex and regulates EGF receptor degradation.

ACK1 associates with EGFR upon EGF stimulation and promotes ligand-induced EGFR degradation.

"ACK1 interacted with epidermal growth factor receptor (EGFR) upon EGF stimulation"

PMID:17284441

Epidermal growth factor directs sex-specific steroid signaling through Src activation.

EGFR forms a complex with estrogen receptor and Src during E2 signaling in breast cancer cells.

"EGFR, estrogen receptor, and Src were found to form a complex upon E2 stimulation."

PMID:17334392

A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells.

NEU3 enhances EGF-stimulated EGFR tyrosine phosphorylation.

"NEU3 actually enhanced EGF-stimulated tyrosine-phosphorylation of EGFR"

PMID:17403676

Rin1 interacts with signal-transducing adaptor molecule (STAM) and mediates epidermal growth factor receptor trafficking and degradation.

Rin1 promotes EGFR degradation after EGF stimulation.

"overexpression of Rin1 accelerates EGFR degradation in EGF-stimulated cells."

PMID:17599051

The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity.

RALT/MIG6 suppresses EGFR catalytic activity via its ErbB-binding region.

"We report that RALT suppresses EGFR function by inhibiting its catalytic activity. The evolutionarily conserved ErbB-binding region (EBR) is necessary and sufficient to carry out RALT-dependent suppression of EGFR kinase activity in vitro and in intact cells."

PMID:17655843

EGF receptor transactivation and PI3-kinase mediate stimulation of ERK by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role in wound healing.

alpha2A-adrenoreceptor activates ERK/Akt via EGFR transactivation in intestinal epithelial cells.

"Both effects are strongly attenuated by inhibition or desensitization of epidermal growth factor (EGF) receptor, matrix metalloproteinase (MMP) blockade, heparin-binding-EGF neutralization or phosphatidylinositol 3-kinase (PI3-kinase) inhibitors."

PMID:17697999

Ligand-induced structural transitions in ErbB receptor extracellular domains.

Ligand binding shifts EGFR extracellular domain from a tethered autoinhibited state to an extended dimerization-competent conformation.

"Without bound ligand, the extracellular region of the receptor (sEGFR) adopts a "tethered" configuration with its dimerization site occluded by apparently autoinhibitory intramolecular interactions. Ligand binding causes the receptor to become "extended," breaking the tether and exposing the dimerization site."

PMID:17714434

Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation.

Vps22 is required for ligand-induced EGFR degradation and proper endosomal sorting.

"Depletion of Vps22 by small interfering RNA, which was accompanied by decreased levels of other ESCRT-II subunits, greatly reduced degradation of EGFR and its ligand EGF as well as the chemokine receptor CXCR4."

PMID:17726113

Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models.

LINGO-1 antagonists improve dopaminergic neuron survival via EGFR/Akt activation by blocking LINGO-1 binding to EGFR.

"LINGO-1 antagonists (LINGO-1-Fc, dominant negative LINGO-1, and anti-LINGO-1 antibody) improved DA neuron survival in response to MPP+ in part by mechanisms that involve activation of the EGFR/Akt signaling pathway through a direct inhibition of LINGO-1's binding to EGFR."

PMID:17909029

The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus.

PIKfyve mediates HB-EGF-stimulated EGFR nuclear trafficking and EGFR binding to the cyclin D1 promoter.

"RNA silencing indicated that PIKfyve is a mediator of HB-EGF-stimulated EGFR nuclear trafficking, EGFR binding to the cyclin D1 promoter, and cell cycle progression."

PMID:18042729

Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation.

The EGFR juxtamembrane region is required for allosteric kinase activation.

"Deletion of the JM region (DeltaJM) results in a severe loss of ICD tyrosine phosphorylation, indicating that this region is required for maximal activity of the tyrosine kinase domain."

PMID:18046415

Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.

MIG6 inhibits EGFR by blocking formation of the activating asymmetric dimer interface.

"Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface."

PMID:18070883

A novel role of Sprouty 2 in regulating cellular apoptosis.

Spry2 supports EGFR signaling and survival pathways; its silencing reduces EGFR levels and EGF-elicited AKT/ERK activation.

"Silencing of hSPRY2 decreased serum- or epidermal growth factor (EGF)-elicited activation of AKT and ERK1/2 and reduced the levels of EGF receptor."

PMID:18273061

Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.

The c-Cbl TKB domain binds phosphorylated EGFR peptides as substrates for ubiquitination.

"To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins"

PMID:18455122

Survival of cancer cells is maintained by EGFR independent of its kinase activity.

Kinase-independent EGFR maintains survival by stabilizing SGLT1 and preventing autophagic death.

"the function of kinase-independent EGFR is to prevent autophagic cell death by maintaining intracellular glucose level through interaction and stabilization of the sodium/glucose cotransporter 1 (SGLT1)."

PMID:18483258

UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes.

UVA activates EGFR upstream of AKT/cyclin D1 to drive cell cycle progression in keratinocytes.

"Activation of epidermal growth factor receptor (EGFR) was observed after UVA exposure. EGFR kinase inhibitor AG attenuated the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, indicating that EGFR is upstream of AKT/cyclin D1 pathway activation."

PMID:18542056

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII.

LRIG1 binds EGFRvIII and suppresses its oncogenic signaling.

"We find that EGFRvIII retains interaction with LRIG1 and is in fact more sensitive to LRIG1 action than wild-type receptor."

PMID:18602463

Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking.

Ataxin-2 influences EGFR endocytic trafficking.

"Functional studies demonstrated that ataxin-2 affects endocytic trafficking of the epidermal growth factor receptor (EGFR)."

PMID:18722344

BCAR3 regulates EGF-induced DNA synthesis in normal human breast MCF-12A cells.

BCAR3 associates with activated EGFR and is required for EGF-induced DNA synthesis.

"Direct association of BCAR3 with activated EGF receptor and Cas was observed."

PMID:18776048

Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS.

Mutant EGFR increases tyrosine phosphorylation of signaling proteins relative to WT EGFR.

"Tyrosine phosphorylation of signaling molecules was greater in HBECs expressing the mutant EGFRs than in cells expressing WT EGFR or mutant KRAS."

PMID:18824549

Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells.

AMCase secretion is EGFR-dependent and involves EGFR interaction.

"In vitro cotransfection experiments in A549 cells demonstrated that AMCase and EGFR physically interact with each other. Cotransfection of AMCase and EGFR also increased, whereas EGFR inhibition decreased AMCase secretion."

PMID:19167335

Large-scale structural analysis of the classical human protein tyrosine phosphatome.

Protein tyrosine phosphatases regulate signaling by selectively dephosphorylating substrates.

"Protein tyrosine phosphatases (PTPs) play a critical role in regulating cellular functions by selectively dephosphorylating their substrates."

PMID:19172738

Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein.

14-3-3 binding to phosphorylated Gab2 terminates receptor-associated signaling by uncoupling Gab2 from Grb2.

"We now demonstrate that growth factor-induced phosphorylation of Gab2 on two residues, S210 and T391, leads to recruitment of 14-3-3 proteins."

PMID:19509291

GAREM, a novel adaptor protein for growth factor receptor-bound protein 2, contributes to cellular transformation through the activation of extracellular signal-regulated kinase signaling.

GAREM is phosphorylated after EGF stimulation and binds Grb2 to regulate ERK signaling downstream of EGFR.

"GAREM is phosphorylated at tyrosine 105 and 453 after EGF stimulation. Grb2 was identified as its binding partner, and the proline-rich motifs of GAREM are recognized by the N- and C-terminal SH3 domains of Grb2."

PMID:19563760

Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.

The EGFR juxtamembrane segment promotes kinase activation by dimerizing kinase domains.

"We show that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains."

PMID:19602593

Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor.

Cetuximab induces EGFR endocytosis and trafficking to the ER and nucleus.

"The data herein show that C225-dependent EGFR trafficking relocalizes the receptor to the endoplasmic reticulum (ER) and nucleus."

PMID:19650109

Flow cytometric in situ proximity ligation analyses of protein interactions and post-translational modification of the epidermal growth factor receptor family.

In situ PLA quantifies EGFR-HER2 interactions and EGFR activation in cells.

"The in situ proximity ligation assay (in situ PLA) was used to quantify homo- and heteromeric interactions between EGFR and HER2 in cultured cells, using flow cytometry as the readout method."

PMID:19798056

Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor.

Tom1L1 is required for EGFR endocytosis following EGF stimulation.

"RNAi-mediated knockdown of Tom1L1 inhibits endocytosis of EGFR."

PMID:20007378

Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.

HER3 is catalytically inactive but can activate the EGFR kinase domain.

"we confirm that it is catalytically inactive but can serve as an activator of the EGFR kinase domain."

PMID:20029029

Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.

HDAC6 negatively regulates EGFR endocytosis and degradation by controlling tubulin acetylation.

"histone deacetylase 6 (HDAC6), a cytoplasmic lysine deacetylase, which we found negatively regulated EGFR endocytosis and degradation"

PMID:20153921

EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity.

EGFR/EGFRvIII bind PUMA and sequester it in the cytoplasm, inhibiting apoptosis independently of EGFR kinase activity.

"EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition."

PMID:20302655

Epidermal growth factor receptor regulates beta-catenin location, stability, and transcriptional activity in oral cancer.

EGFR activation increases nuclear beta-catenin and regulates its transcriptional activity in oral cancer.

"Activation of EGFR signaling increased the amount of beta-catenin in the nucleus and decreased the amount in the membranes."

PMID:20308550

The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation.

PTEN inactivation elevates EGFR activity by impairing Cbl-mediated ubiquitylation and degradation.

"PTEN inactivation specifically raises EGFR activity by impairing the ligand-induced ubiquitylation and degradation of the activated receptor through destabilization of newly formed ubiquitin ligase Cbl complexes."

PMID:20359299

A proximity ligation assay using transiently transfected, epitope-tagged proteins: application for in situ detection of dimerized receptor tyrosine kinases.

PLA enables in situ detection and quantification of ligand-dependent EGFR dimerization.

"utility of a proximity ligation assay (PLA)-based methodology for in situ visualization and quantification of ligand-dependent EGFR receptor dimerization in intact cells."

PMID:20403327

TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.

TRPV3 forms a signaling complex with TGF-alpha/EGFR and amplifies EGFR signaling via TGF-alpha release.

"keratinocyte TRPV3, a member of the transient receptor potential (TRP) family of Ca(2+)-permeant channels, forms a signaling complex with TGF-alpha/EGFR. Activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-alpha release."

PMID:20462955

A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate.

GIV directly interacts with EGFR and enhances EGFR autophosphorylation while prolonging membrane association.

"GIV directly interacts with EGFR, and when its GEF function is intact, a Galpha(i)-GIV-EGFR signaling complex assembles, EGFR autophosphorylation is enhanced, and the receptor's association with the plasma membrane (PM) is prolonged."

PMID:20473329

SIRPalpha1 receptors interfere with the EGFRvIII signalosome to inhibit glioblastoma cell transformation and migration.

SIRPalpha1 reduces EGFRvIII signalosome interactions and inhibits EGFRvIII-driven migration and transformation.

"We observed reduced EGFRvIII/SHP-2/Gab1/Grb2/Sos-1 interaction and enhanced SIRP/SHP-2 association in U87MG.EGFRvIII/SIRPalpha1 cells when compared with empty vector control cells."

PMID:20551055

Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.

E2 promotes a physical interaction between GPR30 and phosphorylated EGFR at the cyclin D1 promoter.

"E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter."

PMID:20562913

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells.

ERK inhibition enhances EGF-induced EGFR activation, ubiquitination, and downregulation.

"pharmacological inhibition of ERK (but not Akt) signaling enhances EGF-induced EGFR activation, ubiquitination and downregulation"

PMID:20624308

EGFR/Met association regulates EGFR TKI resistance in breast cancer.

EGFR and Met form a complex that supports ligand-independent Met phosphorylation and EGFR TKI resistance.

"we identified an EGFR/Met complex via co-immunoprecipitation. However, we only observed Met constitutive phosphorylation when c-Src also was part of this complex."

PMID:20878056

Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis.

RQCD1 knockdown reduces EGF-induced Akt phosphorylation downstream of EGFR.

"Knockdown of RQCD1 reduced the Akt phosphorylation level that was induced by epidermal growth factor (EGF) stimulation."

PMID:20935677

A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells.

ER-alpha36 mediates estrogen-induced EGFR phosphorylation via interaction with EGFR/Src/Shc.

"ER-α36 physically interacted with the EGFR/Src/Shc complex and mediated estrogen-induced phosphorylation of epidermal growth factor receptor (EGFR) and Src."

PMID:21203579

HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer.

HER2 phosphorylation is maintained by ligand-mediated EGFR/HER3/HER4 activation via ADAM17.

"HER2 phosphorylation is maintained by ligand-mediated activation of EGFR, HER3, and HER4 receptors, resulting in their dimerisation with HER2. The release of HER ligands was mediated by ADAM17 through a PKB negative feedback loop."

PMID:21258405

Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells.

Galectin-3 promotes endocytosis of EGFR; its depletion increases EGFR phosphorylation and nuclear translocation.

"galectin-3, an endogenous lectin, is co-expressed with MUC1 in human pancreatic ductal adenocarcinoma, and that it favours the endocytosis of MUC1 and EGFR. Depletion of galectin-3 by RNA interference increased the interaction between MUC1 and EGFR, EGFR and ERK-1,2 phosphorylation, and translocation of EGFR to the nucleus."

PMID:21266349

EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment.

EGFR nuclear localization and DNA-PKcs binding enhance DNA repair after cisplatin or IR.

"Immunoprecipitation showed wtEGFR and EGFRvIII binding to DNA-PKcs, increasing 2-fold 18 hours after cisplatin therapy."

PMID:21278786

PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer.

PI3K inhibition enhances HER receptor dimerization and phosphorylation, including EGFR, leading to ERK activation.

"This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3."

PMID:21278788

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src.

TCTP activates Src and induces phosphorylation of EGFR tyrosines.

"We found that TCTP (a) induces Src release from Na,K-ATPase α subunit and Src activation"

PMID:21349850

MAPK scaffold IQGAP1 binds the EGF receptor and modulates its activation.

IQGAP1 binds EGFR and is required for robust EGFR autophosphorylation.

"In IQGAP1-null cells, EGF-stimulated tyrosine phosphorylation of EGFR is severely attenuated. Normal levels of autophosphorylation are restored by reconstituting wild type IQGAP1 and enhanced by an IQGAP1 S1443D mutant."

PMID:21376233

Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.

PTPN12 suppresses EGFR and HER2 signaling by inhibiting multiple oncogenic tyrosine kinases.

"PTPN12 suppresses transformation by interacting with and inhibiting multiple oncogenic tyrosine kinases, including HER2 and EGFR."

PMID:21423176

Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.

β-Pix negatively regulates focal adhesion maturation and promotes lamellipodial protrusion.

"We focused on the Rac guanine nucleotide exchange factor β-Pix, documenting its role in the negative regulation of focal adhesion maturation and the promotion of lamellipodial protrusion and focal adhesion turnover to drive cell migration."

PMID:21439278

Engineered epidermal growth factor mutants with faster binding on-rates correlate with enhanced receptor activation.

EGF mutants with faster binding on-rates increase EGFR activation compared to wild-type EGF.

"We found that EGF mutants with faster kinetic on-rates stimulate increased EGFR activation compared to wild-type EGF."

PMID:21480528

Comparative analysis of fluorescence resonance energy transfer (FRET) and proximity ligation assay (PLA).

PLA is semiquantitative due to signal saturation, whereas FRET signals scale linearly with expression.

"Our data imply that PLA is a semiquantitative measure of protein colocalizations due to non-linear effects in the reaction and that caution should be exercised when interpreting PLA data in a quantitative way."

PMID:21482778

Quantification of receptor tyrosine kinase transactivation through direct dimerization and surface density measurements in single cells.

SpIDA quantifies EGFR dimerization and surface trafficking during GPCR-driven transactivation.

"Here, we show the use of SpIDA to quantify dimerization/activation and surface transport of receptor protein kinases--EGF receptor and TrkB--at early stages of their transactivation by several G protein-coupled receptors (GPCRs)."

PMID:21673316

TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer.

miR-221/222 abundance decreases with EGFR or MEK inhibition, placing these miRNAs downstream of EGFR-RAS signaling.

"the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway."

PMID:21706016

Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor.

AP-SRM profiling defines time-dependent GRB2 interaction networks after stimulation.

"Our data reliably define context-specific and time-dependent networks that form around GRB2 after stimulation, and reveal core and growth factor-selective complexes comprising 90 proteins identified as interacting with GRB2 in HEK293T cells."

PMID:2176151

The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma.

EGFR C-terminal autophosphorylation sites mediate binding of GAP SH2 and PLC-gamma.

"This fragment bound both TRP E GAP SH2 and PLC-gamma but only when tyrosine phosphorylated."

PMID:21822280

Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor.

Liganded EGFR ectodomain can couple to both active asymmetric kinase dimers and inactive symmetric dimers.

"The liganded, dimeric EGFR ectodomain can couple both to putatively active, asymmetrically associated kinase dimers and to putatively inactive, symmetrically associated kinase dimers and monomers."

PMID:21951318

Ligand-dependent differences in estrogen receptor beta-interacting proteins identified in lung adenocarcinoma cells corresponds to estrogenic responses.

ERbeta and EGFR interact in lung adenocarcinoma cells in response to E2 or EGF.

"Coimmunoprecipitation experiments in these and other lung adenocarcinoma cells confirmed that ERβ and EGFR interact in a gender-dependent manner and in response to E2 or EGF."

PMID:22232519

In situ analysis of mutant EGFRs prevalent in glioblastoma multiforme reveals aberrant dimerization, activation, and differential response to anti-EGFR targeted therapy.

PMID:22298428

The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane.

PMID:22411794

Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1.

PMID:22439932

NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma.

PMID:22579287

Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.

PMID:22719997

SNX12 role in endosome membrane transport.

PMID:22732145

Diacylglycerol kinase θ counteracts protein kinase C-mediated inactivation of the EGF receptor.

PMID:22939624

Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.

PMID:23069713

The promotion of cardiogenic differentiation of hMSCs by targeting epidermal growth factor receptor using microRNA-133a.

PMID:23178489

The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents.

PMID:23178716

SnoN/SkiL expression is modulated via arsenic trioxide-induced activation of the PI3K/AKT pathway in ovarian cancer cells.

PMID:23273428

Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition.

PMID:23374349

Conformational coupling across the plasma membrane in activation of the EGF receptor.

PMID:23382219

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.

PMID:23397142

Analysis of protein-protein interactions in cross-talk pathways reveals CRKL protein as a novel prognostic marker in hepatocellular carcinoma.

PMID:23418353

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor.

PMID:23436906

Parallel visualization of multiple protein complexes in individual cells in tumor tissue.

PMID:23520446

Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells.

PMID:23597562

Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.

PMID:23636329

EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2.

PMID:23764002

Epidermal growth factor receptor potentiates MCM7-mediated DNA replication through tyrosine phosphorylation of Lyn kinase in human cancers.

PMID:23799367

Threshold-controlled ubiquitination of the EGFR directs receptor fate.

PMID:23866081

Lyn, a Src family kinase, regulates activation of epidermal growth factor receptors in lung adenocarcinoma cells.

PMID:23912460

Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B.

PMID:24034250

EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance.

PMID:24076656

Endophilin, Lamellipodin, and Mena cooperate to regulate F-actin-dependent EGF-receptor endocytosis.

PMID:24135280

EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma.

PMID:24189400

Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.

PMID:24557338

Characterisation of HER heterodimers in breast cancer using in situ proximity ligation assay.

PMID:24658140

The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells.

PMID:2472218

EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling.

PMID:24780295

Importance of EGFR/ERCC1 interaction following radiation-induced DNA damage.

PMID:24854121

Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway.

PMID:24947832

Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:25136068

Mycoplasma hyorhinis infection promotes NF-κB-dependent migration of gastric cancer cells.

PMID:25187647

Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin.

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:25311788

EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.

PMID:25353163

Soluble LRIG2 ectodomain is released from glioblastoma cells and promotes the proliferation and inhibits the apoptosis of glioblastoma cells in vitro and in vivo in a similar manner to the full-length LRIG2.

PMID:25468996

E-cadherin interactome complexity and robustness resolved by quantitative proteomics.

PMID:25594178

A kinase-independent role for EGF receptor in autophagy initiation.

PMID:25666625

Epidermal growth factor receptor (EGFR) signaling requires a specific endoplasmic reticulum thioredoxin for the post-translational control of receptor presentation to the cell surface.

PMID:25678558

Navigator-3, a modulator of cell migration, may act as a suppressor of breast cancer progression.

PMID:25796184

PEA-15 facilitates EGFR dephosphorylation via ERK sequestration at increased ER-PM contacts in TNBC cells.

PMID:25873175

AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

PMID:25970784

PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma.

PMID:26005835

RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth.

PMID:26280537

Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation.

PMID:26551075

EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src.

PMID:26751287

The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.

PMID:26988023

Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance.

PMID:27057632

Tumor-suppressive miR-218-5p inhibits cancer cell proliferation and migration via EGFR in non-small cell lung cancer.

PMID:27059931

Weak binding to E3 ubiquitin ligase c-Cbl increases EGFRvA protein stability.

PMID:27569582

GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis.

PMID:27872189

Biophysical Evidence for Intrinsic Disorder in the C-terminal Tails of the Epidermal Growth Factor Receptor (EGFR) and HER3 Receptor Tyrosine Kinases.

PMID:2790960

Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation.

PMID:27956147

Systematic Identification of Oncogenic EGFR Interaction Partners.

PMID:28065597

A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.

PMID:28479384

Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in gastric cancer cells.

PMID:28759036

Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration.

PMID:28988771

EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics.

PMID:29455656

The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells.

PMID:29844572

RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.

PMID:30083275

The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival.

PMID:30662352

COPI-Mediated Nuclear Translocation of EGFRvIII Promotes STAT3 Phosphorylation and PKM2 Nuclear Localization.

PMID:31585087

Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites.

PMID:31862538

Neuropeptide bombesin receptor activation stimulates growth of lung cancer cells through HER3 with a MAPK-dependent mechanism.

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:33420426

AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells.

PMID:34591612

A protein interaction landscape of breast cancer.

PMID:34591642

A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.

PMID:35384245

Physical and functional interactome atlas of human receptor tyrosine kinases.

PMID:35512704

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

PMID:37100772

Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs.

PMID:38572507

DRD1 suppresses cell proliferation and reduces EGFR activation and PD-L1 expression in NSCLC.

PMID:39073202

SNX32 Regulates Sorting and Trafficking of Activated EGFR to the Lysosomal Degradation Pathway.

PMID:6325948

ATP-stimulated interaction between epidermal growth factor receptor and supercoiled DNA.

PMID:7518560

Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor.

PMID:7542744

The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor.

PMID:7588596

WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis.

PMID:7657591

Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation.

PMID:7685104

Substrate specificity of the protein tyrosine phosphatases.

PMID:7693694

Sequence specificity in recognition of the epidermal growth factor receptor by protein tyrosine phosphatase 1B.

PMID:7736574

Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.

PMID:7797556

Src phosphorylation of the epidermal growth factor receptor at novel sites mediates receptor interaction with Src and P85 alpha.

PMID:7993895

Identification of amino acids in the N-terminal SH2 domain of phospholipase C gamma 1 important in the interaction with epidermal growth factor receptor.

PMID:8034616

Tyrosines 1148 and 1173 of activated human epidermal growth factor receptors are binding sites of Shc in intact cells.

PMID:8305738

The human GRB2 and Drosophila Drk genes can functionally replace the Caenorhabditis elegans cell signaling gene sem-5.

PMID:8621392

Determinants of substrate recognition in the protein-tyrosine phosphatase, PTP1.

PMID:8887653

The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.

PMID:8940013

The Grb2-mSos1 complex binds phosphopeptides with higher affinity than Grb2.

PMID:9020117

Subsets of epidermal growth factor receptors during activation and endocytosis.

PMID:9050838

Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases.

PMID:9103388

Expression of a truncated epidermal growth factor receptor-like protein (TEGFR) in ovarian cancer.

PMID:9135143

Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation.

PMID:9355745

Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor.

PMID:9419975

Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4.

PMID:9506989

Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains.

PMID:9544989

Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells.

PMID:9852145

Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells.

PMID:9890893

Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro.

Reactome:R-HSA-1169421

Trans-autophosphorylation of activated ligand-responsive EGFR mutant dimers

Ligand-responsive EGFR mutant dimers trans-autophosphorylate multiple tyrosine residues after activation.

"Activation of ligand-responsive EGFR mutants through spontaneous or EGF-induced dimerization results in trans-autophosphorylation of 5 tyrosine residues"

Reactome:R-HSA-1218833

Binding of ligand-responsive EGFR mutants to chaperoning proteins HSP90 and CDC37

EGFR kinase domain mutants require continuous association with HSP90 for proper functioning.

"EGFR kinase domain mutants need continuous association with HSP90 chaperone protein for proper functioning."

Reactome:R-HSA-1220610

Non-covalent tyrosine kinase inhibitors bind and inactivate sensitive ligand-responsive EGFR cancer mutants

Reversible TKIs inhibit mutant EGFR autophosphorylation by competitively blocking ATP binding.

"Non-covalent (reversible) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, lapatinib and vandetanib, selectively inhibit EGFR-stimulated tumor cell growth by blocking EGFR mutant autophosphorylation through competitive inhibition of ATP binding to the kinase domain."

Reactome:R-HSA-1220611

Covalent tyrosine kinase inhibitors bind and inactivate EGFR kinase domain mutant dimers resistant to non-covalent tyrosine kinase inhibitors

Covalent TKIs bind EGFR C397 and inhibit trans-autophosphorylation of mutants resistant to non-covalent TKIs.

"Covalent (irreversible) tyrosine kinase inhibitors (TKIs), pelitinib, WZ4002, HKI-272, canertinib and afatinib, form a covalent bond with the EGFR cysteine residue C397 and inhibit trans-autophosphorylation of mutants resistant to non-covalent TKIs."

Reactome:R-HSA-1220612

Binding of EGF to ligand-responsive EGFR mutants

Ligand-responsive EGFR mutants bind EGF and show increased activity in its presence.

"Ligand-responsive EGFR mutants are able to bind EGF and exhibit increased activity in the presence of EGF."

Reactome:R-HSA-1220613

EGF-induced dimerization of ligand-responsive EGFR mutants

EGF increases dimerization of ligand-responsive EGFR mutants.

"Although ligand-responsive EGFR mutants dimerize spontaneously, dimerization is increased in the presence of EGF."

Reactome:R-HSA-1220614

Spontaneous dimerization of ligand-responsive EGFR mutants

Ligand-responsive EGFR mutants spontaneously dimerize without ligand binding.

"EGFR ligand-responsive mutants dimerize spontaneously, without ligand binding, although ligand binding ability is preserved."

Reactome:R-HSA-1225947

Binding of SHC1 to p-6Y-EGFR mutants

SHC1 binds phosphorylated EGFR docking sites Y1148 and Y1173 in EGFR mutants.

"SHC1 (Src homology 2 domain-containing transforming protein) is known to bind two phosphorylated tyrosine docking sites of EGFR: Y1148 and Y1173"

Reactome:R-HSA-1225949

Binding of CBL to ligand-responsive p-6Y-EGFR mutants

CBL binds phosphorylated Y1069 (Y1045) on EGFR cancer mutants.

"CBL binds to phosphorylated tyrosine Y1069 (i.e. Y1045 in the mature protein) residue of EGFR cancer mutants."

Reactome:R-HSA-1225950

Binding of GRB2:SOS1 complex to phosphorylated ligand-responsive EGFR mutants

GRB2 binds phosphorylated EGFR mutant tyrosines Y1068 and Y1086.

"GRB2 binds to phosphorylated tyrosine residues Y1068 and Y1086"

Reactome:R-HSA-1225951

SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with ligand-responsive p-6Y-EGFR mutants)

SOS1 recruited via GRB2 to phosphorylated EGFR mutants activates RAS.

"Based on the wild-type EGFR signaling, it is assumed that the guanine nucleotide exchange factor SOS1 interacts with phosphorylated EGFR mutants through the adaptor protein, GRB2. Upon formation of this complex, SOS1 activates RAS by promoting GDP release and GTP binding."

Reactome:R-HSA-1225952

Phosphorylation of SHC1 by ligand-responsive p-6Y-EGFR mutants

EGFR L858R mutant constitutively phosphorylates SHC1.

"Constitutive phosphorylation of SHC1 was directly demonstrated in cells expressing EGFR L858R mutant (Greulich et al. 2005)."

Reactome:R-HSA-1225956

Inefficient ubiquitination of ligand-responsive p-6Y-EGFR mutants by p-Y371-CBL

Phosphorylated CBL does not efficiently ubiquitinate EGFR kinase domain mutants.

"Phosphorylated CBL does not ubiquitinate EGFR kinase domain mutants efficiently, which enables mutant proteins to escape degradation."

Reactome:R-HSA-1225957

SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with phosphorylated SHC1 and ligand-responsive p-6Y-EGFR mutants)

GRB2-bound SOS1 is assumed to activate RAS downstream of p-SHC1:p-EGFR mutants.

"SOS1, recruited by GRB2 bound to p-SHC1:p-EGFR mutants, is assumed to activate RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP)."

Reactome:R-HSA-1225960

Phosphorylation of CBL by ligand-responsive p-6Y-EGFR mutants

EGFR L858R mutant directly phosphorylates CBL on Y371.

"EGFR L858R mutant was shown to directly phosphorylate CBL on tyrosine residue Y371."

Reactome:R-HSA-1225961

Phosphorylated SHC1 in complex with ligand-responsive p-6Y-EGFR mutants recruits GRB2:SOS1 complex

SHC1 bound to phosphorylated EGFR mutant dimers is assumed to recruit GRB2:SOS1.

"Recruitment of GRB2:SOS1 complex by SHC1 bound to phosphorylated dimers of EGFR cancer mutants has not been directly tested, but is assumed to happen in the same way it happens with the SHC1 bound to the phosphorylated homodimer of wild-type EGFR."

Reactome:R-HSA-1225978

Covalent tyrosine kinase inhibitors bind and inhibit wild-type EGF:EGFR dimers

Covalent TKIs inhibit wild-type EGFR by covalently binding Cys397.

"Covalent (irreversible) TKIs, pelitinib, WZ4002, HKI-272, canertinib and afatinib, inhibit the wild-type EGFR through formation of the covalent bond with the cysteine residue C397."

Reactome:R-HSA-1226012

Binding of PI3K to complex of GRB2:GAB1 and ligand-responsive p-6Y-EGFR mutants

EGFR cancer mutants are assumed to recruit PI3K in a manner similar to wild-type EGFR.

"EGFR cancer mutants are assumed to recruit the PI3K complex PIK3CA:PIK3R1 in a manner similar to wild-type EGFR."

Reactome:R-HSA-1226014

Conversion of PIP2 to PIP3 by PI3K bound to ligand-responsive p-6Y-EGFR mutants

EGFR cancer mutants are assumed to induce PI3K/AKT signaling via PI3K-mediated conversion of PIP2 to PIP3.

"The kinase activity of PI3K mediates the phosphorylation of PIP2 to form PIP3. It is assumed that EGFR cancer mutants induce PI3K/AKT signaling in a manner similar to wild-type EGFR."

Reactome:R-HSA-1226016

Binding of GRB2:GAB1 complex to ligand-responsive p-6Y-EGFR mutants

Recruitment of GRB2:GAB1 to phosphorylated EGFR cancer mutants is assumed and not directly tested.

"Direct binding of GRB2:GAB1 complex to phosphorylated homodimers of EGFR cancer mutants has not been tested."

Reactome:R-HSA-1247841

PLCG1 binds to ligand-responsive p-6Y-EGFR mutants

EGFR cancer mutants phosphorylate Y992 and are expected to recruit PLCG1 similarly to wild-type EGFR.

"Tyrosine residue Y992 (corresponding to Y1016 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus), a docking site for PLC-gamma 1 (PLCG1), is phosphorylated in EGFR cancer mutants and expected to recruit PLC-gamma 1 in the same way as the wild-type EGFR receptor."

Reactome:R-HSA-1247842

Dissociation of phosphorylated PLCG1 from ligand-responsive p-6Y-EGFR mutants

After EGFR mutant-driven phosphorylation, PLCG1 is expected to dissociate, a release event following activation rather than an active EGFR role at this step.

"Once phosphorylated, PLC-gamma 1 is expected to dissociate from phosphorylated EGFR cancer mutants and induce downstream signaling in the same way it does when activated by the wild-type EGFR."

Reactome:R-HSA-1247844

Phosphorylation of PLCG1 by ligand-responsive p-6Y-EGFR mutants

EGFR cancer mutants are assumed to phosphorylate PLCG1 after recruitment.

"Once recruited, PLC-gamma 1 is assumed to be phosphorylated by EGFR cancer mutants in the same way it is phosphorylated by the wild-type EGFR."

Reactome:R-HSA-1247999

EGFRvIII mutant binds chaperone proteins HSP90 and CDC37

EGFRvIII requires HSP90 and CDC37 chaperones for proper function.

"Association of EGFRvIII mutant with HSP90 chaperone protein and its co-chaperone CDC37 is necessary for the proper functioning of mutant EGFR."

Reactome:R-HSA-1248002

Ligand-independent dimerization of EGFRvIII mutant

EGFRvIII cannot bind ligand but dimerizes spontaneously, potentially influenced by N-linked glycosylation.

"EGFRvIII mutant lacks the ligand binding domain and is therefore unable to bind EGFR ligands, but is able to dimerize spontaneously. Self-dimerization may be dependent on N-linked glycosylation."

Reactome:R-HSA-1248655

Trans-autophosphorylation of EGFRvIII mutant dimers

EGFRvIII dimers trans-autophosphorylate multiple tyrosines while Y1045 remains hypo/unphosphorylated, enabling signaling and reduced downregulation.

"Upon dimerization, EGFRvIII mutants trans-autophosphorylate on tyrosine residues Y1016 i.e. Y992 in the mature protein, Y1092 i.e. Y1068 in the mature protein, Y1110 i.e. Y0186 in the mature protein, Y1172 i.e. Y1148 in the mature protein and Y1197 i.e. Y1173 in the mature protein, while the tyrosine residue Y1069 i.e. Y1045 in the mature protein, a docking site for CBL, remains either unphosphorylated or hypophosphorylated, allowing EGFRvIII to activate downstream signaling cascades while escaping downregulation."

Reactome:R-HSA-1248677

Inactivation of over-expressed wild type EGFR by Cetuximab recombinant antibody

Cetuximab inhibits EGFR by blocking ligand binding and promoting receptor inactivation and degradation.

"Cetuximab binds to the extracellular domain of EGFR and blocks ligand binding, leading to receptor inactivation, internalization and degradation."

Reactome:R-HSA-1250195

SHC1 phosphorylation by ERBB2 heterodimers

In ERBB2 heterodimers, EGFR can phosphorylate SHC1 on tyrosine residues.

"Once bound to ERBB2 heterodimers, SHC1 is phosphorylated on tyrosine residues by the tyrosine kinase activity of either ERBB2 or its heterodimerization partners EGFR and ERBB4 (Segatto et al. 1993, Soler et al. 1994)."

Reactome:R-HSA-1306957

PIP2 to PIP3 conversion by PI3K bound to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR

PI3K associated with phosphorylated ERBB2:EGFR converts PIP2 to PIP3 to activate AKT signaling.

"Active PI3K in complex with p-EGFR:p-ERBB2:GRB2:GAB1 phosphorylates PIP2 into PIP3, leading to activation of AKT signaling (Jackson et al. 2004)."

Reactome:R-HSA-1306963

Binding of GRB2:GAB1 to p-ERBB2:p-EGFR

GRB2:GAB1 is recruited to activated ERBB2:EGFR via phosphorylated docking tyrosines.

"GAB1 in complex with GRB2 is recruited to activated ERBB2:EGFR heterodimer through phosphorylated tyrosine residues that serve as docking sites for GRB2 (Jackson et al. 2004)."

Reactome:R-HSA-1306965

Binding of PI3K to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR

PI3K activation follows PIK3R1 binding to GRB2:GAB1 in complex with phosphorylated ERBB2:EGFR.

"Binding of PIK3R1 to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR triggers a conformational change in the PI3K complex, resulting in PI3K activation (Jackson et al. 2004)."

Reactome:R-HSA-177922

EGFR dimerization

EGF binding stabilizes the active dimeric form of EGFR.

"EGF and other growth factors induce oligomerization of their specific receptors. Inactive EGFR monomers are in equilibrium with active EGFR dimers and binding of the EGF ligand stabilizes the active dimeric form."

Reactome:R-HSA-177923

Sustained activation of SRC kinase by SHP2

SHP2-mediated dephosphorylation of paxillin promotes SRC activation in EGF-stimulated signaling.

"SHP2 can dephosphorylate paxillin, which leads to CSK dissociation from the paxillin-SRC complex and SRC activation."

Reactome:R-HSA-177924

Dephosphorylation of Gab1 by SHP2

SHP2 dephosphorylation of GAB1 blocks PI3K binding and activation.

"SHP2 dephosphorylation of the tyrosine residues 447, 472 and 589 on GAB1 means PI3 kinase can no longer bind to the complex in the plasma membrane and cannot be activated."

Reactome:R-HSA-177925

SHC1 binds to the phosphorylated EGF receptor:ligand complex

SHC1 binds phosphorylated EGFR at Y1148 or Y1173 sites.

"SHC1 (Src homology 2 domain-containing) transforming protein can bind to either phosphorylated tyrosine sites Y1172 (p-Y1172) i.e. Y1148 (p-Y1148) in the mature protein and/or tyrosine Y1197 (p-Y1197) i.e. Y1173 (p-Y1173) in the mature protein on the EGF receptor."

Reactome:R-HSA-177926

Dephosphorylation of PAG by SHP2

SHP2 dephosphorylation of CBP/PAG reduces recruitment of Csk and limits Src inhibition.

"Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk."

Reactome:R-HSA-177927

PI3K binds to EGF:EGFR:GRB2:GAB1

PI3K regulatory subunit PIK3R1 binds GAB1 to recruit PI3K to EGFR signaling complexes.

"The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner."

Reactome:R-HSA-177929

Signaling by EGFR

EGFR ligand binding triggers dimerization and trans-autophosphorylation to initiate downstream signaling.

"Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor."

Reactome:R-HSA-177930

GAB1 phosphorylation by EGFR kinase

EGFR kinase phosphorylates GAB1 at Y627 and Y659.

"EGFR kinase phosphorylates the phosphorylation sites tyrosine 627 and 659 on GAB1"

Reactome:R-HSA-177933

SHC1 phosphorylation by phosphorylated EGFR

EGFR-bound SHC1 is phosphorylated on Y349 and Y350.

"Once bound to EGFR, SHC1 is phosphorylated on two tyrosines (Y349, Y350)."

Reactome:R-HSA-177934

EGFR autophosphorylation

EGFR dimerization activates kinase activity and leads to autophosphorylation of six tyrosines in the cytoplasmic tail.

"Dimerization of EGFR activates its intrinsic protein kinase activity and results in autophosphorylation of 6 tyrosine residues in the cytoplasmic tail of EGFR."

Reactome:R-HSA-177935

SHP2 dephosphorylates Tyr 992 on EGFR

SHP2 dephosphorylates a RasGAP binding site on EGFR to prevent RasGAP recruitment.

"This inhibition is achieved by the dephosphorylation of a RasGAP binding site on the EGF receptor."

Reactome:R-HSA-177936

GRB2:SOS1 binds to phosphorylated SHC1 in complex with EGFR

Phosphorylated SHC1 provides binding sites for the GRB2:SOS1 complex.

"The tyrosine sites on SHC1 become possible binding sites for the GRB2:SOS1 complex."

Reactome:R-HSA-177937

Phosphorylation of EGFR by SRC kinase

SRC can tyrosine-phosphorylate EGFR in addition to EGFR autophosphorylation.

"Besides autophosphorylation, EGFR can become tyrosine-phosphorylated by the action of the proto-oncogene tyrosine-protein kinase, c-src."

Reactome:R-HSA-177938

SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:GRB2:SOS1)

SOS1 interacts with EGFR via GRB2 to activate RAS by GDP-GTP exchange.

"The guanine nucleotide exchange factor SOS1 interacts with EGFR through the adaptor protein, GRB2. Upon formation of this complex, SOS activates RAS by promoting GDP release and GTP binding."

Reactome:R-HSA-177939

PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3)

PI3K phosphorylates PIP2 to form PIP3.

"The kinase activity of PIK3 mediates the phosphorylation of PIP2 to form PIP3"

Reactome:R-HSA-177941

GRB2:GAB1 binds to phosphorylated EGFR

PIK3 regulatory subunit mediates GAB1 association with EGFR, enabling GAB1 phosphorylation.

"The regulatory subunit of PIK3 mediates the association of GAB1 and receptor protein-tyrosine kinases such as the EGF receptor, which can phosphorylate GAB1."

Reactome:R-HSA-177942

EGFR binds EGF ligand

EGF binding to EGFR transmits the signal from the extracellular to cytoplasmic domain.

"EGF binds to the extracellular domain from where the signal is transmitted to the cytoplasmic domain."

Reactome:R-HSA-177943

GRB2:SOS1 complex binds to EGF:EGFR complex

GRB2 binds activated EGFR while in complex with SOS1.

"One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain."

Reactome:R-HSA-177944

Activation of SHP2 through the binding to phospho-Gab1

SHP2 activation occurs when its SH2 domains bind phosphotyrosine proteins to relieve autoinhibition.

"Binding of these domains to phosphotyrosine-containing proteins relieves this autoinhibition, possibly by inducing a conformational change in the enzyme."

Reactome:R-HSA-177945

SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:SHC1:GRB2:SOS1)

SOS1 activates RAS by promoting nucleotide exchange from GDP to GTP.

"SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP)."

Reactome:R-HSA-182969

Phosphorylation of CBL (EGFR:CBL)

EGF stimulation leads to CBL phosphorylation on Tyr-371, enabling its ubiquitin ligase activity.

"EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity."

Reactome:R-HSA-182971

EGFR downregulation

CBL proteins poly-ubiquitinate activated EGFR, promoting degradation and downregulation.

"The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation."

Reactome:R-HSA-182986

CBL-mediated ubiquitination of CIN85

CBL monoubiquitinates CIN85 after EGF stimulation, influencing receptor internalization.

"The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation."

Reactome:R-HSA-182990

Sprouty sequesters CBL away from active EGFR

Sprouty can block CIN85-mediated CBL clustering and thereby reduce EGFR ubiquitination and downregulation.

"This allows Sprouty to block CIN85-mediated clustering of CBL molecules, stablization of CBL-EGFR interactions and efficient ubiquitination and down-regulation of EGFR."

Reactome:R-HSA-182993

Ubiquitination of stimulated EGFR (CBL)

CBL ubiquitinates activated EGFR to drive receptor internalization and degradation.

"CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation."

Reactome:R-HSA-182994

Assembly of EGFR complex in clathrin-coated vesicles

The CBL-CIN85-Endophilin complex mediates ligand-induced EGFR downregulation.

"CBL-CIN85-Endophilin complex mediates ligand-induced down-regulation of the EGF receptor."

Reactome:R-HSA-183002

Beta-Pix:CDC42:GTP binds CBL in EGF:p-6Y-EGFR:CBL:CIN85

Active CDC42 and Beta-Pix can promote Beta-Pix binding to CBL, displacing CIN85 and potentially blocking CBL clustering.

"High concentrations of active CDC42 (bound to GTP) and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 (SH3KBP1) from the CBL complex."

Reactome:R-HSA-183036

Ubiquitination of stimulated EGFR (CBL:GRB2)

CBL ubiquitinates activated EGFR, leading to receptor internalization and degradation.

"CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation."

Reactome:R-HSA-183051

CBL ubiquitinates Sprouty

EGF stimulation induces Sprouty phosphorylation and CBL-mediated ubiquitination for proteasomal degradation.

"Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL."

Reactome:R-HSA-183055

Binding of CBL to EGFR

EGFR phosphorylation at Y1069 (Y1045) creates a docking site for CBL required for lysosomal sorting.

"Phosphorylation at tyrosine Y1069 (i.e. Y1045 in the mature protein) of EGFR creates a major docking site for E3 ubiquitin-protein ligase, CBL (Casitas B-lineage lymphoma proto- oncogene) and is required to sort the EGFR to lysosomes for degradation."

Reactome:R-HSA-183058

Phosphorylation of CBL (EGFR:GRB2:CBL)

EGF stimulation leads to CBL phosphorylation on Tyr-371, enabling ubiquitin ligase activity.

"EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity."

Reactome:R-HSA-183067

Localization of CBL:GRB2 to the membrane

EGFR phosphorylation after EGF stimulation allows GRB2 binding to phosphorylated tyrosines.

"Upon EGF stimulation and consequent EGFR phosphorylation, GRB2 binds phosphorylated tyrosines"

Reactome:R-HSA-183072

EGFR non-clathrin mediated endocytosis

At high ligand levels, EGFR undergoes clathrin-independent endocytosis when Y1069 is phosphorylated and ubiquitinated.

"At higher concentrations of ligand, a substantial fraction of the receptor (>50%) is endocytosed through a clathrin independent, lipid-raft-dependent route as the receptor becomes Y1069 (i.e. Y1045 in the mature protein) phosphorylated and ubiquitnated."

Reactome:R-HSA-183084

CBL escapes CDC42-mediated inhibition by down-regulating the adaptor molecule Beta-Pix

Beta-Pix association with CBL is a critical step in CDC42-mediated inhibition of EGFR ubiquitylation and downregulation.

"Beta-Pix (Cool-1) associates with CBL, which appears to be a critical step in CDC42-mediated inhibition of EGFR ubiquitylation and downregulation."

Reactome:R-HSA-183089

CBL binds and ubiquitinates phosphorylated Sprouty

EGF stimulation promotes Sprouty phosphorylation and CBL-mediated ubiquitination for degradation.

"Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL."

Reactome:R-HSA-1963563

MATK (CSK homologous kinase) binds phosphorylated ERBB2

MATK binds ERBB2 at phosphorylated Y1253 to inhibit downstream signaling.

"MATK (also known as CHK or CSK homologous kinase) binds to ERBB2 through phosphorylated tyrosine residue Y1253 in the C-tail of ERBB2 and, through an unknown mechanism, inhibits ERBB2 downstream signaling."

Reactome:R-HSA-1963581

Trans-autophosphorylation of p-Y877-ERBB2 heterodimers

ERBB2 Y877 phosphorylation by SRC kinases increases the trans-autophosphorylation rate of ERBB2 heterodimers.

"Phosphorylation of ERBB2 on tyrosine residue Y877 by SRC family kinases significantly increases trans-autophosphorylation rate of ERBB2 heterodimers, presumably by enabling the kinase domain of ERBB2 to achieve a conformation that positively affects ERBB2 kinase activity."

Reactome:R-HSA-1963582

Trans-autophosphorylation of ERBB2 heterodimers

ERBB2 and EGF-bound EGFR heterodimers trans-autophosphorylate on multiple tyrosines to activate signaling.

"Dimers of ERBB2 and EGF-bound EGFR trans-autophosphorylate on six EGFR tyrosine residues and six ERBB2 tyrosine residues to form phosphorylated heterodimers that activate downstream signaling cascades (Ricci et al. 1995, Pinkas-Kramarski et al. 1996, Walton et al. 1990, Margolis et al. 1989, Hazan et al. 1990, Helin et al. 1991)."

Reactome:R-HSA-1963586

SRC family kinases phosphorylate ERBB2

After ERBB2 heterodimerization, SRC family kinases phosphorylate ERBB2 Y877, enhancing kinase activity.

"Dissociation of HSP90 from ERBB2 upon formation of ERBB2 heterodimers (with either EGFR, ERBB3 or ERBB4) enables phosphorylation of ERBB2 on the tyrosine residue Y877, mediated by one of SRC family kinases - SRC, FYN or YES1."

Reactome:R-HSA-1963589

ERBB2 forms heterodimers with ligand-activated ERBB receptors: EGFR, ERBB3 and ERBB4

ERBB2 is activated by heterodimerization with ligand-activated EGFR, ERBB3, or ERBB4.

"ERBB2, which does not bind any known ligand, is activated through formation of a heterodimer with another ligand-activated ERBB family member."

Reactome:R-HSA-1977959

ERBB4 forms heterodimers with EGFR

Ligand-stimulated ERBB4 forms heterodimers with ligand-stimulated EGFR that undergo trans-autophosphorylation.

"Heterodimers of ERBB4 and EGFR undergo trans-autophosphorylation, but the exact phosphorylation pattern, downstream signaling and physiological significance of these heterodimers have not been studied (Riese et al. 1995, Cohen et al. 1996)."

Reactome:R-HSA-212706

Phospholipase C-gamma1 binds to the activated EGF receptor

Inactive PLCG1 binds activated EGFR.

"Inactive phospholipase C-gamma1 (PLCG1) binds to activated epidermal growth factor receptor (EGFR)."

Reactome:R-HSA-212710

EGFR activates PLC-gamma1 by phosphorylation

EGFR phosphorylates PLCG1 to activate it.

"EGFR phosphorylates PLC-gamma1, thus activating it."

Reactome:R-HSA-212713

Active PLC-gamma1 dissociates from EGFR

Activated PLCG1 dissociates from EGFR as a release step before hydrolyzing PIP2.

"Once activated PLC-gamma1 dissociates from EGFR, it can hydrolyze PIP2."

Reactome:R-HSA-212718

EGFR interacts with phospholipase C-gamma

Activated EGFR activates PLCG1 to hydrolyze PIP2 into IP3 and DAG.

"Activated EGFR can activate phospholipase C-gamma1 (PLC-gamma1, i.e. PLCG1) which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG)."

Reactome:R-HSA-2179387

Mature HBEGF binds to EGFR, triggering dimerisation and autophosphorylation of the receptor

HBEGF binds and activates EGFR/ErbB1 and ErbB4.

"The heparin-binding EGF growth factor (HBEGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor EGFR/ErbB1 and ErbB4 (not shown here) (Higashiyama et al. 1991, Elenius et al. 1997)."

Reactome:R-HSA-2179407

SOS1-mediated nucleotide exchange of RAS (HB-EFG-initiated)

SOS1 activates RAS by promoting GDP-GTP exchange.

"SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP) (Chardin et al. 1993)."

Reactome:R-HSA-2179415

GRB2:SOS1 binds to HBEGF:p-Y-EGFR

GRB2 binds activated EGFR while in complex with SOS, at Y1068 and/or Y1086.

"One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 autophosphorylation sites on the receptor (Batzer et al. 1994, Okutani et al. 1994)."

Reactome:R-HSA-2316434

PI3K phosphorylates PIP2 to PIP3

PI3K can be activated downstream of EGFR and other RTKs.

"PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009)."

Reactome:R-HSA-2400009

PI3K inhibitors block PI3K catalytic activity

Multiple inhibitors have been developed that block the phosphoinositide kinase activity of PI3K.

"A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed."

Reactome:R-HSA-445069

L1-EGFR trans-heterodimerization

L1CAM-EGFR trans interaction induces EGFR kinase activity, but autophosphorylation requires additional cis interactions.

"L1CAM and EGFR engage in a weak heterophilic trans interaction and this induces EGFR tyrosine kinase activity and its activation. However, this trans interaction alone is not sufficient to induce EGFR autophosphorylation, which requires additional cis type interactions between the two proteins."

Reactome:R-HSA-5637764

Binding of GRB2:GAB1 complex to p-EGFRvIII mutant

GRB2:GAB1 binding to phosphorylated EGFRvIII is assumed and not directly tested.

"Direct binding of the GRB2:GAB1 complex to phosphorylated homodimers of EGFRvIII cancer mutant has not been tested."

Reactome:R-HSA-5637765

Binding of PI3K to complex of GRB2:GAB1 and p-EGFRvIII

EGFRvIII is assumed to recruit the PI3K complex similarly to wild-type EGFR.

"EGFRvIII cancer mutant is assumed to recruit the PI3K complex PIK3CA:PIK3R1 in a manner similar to wild-type EGFR (Rodrigues et al. 2000)."

Reactome:R-HSA-5637766

Binding of SHC1 to p-5Y-EGFRvIII

SHC1 binding to EGFRvIII is assumed based on its binding to phosphorylated EGFR Y1148 and Y1173.

"Binding of SHC1 to EGFRvIII cancer mutant has not been tested but SHC1 is assumed to bind EGFRvIII in the same way it binds wild-type EGFR."

Reactome:R-HSA-5637770

Binding of GRB2:SOS1 complex to phosphorylated EGFRvIII

Direct binding of GRB2:SOS1 to phosphorylated EGFRvIII has not been tested, but GRB2 binds Y1068 and Y1086.

"Direct binding of GRB2:SOS1 complex to phosphorylated homodimers of EGFRvIII cancer mutant has not been tested."

Reactome:R-HSA-5637792

PLC-gamma 1 binds to p-EGFRvIII mutant

EGFRvIII phosphorylates Y992 and is expected to recruit PLCG1 like wild-type EGFR.

"Tyrosine residue Y992 (corresponding to Y1016 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus), a docking site for PLC-gamma 1 (PLCG1), is phosphorylated in EGFRvIII cancer mutant and expected to recruit PLC-gamma 1 in the same way as the wild-type EGFR receptor (Grandal et al. 2007)."

Reactome:R-HSA-5637794

EGFRvIII does not bind CBL

EGFRvIII lacks Y1069 phosphorylation and shows little or no CBL binding.

"In EGFRvIII mutant, Y1069 (i.e. Y1045 in the mature protein) is not phosphorylated (Han et al. 2006, Grandal et al. 2007)."

Reactome:R-HSA-5637795

Phosphorylation of PLC-gamma 1 by p-EGFRvIII mutant

EGFRvIII is assumed to phosphorylate PLCG1 after recruitment, as in wild-type EGFR.

"Once recruited, PLC-gamma 1 is assumed to be phosphorylated by EGFRvIII cancer mutant in the same way it is phosphorylated by the wild-type EGFR (Meisenhelder et al. 1989, Wahl et al. 1990)."

Reactome:R-HSA-5637796

Phosphorylation of SHC1 by p-5Y-EGFRvIII

EGFRvIII phosphorylation of SHC1 is assumed based on wild-type EGFR behavior.

"EGFRvIII cancer mutant was not directly tested for its ability to phosphorylate SHC1, but is assumed to interact with SHC1 in the same way as the wild-type EGFR protein (Soler et al. 1994, VanderKuur et al. 1995)."

Reactome:R-HSA-5637798

Phosphorylated SHC1 in complex with p-5Y-EGFRvIII recruits GRB2:SOS1 complex

GRB2:SOS1 recruitment by SHC1 bound to EGFRvIII is assumed and not directly tested.

"Recruitment of GRB2:SOS1 complex by SHC1 bound to phosphorylated dimers of EGFRvIII cancer mutant has not been directly tested, but is assumed to happen in the same way it happens with the SHC1 bound to the phosphorylated homodimer of wild-type EGFR (Chardin et al. 1993)."

Reactome:R-HSA-5637800

Dissociation of phosphorylated PLC-gamma 1 from p-EGFRvIII mutant

Phosphorylated PLCG1 is expected to dissociate from EGFRvIII as a release step before downstream signaling.

"Once phosphorylated, PLC-gamma 1 is expected to dissociate from phosphorylated EGFRvIII cancer mutant and induce downstream signaling in the same way it does when activated by the wild-type EGFR."

Reactome:R-HSA-5637801

Conversion of PIP2 to PIP3 by PI3K bound to phosphorylated EGFRvIII

EGFRvIII is assumed to induce PI3K/AKT signaling via PI3K-mediated conversion of PIP2 to PIP3.

"The kinase activity of PI3K mediates the phosphorylation of PIP2 to form PIP3. It is assumed that EGFRvIII cancer mutant induces PI3K/AKT signaling in a manner similar to wild-type EGFR."

Reactome:R-HSA-5637806

SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with p-EGFRvIII)

SOS1 is assumed to activate RAS downstream of EGFRvIII via GRB2, with RAS-MAPK activation observed in EGFRvIII cells.

"Based on the wild-type EGFR signaling, it is assumed that the guanine nucleotide exchange factor SOS1 interacts with phosphorylated EGFRvIII mutant through the adaptor protein, GRB2. Upon formation of this complex, SOS1 activates RAS by promoting GDP release and GTP binding."

Reactome:R-HSA-5637808

SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with phosphorylated SHC1 and p-EGFRvIII)

SOS1 recruited by GRB2 bound to p-SHC1:p-EGFRvIII is assumed to activate RAS.

"SOS1, recruited by GRB2 bound to p-SHC1:p-EGFRvIII mutant, is assumed to activate RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP)."

Reactome:R-HSA-5638137

EGFRvIII cancer variant does not bind EGF ligand

EGFRvIII lacks the ligand-binding domain and cannot bind EGFR ligands.

"EGFRvIII mutant lacks the ligand binding domain and is therefore unable to bind EGFR ligands (Fernandes et al. 2001)."

Reactome:R-HSA-5672965

RAS GEFs promote RAS nucleotide exchange

RAS GEFs promote GDP-GTP exchange on membrane-associated RAS in response to signaling.

"The human genome is predicted to encode 27 RAS guanine nucleotide exchange factors (GEFs) that promote the exchange of GDP for GTP on membrane-associated RAS in response to RAS-MAPK pathway activation by growth factors, hormones, cytokines and other stimuli (reviewed in Cherfils and Zeghouf, 2013; Cargnello and Roux, 2011)."

Reactome:R-HSA-6785636

Phosphorylated ERBB2 heterodimers bind MEMO1

ERBB2 phosphorylated at Y1222 binds MEMO1.

"ERBB2 phosphorylated on tyrosine residue Y1222 binds MEMO1 (mediator of ERBB2-driven cell motility) (Marone et al. 2004, Qiu et al. 2008, Zaoui et al. 2010, Feracci et al. 2011)."

Reactome:R-HSA-6785648

MEMO1 binds RHOA:GTP:DIAPH1

MEMO1 associated with phosphorylated ERBB2 heterodimers binds the RHOA:GTP:DIAPH1 complex.

"MEMO1, in complex with phosphorylated ERBB2 heterodimers, associates with the complex of activated RHOA and formin family member DIAPH1."

Reactome:R-HSA-8847995

Activated ERBB2 binds PTK6 (BRK)

PTK6 (BRK) binds activated ERBB2.

"PTK6 (BRK) is a nonreceptor tyrosine kinase that can bind activated ERBB2 receptor (Xiang et al. 2008)."

Reactome:R-HSA-8848005

ERBB2 promotes PTK6 autophosphorylation

PTK6 binding to activated ERBB2 stimulates PTK6 Y342 autophosphorylation, increasing catalytic activity.

"Binding of PTK6 (BRK) to activated ERBB2 receptor stimulates autophosphorylation of PTK6 on tyrosine residue Y342 (Xiang et al. 2008, Peng et al. 2015). Autophosphorylation at Y342 significantly increases catalytic activity of PTK6 (Qiu and Miller 2002)."

Reactome:R-HSA-8857549

HBEGF-bound EGFR forms a heterodimer with GPNMB

HBEGF-bound EGFR forms heterodimers with GPNMB via interaction of the GPNMB intracellular domain with the EGFR kinase domain.

"EGFR bound to HBEGF (HB-EGF) can form heterodimers with the transmembrane glycoprotein GPNBM. The intracellular domain of GPNMB interacts with the kinase domain of EGFR (Lin et al. 2016)."

Reactome:R-HSA-8857555

EGFR phosphorylates GPNMB

HBEGF-bound EGFR phosphorylates GPNMB at Y525.

"HBEGF-bound EGFR phosphorylates its heterodimerization partner GPNMB at tyrosine residue Y525 (Lin et al. 2016)."

Reactome:R-HSA-8857565

Phosphorylated GPNMB recruits PTK6 and LRRK2 in the presence of LINC01139

GPNMB phosphorylation at Y525 recruits PTK6 and LRRK2 in the presence of LINC01139.

"Phosphorylation of GPNBM at tyrosine residue Y525 upon heterodimerization with HBEGF-bound EGFR promotes, in the presence of long non-coding RNA LINC011139 (LINK-A), the recruitment of PTK6 (BRK). In addition to PTK6, LINC01139 simultaneously recruits serine/threonine kinase LRRK2 to phosphorylated GPNBM (Lin et al. 2016)."

Reactome:R-HSA-8857577

LINC01139 facilitates PTK6 autophosphorylation

LINC01139 induces a PTK6 conformational change that facilitates PTK6 autophosphorylation on Y351.

"The long non-coding RNA LINC01139 (LINK-A) induces conformational change of PTK6 (BRK), which facilitates PTK6 autophosphorylation on tyrosine residue Y351 and possibly other sites (Lin et al. 2016)."

Reactome:R-HSA-8857583

LINC01139 promotes phosphorylation of HIF1A by PTK6

PTK6 activated via LINC01139-mediated recruitment phosphorylates HIF1A at Y565.

"PTK6 (BRK) tyrosine kinase, activated via long non-coding RNA LINC01139 (LINK-A) mediated recruitment to phosphorylated GPNMB (bound to HBEGF-activated EGFR), phosphorylates hypoxia inducible factor 1 alpha (HIF1A) at tyrosine residue Y565."

Reactome:R-HSA-8863804

PTPN12 dephosphorylates ERBB2 on tyrosine Y1248

PTPN12 dephosphorylates ERBB2 Y1248, attenuating downstream RAS activation.

"PTPN12 protein tyrosine phosphatase dephosphorylates activated ERBB2 at tyrosine residue Y1248 and activated EGFR at tyrosine residue Y1148 (Y1148 corresponds to Y1172 of the nascent EGFR, with 24 amino acid signal peptide at the N-terminus). PTPN12-mediated dephosphorylation of ERBB2 attenuates downstream RAS activation, as Y1248 is involved in SHC1 recruitment."

Reactome:R-HSA-8864029

PTPN12 dephosphorylates EGFR at Y1172 (Y1148)

PTPN12 dephosphorylates EGFR Y1148 (Y1172), inhibiting SHC1 recruitment and downstream RAS activation.

"PTPN12-mediated dephosphorylation of activated EGFR inhibits SHC1 recruitment to the p-Y1148 (i.e. p-Y1172) docking site, thus attenuating downstream RAS activation (Sun et al. 2011)."

Reactome:R-HSA-8864105

PTPN18 binds ERBB2:EGFR heterodimers

PTPN18 binds ERBB2 activated in response to EGF stimulation.

"PTPN18 protein tyrosine phosphatase (BDP1) binds ERBB2, activated in response to EGF stimulation, via PEST and catalytic domains of PTPN18 (Wang et al. 2014)."

Reactome:R-HSA-8864125

PTPN18 dephosphorylates ERBB2 at Y1196, Y1112 and Y1248

PTPN18 dephosphorylates ERBB2 Y1196, Y1112, and Y1248, attenuating PI3K/AKT and RAS signaling.

"Dephosphorylation of ERBB2 tyrosines Y1196 and Y1248 attenuates downstream activation of PI3K/AKT and RAS signaling."

Reactome:R-HSA-8866279

Epsin family proteins bind ubiquitinated cargo

EGFR undergoes ubiquitination at the plasma membrane, triggering endocytosis.

"A number of receptor tyrosine kinases, including EGFR, VEGFR, FGFR and others undergo ubiquitination at the plasma membrane, triggering endocytosis."

Reactome:R-HSA-8867041

EGFR phosphorylates EPS15

Activated EGFR phosphorylates EPS15 at Y849, influencing endocytic routing.

"EPS15 is phosphorylated at Y849 by activated EGFR (Confalonieri et al, 2000)."

Reactome:R-HSA-8867044

EGFR binds EPS15, EPN1, EPS15L1

EPS15, EPN1, and EPS15L1 are required for endocytosis of ligand-activated EGFR.

"EH-containing proteins such as EPS15, EPN1 and EPS15L1 are required for the endocytosis of ligand-activated EGFR (Confalonieri et al, 2000; Huang et al, 2004; reviewed in van Bergen en Henegouwen, 2009)."

Reactome:R-HSA-8867047

PTPN3 dephosphorylates EPS15

PTPN3 dephosphorylates EPS15, promoting EGFR internalization into caveolin-enriched structures.

"Overexpression of the phosphatase PTPN3, which dephosphorylates EPS15 in vitro and in vivo, promotes the internalization of EGFR into caveolin-enriched structures and targets it for lysosomal degradation (Li et al, 2015)."

Reactome:R-HSA-8867754

F- and N- BAR domain proteins bind the clathrin-coated pit

F-BAR domain proteins such as FCHo1 and FCHo2 are recruited early to clathrin-coated pit formation by recognizing shallow membrane curvature.

"F-BAR domain proteins such as FCHo 1 and 2 recognize shallow membrane curvature and are generally recruited early in the formation of clathrin-coated pit (Itoh et al, 2005; Kamioka et al, 2004; Henne et al, 2007; Shimada et al, 2007; Henne et al, 2010)."

Reactome:R-HSA-8867756

CLASP proteins and cargo are recruited to the nascent clathrin-coated pit

CLASP proteins are recruited to nascent clathrin-coated pits via interactions with AP-2 and clathrin, bringing cargo into the pit.

"CLASP proteins are recruited to nascent clathrin-coated pits (CCPs) through interactions with AP-2 and clathrin."

Reactome:R-HSA-8868071

Clathrin recruits PIK3C2A

PIK3C2A binds clathrin and localizes to late-stage clathrin-coated pits, where clathrin binding stimulates its kinase activity.

"PIK3C2A interacts with clathrin through a clathrin-binding domain in its unique N-terminal tail and localizes to late-stage clathrin-coated pits (Domin et al, 2000; Gaidarov et al, 2001; Gaidarov et al, 2005). Binding to clathrin stimulates the kinase activity of PIK3C2A and promotes the production of PI(3,4)P2 at the plasma membrane (Gaidarov et al, 2001)."

Reactome:R-HSA-8868072

Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2

Clathrin-associated PIK3C2A converts PI(4)P to PI(3,4)P2, promoting recruitment of BAR domain proteins such as SNX9.

"Clathrin-associated PIK3C2A catalyzes the conversion of PI(4)P to PI(3,4)P2, which contributes to the recruitment of BAR domain proteins such as SNX9 to the clathrin-coated pit (Domin et al, 2000; Gaidarov et al, 2001; Gaidarov et al, 2005; Posor et al, 2013; reviewed in Daumke et al, 2014)."

Reactome:R-HSA-8868230

SNX9 recruits components of the actin polymerizing machinery

Actin is recruited late to clathrin-coated pits via ARP2/3 and N-BAR proteins such as SNX9 when required for vesicle formation.

"In cases where actin is required, it appears to be recruited late to the emerging clathrin-coated pit, just prior to or coincident with the recruitment of dynamin and vesicle scission (Taylor et al, 2011; Taylor et al, 2012; reviewed in McMahon and Boucrot, 2011)."

Reactome:R-HSA-8868236

BAR domain proteins recruit dynamin

Dynamin self-assembly stimulates its GTPase activity to drive vesicle scission from the plasma membrane.

"dynamin self assembles into helical oligomers, stimulating its GTPase activity"

Reactome:R-HSA-8868648

SYNJ hydrolyze PI(4,5)P2 to PI(4)P

SYNJ/OCRL hydrolyze PI(4,5)P2 to PI(4)P, aiding scission and clathrin uncoating during endocytosis.

"Inositol-5-phosphatases like SYNJs and OCRL hydrolyze PI(4,5)P2 to PI(4)P. In the context of CME, this promotes the abortive turnover (disassembly) of some CCPs, contributes to the dynamin-mediated scission of the clathrin-coated vesicle neck, and promotes clathrin uncoating following scission (Guan et al, 2010; Cremona et al, 1999; Mani et al, 2007; Chang-Ileto et al, 2011; Antonescu et al, 2011; reviewed in McMahon and Boucrot, 2011; Daumke et al, 2014)."

Reactome:R-HSA-8868651

Endophilins recruit synaptojanins to the clathrin-coated pit

Synaptojanins are recruited to clathrin-coated pits through interactions with endophilins and other endocytic proteins.

"SYNJ proteins are recruited to the clathrin-coated pit through interactions with a number of endocytic proteins including ITSNs, EPS15, PACSIN proteins and endophilins, as well as with clathrin and AP-2 (Haffner et al, 1997; Cestra et al, 1999; Maire et al, 2004; Schuske et al, 2003; Verstreken et al, 2003; Modregger et al, 2000; Perera et al 2006; Milosevic et al, 2011; reviewed in Dittman and Ryan, 2009)."

Reactome:R-HSA-8868658

HSPA8-mediated ATP hydrolysis promotes vesicle uncoating

HSPA8 ATP hydrolysis promotes dissociation of the clathrin coat from vesicles.

"HSPA8 hydrolyzes ATP to promote dissociation of the clathrin coat from the vesicle (reviewed in Sousa and Lafer, 2015)."

Reactome:R-HSA-8868659

Clathrin recruits auxilins to the clathrin-coated vesicle

Auxilin proteins DNAJC6 and GAK are recruited to clathrin-coated vesicles via clathrin and PI4P.

"After fission from the plasma membrane, auxilin proteins DNAJC6 and GAK are recruited to the vesicle through interaction with clathrin and phosphoinositides, in particular PI4P (Greener et al, 2000; Lee et al, 2006; Massol et al, 2006; Taylor et al, 2011; Scheele et al, 2001; Fotin et al, 2004a; Fotin et al, 2004b; Guan et al, 2010; reviewed in McMahon and Boucrot, 2011; Sousa and Lafer, 2015)."

Reactome:R-HSA-8868660

Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle

Auxilin recruits HSPA8 (HSC70) to clathrin-coated vesicles for uncoating.

"HSPA8 (also known as HSC70) is recruited to the clathrin-coated vesicle through interaction with DNA J proteins GAK and DNAJC6 (Rapoport et al, 2008; Xing et al, 2010; reviewed in Sousa and Lafer, 2015)."

Reactome:R-HSA-8868661

Dynamin-mediated GTP hydrolysis promotes vesicle scission

Dynamin GTP hydrolysis promotes membrane fission of clathrin-coated vesicles.

"Self-assembly of dynamin around the neck of the emerging clathrin-coated vesicle stimulates its GTPase activity. This in turn promotes a conformational change in dynamin organization that is required for membrane fission (Hinshaw and Schmid, 1995; Sweitzer and Hinshaw, 1998; Takei et al, 1999; Yoshida et al, 2004; Chappie et al, 2010; Chappie et al, 2011; Ford et al, 2011; Faelber et al, 2011; reviewed in Daumke et al, 2014)."

Reactome:R-HSA-8869438

Dissociation of clathrin-associated proteins

After clathrin coat removal, associated proteins dissociate in a poorly understood step.

"After the removal of the clathrin coat, it is likely that many of the proteins that contributed to vesicle formation are lost, although the timing and mechanism of this step are poorly understood (reviewed in McMahon and Boucrot, 2011; Lemmon, 2001)."

Reactome:R-HSA-8871193

Dissociation of AAK1 and dephosphorylation of AP-2 mu2

GAPVD1 binding to AP-2 mu2 displaces AAK1 and promotes dephosphorylation of AP-2 mu2, destabilizing AP-2 membrane interactions.

"GAPVD1 binds the alpha adaptin ear domain of AP-2 mu2, activating its RAB5-directed GEF activity and displacing AAK1. AAK1 displacement results in a net dephosphorylation of the AP-2 mu2 subunit, destabilizing the interaction of AP-2 with the vesicle membrane (Sato et al, 2005; Smerdjieva et al, 2008)."

Reactome:R-HSA-8871194

RAB5 and GAPVD1 bind AP-2

RAB5 and GAPVD1 may promote AP-2 uncoating by displacing AAK1 and dephosphorylating AP-2 mu2.

"RAB5 and its associated GEF GAPVD1 may contribute to AP-2 uncoating by displacing AAK1 and promoting the net dephosphorylation of the AP-2 mu2 subunit."

Reactome:R-HSA-8874797

EGFR gene expression is stimulated by TFAP2C

TFAP2C homodimers bind the EGFR promoter and stimulate EGFR transcription.

"Binding of TFAP2C homodimers to the EGFR gene promoter region stimulates EGFR transcription and may play an important role in the etiology of luminal breast cancer (Park et al. 2015, de Andrade et al. 2016)."

Reactome:R-HSA-8951490

CIN85 dissociates from EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP:CIN85

Active CDC42 and Beta-Pix promote displacement of CIN85 from the CBL complex, a release step that can block CBL clustering.

"High concentrations of active CDC42 (bound to GTP) and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 (SH3KBP1) from the CBL complex."

Reactome:R-HSA-9018572

EGFR phosphorylates NOTCH3

EGFR phosphorylates the NOTCH3 intracellular domain and inhibits NOTCH3-mediated transcription.

"EGFR phosphorylates intracellular domain of NOTCH3 (NICD3) on an unknown tyrosine residue. EGFR signaling inhibits NICD3-mediated transcription."

Reactome:R-HSA-9018573

NOTCH3 binds activated EGFR

NOTCH3 intracellular domain binds activated EGFR, and this binding is inhibited by erlotinib.

"The intracellular domain of NOTCH3 (NICD3) co-immunoprecipitates with ligand activated, autophosphorylated EGFR. Binding of NOTCH3 to EGFR is inhibited by erlotinib treatment, which prevents EGFR activation (Arasada et al. 2014)."

Reactome:R-HSA-9609689

HCMV Binds to the Host Cell via heparan sulfate proteoglycans (HSPG)

HCMV entry occurs by fusion or endocytosis, with a pentameric complex facilitating entry into endothelial and epithelial cells.

"Viral attachment and penetration of Human Cytomegalovirus (HCMV) occurs either via direct HCMV fusion with the cell membrane or via endocytosis. The endocytic mechanism occurs with cell types including endothelial and epithelial cells, where the pentameric viral protein complex, gH:gL:p128:p130:p131A, facilitates entry."

Reactome:R-HSA-9610867

HCMV Binds Host Cell Receptor - Endocytic Pathway

HCMV can enter via endocytosis in endothelial and epithelial cells using the pentameric gH:gL:p128:p130:p131A complex.

"Viral attachment and penetration of Human Cytomegalovirus (HCMV) occurs either via direct HCMV fusion with the cell membrane or via endocytosis. The endocytic mechanism occurs with cell types including endothelial and epithelial cells, where the pentameric viral protein complex, gH:gL:p128:p130:p131A, facilitates entry."

Reactome:R-HSA-9611147

Endocytic Uptake of HCMV Virion

HCMV enters epithelial and endothelial cells via endocytic uptake and is released by low-pH-dependent fusion with endosomal membranes.

"Once the pentameric viral protein complex, gH:gL:p128:p130:p131A, facilitates attchment of the Human Cytomegalovirus (HCMV) endocytic uptake allows the virion to enter epithelial and endothelial cells. The virion is released from the endocytic vesicle by low-pH-dependent fusion of the virion coat with endosomes membrane."

Reactome:R-HSA-9611158

Fusion of HCMV Envelope with Plasma Membrane

HCMV fuses with the cell membrane after initial attachment to heparan sulfate proteoglycans.

"Once Human cytomegalovirus (HCMV) initial attachs to cell surface heparan sulfate proteoglycans (HSPGs), the virus fuses with thecell membrane."

Reactome:R-HSA-9625482

PTK2 binds activated EGFR

PTK2 (FAK) binds activated EGFR.

"PTK2 (also known as FAK, focal adhesion kinase) binds to the activated EGFR receptor as assessed by affinity chromatography and co-immunoprecipitation (Sieg et al, 2000; Thelemann et al, 2005; Liu et al, 2010)."

Reactome:R-HSA-9625487

PTK2 autophosphorylates downstream of EGFR

EGFR-dependent signaling enhances FAK autophosphorylation at Y397.

"Stimulation of cells with either E2 (beta-estradiol), tamoxifen or G1 (a GPER1 agonist) enhances EGFR-dependent FAK autophosphorylation at Y397 (Sieg et al, 2000; Liu et al, 2010; Tsai et al, 2013)."

Reactome:R-HSA-9634702

LINC01139 promotes phosphorylation of HIF1A by LRRK2

LRRK2 recruited via LINC01139 to phosphorylated GPNMB phosphorylates HIF1A at S797.

"LRRK2 serine/threonine kinase, activated via long non-coding RNA LINC01139 (LINK-A) mediated recruitment to phosphorylated GPNMB (bound to HBEGF-activated EGFR), phosphorylates hypoxia inducible factor 1 alpha (HIF1A) at serine residue S797."

Reactome:R-HSA-9664567

ERBB2 KD mutants heterodimerize

Multiple ERBB2 kinase domain mutants are reported to form heterodimers with EGFR.

"The following ERBB2 KD mutants were directly or indirectly shown to form heterodimers with EGFR:"

Reactome:R-HSA-9664588

ERBB2 KD mutants trans-autophosphorylate

ERBB2 kinase domain mutants undergo trans-autophosphorylation in the presence of EGFR.

"The following ERBB2 KD mutants were shown to undergo trans-autophosphorylation in the presence of EGFR:"

Reactome:R-HSA-9664918

Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind GRB2:GAB1

Phosphorylated ERBB2 KD mutant:EGFR heterodimers are assumed to bind GRB2:GAB1, like wild-type ERBB2:EGFR.

"Phosphorylated heterodimers of the following ERBB2 KD mutants with EGFR are assumed to, like the wild type ERBB2:EGFR heterodimer, bind to the GRB2:GAB1 complex:"

Reactome:R-HSA-9664933

Phosphorylated heterodimers of ERBB2 KD mutants and EGFR, in complex with GRB2:GAB1, bind PI3K

For EGFR-binding ERBB2 KD mutants, GRB2:GAB1 binding is assumed to recruit PI3K.

"For the following EGFR-binding ERBB2 KD mutants that activate PI3K/AKT signaling, it is assumed that, like the wild type ERBB2:EGFR heterodimer, binding to the GRB2:GAB1 adaptor complex leads to recruitment of the PI3K complex:"

Reactome:R-HSA-9664940

PI3K bound to phosphorylated heterodimers of ERBB2 KD mutants and EGFR converts PIP2 to PIP3

EGFR-binding ERBB2 KD mutant heterodimers are assumed to drive PI3K-mediated conversion of PIP2 to PIP3.

"For the following EGFR-binding ERBB2 KD mutants that were shown to activate PI3K/AKT signaling, it is assumed that heterodimers of these mutants with EGFR, like the wild type ERBB2:EGFR heterodimer, bind to the PI3K complex through GRB2:GAB1, leading to conversion of PIP2 to PIP3:"

Reactome:R-HSA-9664950

Phosphorylated heterodimers of ERBB2 KD mutants bind SHC1

Based on RAS/RAF/MAPK activation, phosphorylated ERBB2 KD mutant heterodimers are assumed to bind SHC1.

"Based on downstream activation of RAS/RAF/MAPK cascade, it is assumed that phosphorylated heterodimers of the following ERBB2 KD mutants, like phosphorylated heterodimers of the wild type ERBB2, bind to SHC1:"

Reactome:R-HSA-9664976

Phosphorylated heterodimers of ERBB2 KD mutants phosphorylate SHC1

ERBB2 KD mutant heterodimers that activate RAS/RAF/MAPK are assumed to bind and phosphorylate SHC1.

"For the following ERBB2 KD mutants that were shown to activate RAS/RAF/MAPK signaling, it is assumed that they, like phosphorylated heterodimers of the wild type ERBB2, bind to SHC1 and phosphorylate it:"

Reactome:R-HSA-9664983

Phosphorylated heterodimers of ERBB2 KD mutants recruit GRB2:SOS1 through SHC1

ERBB2 KD mutant heterodimers are assumed to recruit GRB2:SOS1 via SHC1 after SHC1 phosphorylation.

"For the following ERBB2 KD mutants that were shown to activate RAS/RAF/MAPK signaling, it is assumed that they, like phosphorylated heterodimers of the wild type ERBB2, bind to and phosphorylate SHC1, leading to recruitment of the GRB2:SOS1 complex:"

Reactome:R-HSA-9664991

RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 KD mutants

ERBB2 KD mutant heterodimers are assumed to recruit GRB2:SOS1 and activate RAS via nucleotide exchange.

"For the following ERBB2 KD mutants that were shown to activate RAS/RAF/MAPK signaling, it is assumed that they, like phosphorylated heterodimers of the wild type ERBB2, bind to and phosphorylate SHC1, leading to recruitment of the GRB2:SOS1 complex and activating guanyl-nucleotide exchange on RAS:"

Reactome:R-HSA-9665000

Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind GRB2:SOS1

EGFR-binding ERBB2 KD mutant heterodimers are assumed to directly bind GRB2:SOS1.

"The following EGFR-binding ERBB2 KD mutants that were shown to activate RAS/RAF/MAPK signaling, evidenced by activating phosphorylation of ERKs (MAPK1 and MAPK3), are assumed to, like the wild type ERBB2:EGFR heterodimer, directly bind to the GRB2:SOS1 complex:"

Reactome:R-HSA-9665009

RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 KD mutants and EGFR

EGFR-binding ERBB2 KD mutant heterodimers are assumed to recruit GRB2:SOS1 and activate RAS via nucleotide exchange.

"The following EGFR-binding ERBB2 KD mutants that were shown to activate RAS/RAF/MAPK signaling, evidenced by activating phosphorylation of ERKs (MAPK1 and MAPK3), are assumed to, like the wild type ERBB2:EGFR heterodimer, directly bind to the GRB2:SOS1 complex, leading to activating guanyl nucleotide exchange on RAS:"

Reactome:R-HSA-9665032

Phosphorylated heterodimers of ERBB2 KD mutants and EGFR phosphorylate PLCG1

EGFR-binding ERBB2 KD mutants that activate PLCG1 are assumed to recruit and phosphorylate PLCG1.

"It is assumed that the following EGFR-binding ERBB2 mutants that were shown to activate PLCG1 (PLCgamma-1) signaling, evidenced by activating phosphorylation of PLCG1, recruit and phosphorylate PLCG1:"

Reactome:R-HSA-9665034

Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind PLCG1

Phosphorylated ERBB2 KD mutant:EGFR heterodimers are assumed to bind PLCG1, similar to wild-type ERBB2:EGFR.

"It is assumed that, like the wild type ERBB2:EGFR heterodimer, phosphorylated heterodimers of these ERBB2 KD mutants and EGFR recruit PLCG1."

Reactome:R-HSA-9665388

ERBB2 ECD mutants heterodimerize with EGFR

ERBB2 ECD mutants G309A, G309E, and S310F preferentially heterodimerize with EGFR.

"The functionally studied ERBB2 ECD mutants, ERBB2 G309A (Bose et al. 2013), ERBB2 G309E (Greulich et al. 2012) and ERBB2 S310F (Greulich et al. 2012) seem to preferntially heterodimerize with EGFR."

Reactome:R-HSA-9665389

Heterodimers of ERBB2 ECD mutants and EGFR trans-autophosphorylate

ERBB2 ECD mutant heterodimers trans-autophosphorylate, with S310F showing stronger C-tail phosphorylation than G309A or G309E.

"ERBB2 S310F shows stronger activation of downstream signaling than ERBB2 G309A and ERBB2 G309E, and is hyperphosphorylated on tyrosine residues in the C-tail (Greulich et al. 2012), while the C-tail phosphorylation of ERBB2 G309A (Bose et al. 2013) and ERBB2 G309E (Greulich et al. 2012) is comparable to the wild type ERBB2."

Reactome:R-HSA-9665404

RAS guanyl nucleotide exchange mediated by the p-6Y- ERBB2 ECD mutants:EGF:p-6Y-EGFR:p-SHC1:GRB2:SOS1

ERBB2 ECD mutant heterodimers are assumed to recruit GRB2:SOS1 via SHC1, activating RAS signaling.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like phosphorylated heterodimers of the wild type ERBB2, can recruit the GRB2:SOS1 complex through phosphorylated SHC1, leading to guanyl nucleotide exchange on RAS and activation of RAS signaling."

Reactome:R-HSA-9665406

Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR phosphorylate SHC1

ERBB2 ECD mutant heterodimers are assumed to bind and phosphorylate SHC1.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like phosphorylated heterodimers of the wild type ERBB2, can bind to and phosphorylate SHC1."

Reactome:R-HSA-9665407

PI3K bound to phosphorylated heterodimers of ERBB2 ECD mutants and EGFR converts PIP2 to PIP3

ERBB2 ECD mutant heterodimers are assumed to recruit PI3K via GRB2:GAB1, leading to PIP2 to PIP3 conversion.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and EGFR, can bind to the GRB2:GAB1 complex, leading to recruitment of the PI3K complex, which results in conversion of PIP2 to PIP3 and activation of the AKT signaling."

Reactome:R-HSA-9665408

RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 ECD mutants and EGFR through GRB2

ERBB2 ECD mutant heterodimers are assumed to recruit GRB2:SOS1 directly to activate RAS.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like phosphorylated heterodimers of the wild type ERBB2, can directly recruit the GRB2:SOS1 complex, leading to guanyl nucleotide exchange on RAS and activation of RAS signaling."

Reactome:R-HSA-9665409

GRB2:SOS1 binds to phosphorylated heterodimers of ERBB2 ECD mutants and EGFR

ERBB2 ECD mutant heterodimers are assumed to recruit GRB2:SOS1.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like phosphorylated heterodimers of the wild type ERBB2, can directly recruit the GRB2:SOS1 complex."

Reactome:R-HSA-9665410

Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR bind PLCG1

ERBB2 ECD mutant heterodimers are assumed to bind PLCG1.

"It is assumed that heterodimers of ERBB2 ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and EGFR, bind to PLCG1."

Reactome:R-HSA-9665411

Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR phosphorylate PLCG1

ERBB2 ECD mutant heterodimers are assumed to bind and phosphorylate PLCG1, activating PLCG1 signaling.

"It is assumed that heterodimers of ERBB2 ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and EGFR, bind to and phosphorylated PLCG1, leading to activation of PLCG1 signaling."

Reactome:R-HSA-9665413

Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR recruit GRB2:SOS1 through SHC1

ERBB2 ECD mutant heterodimers are assumed to recruit GRB2:SOS1 via SHC1.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like phosphorylated heterodimers of the wild type ERBB2, can recruit the GRB2:SOS1 complex through phosphorylated SHC1."

Reactome:R-HSA-9665415

Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, in complex with GRB2:GAB1, bind PI3K

ERBB2 ECD mutant heterodimers are assumed to bind GRB2:GAB1 and recruit PI3K.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and EGFR, can bind to the GRB2:GAB1 complex, leading to the recruitment of the PI3K complex."

Reactome:R-HSA-9665416

Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR bind SHC1

ERBB2 ECD mutant heterodimers are assumed to bind SHC1.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like phosphorylated heterodimers of the wild type ERBB2, bind to SHC1."

Reactome:R-HSA-9665417

Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR bind GRB2:GAB1

ERBB2 ECD mutant heterodimers are assumed to bind GRB2:GAB1.

"It is assumed that phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and EGFR, can bind to the GRB2:GAB1 complex."

Reactome:R-HSA-9665697

ERBB2 TMD/JMD mutants hetrodimerize

ERBB2 TMD/JMD mutants such as S653C and R678Q are assumed to form heterodimers with EGFR and ERBB3.

"Based on trans-autophosphorylation of ERBB2 and its dimerization partners EGFR and ERBB3, the following ERBB2 TMD/JMD mutants are assumed to form heterodimers with EGFR and ERBB3:"

Reactome:R-HSA-9665698

Phosphorylated heterodimers of ERBB2 TMD/JMD mutants and EGFR bind GRB2:SOS1

ERBB2 TMD/JMD mutant heterodimers with EGFR are assumed to directly bind GRB2:SOS1.

"It is assumed that heterodimers of ERBB2 TMD/JMD mutants and EGFR, like the wild type ERBB2:EGFR heterodimers, directly bind to GRB:SOS1 complex."

Reactome:R-HSA-9665699

Phosphorylated heterodimers of ERBB2 TMD/JMD mutants recruit GRB2:SOS1 through SHC1

ERBB2 TMD/JMD mutant heterodimers are assumed to bind and phosphorylate SHC1, recruiting GRB2:SOS1.

"It is assumed that heterodimers of ERBB2 TMD/JMD mutants, like the wild type ERBB2 heterodimers, bind to and phosphorylate SHC1, leading to the recruitment of the GRB2:SOS1 complex."

Reactome:R-HSA-9665700

RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 TMD/JMD mutants

ERBB2 TMD/JMD mutant heterodimers are assumed to recruit GRB2:SOS1 and activate RAS via nucleotide exchange.

"It is assumed that heterodimers of ERBB2 TMD/JMD mutants, like the wild type ERBB2 heterodimers, bind to and phosphorylate SHC1, leading to the recruitment of the GRB2:SOS1 complex and activation of RAS through guanyl nucleotide exchange."

Reactome:R-HSA-9665701

Phosphorylated ERBB2 TMD/JMD heterodimers bind SHC1

ERBB2 TMD/JMD mutant heterodimers are assumed to bind SHC1.

"It is assumed that heterodimers of ERBB2 TMD/JMD mutants, like the wild type ERBB2 heterodimers, bind SHC1."

Reactome:R-HSA-9665704

Phosphorylated heterodimers of ERBB2 TMD/JMD mutants and EGFR phosphorylate PLCG1

ERBB2 R678Q:EGFR heterodimers are assumed to bind and phosphorylate PLCG1, activating PLCG1 signaling.

"It is assumed that the heterodimer of ERBB2 R678Q and EGFR, like the wild type ERBB2:EGFR heterodimer, binds to and phosphorylates PLCG1, leading to activation of PLCgamma1 signaling."

Reactome:R-HSA-9665705

Phosphorylated heterodimers of ERBB2 TMD/JMD mutants phosphorylate SHC1

ERBB2 TMD/JMD mutant heterodimers are assumed to bind and phosphorylate SHC1.

"It is assumed that heterodimers of ERBB2 TMD/JMD mutants, like the wild type ERBB2 heterodimers, bind to and phosphorylate SHC1."

Reactome:R-HSA-9665706

Phosphorylated heterodimers of ERBB2 TMD/JMD mutants and EGFR bind PLCG1

ERBB2 R678Q:EGFR heterodimers are assumed to bind PLCG1.

"It is assumed that the heterodimer of ERBB2 R678Q and EGFR, like the wild type ERBB2:EGFR heterodimer, binds PLCG1."

Reactome:R-HSA-9665707

RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 TMD/JMD mutants and EGFR

ERBB2 TMD/JMD mutant heterodimers with EGFR are assumed to directly bind GRB2:SOS1 and activate RAS.

"It is assumed that heterodimers of ERBB2 TMD/JMD mutants and EGFR, like the wild type ERBB2:EGFR heterodimers, directly bind to GRB:SOS1 complex, resulting in activation of RAS signaling to guanyl nucleotide exchange on RAS."

Reactome:R-HSA-9665709

ERBB2 TMD/JMD heterodimers trans-autophosphorylate

ERBB2 TMD/JMD mutants show C-tail tyrosine phosphorylation and can phosphorylate EGFR/ERBB3 C-tail residues in heterodimers.

"Phosphorylation of tyrosine residues in the C-tail of ERBB2 was shown for the following ERBB2 TMD/JMD mutants:"

Reactome:R-HSA-9674531

AAMP binds EGFR

AAMP binds the intracellular domain of EGFR and promotes EGFR dimerization, trans-autophosphorylation, and downstream ERK activation.

"AAMP (Angio-associated migratory cell protein) binds to EGFR. The interaction involves the intracellular domain of EGFR. AAMP binding, through an unknown mechanism, promotes EGFR dimerization, trans-autophosphorylation and downstream signaling, leading to activation of ERKs (MAPK1 and MAPK3) and expression of cyclin D1 (CCND1)."

Reactome:R-HSA-9851407

FAM83B, (FAM83A, FAM83D) bind EGFR

FAM83B binds EGFR via K230 and stimulates basal and EGF-induced EGFR trans-autophosphorylation before dissociating.

"Both recombinant and endogenous EGFR and FAM83B form a complex. The lysine residue K230 of FAM83B, conserved in other FAM83 family members, including FAM83A and FAM83D, is needed for binding to EGFR and stimulation of EGFR signaling. Through a mechanism that has not been elucidated, FAM83B stimulates basal and EGF-induced EGFR trans-autophosphorylation but dissociates from autophosphorylated EGFR (Cipriano et al. 2014)."

Reactome:R-NUL-1248744

Shc1 binds phosphorylated ERBB2:EGFR heterodimers

Shc1 binds phosphorylated ERBB2:EGFR heterodimers.

"Shc1 binds phosphorylated ERBB2:EGFR heterodimers in engineered mouse 32D cells (Pinkas-Kramarski et al. 1996)."

Reactome:R-NUL-1251923

Plcg1 binds P-ERBB2:P-EGFR

Mouse PLCgamma1 is phosphorylated by human recombinant ERBB2 expressed in mouse fibroblasts.

"Mouse phospholipase C gamma 1 is phosphorylated by human recombinant ERBB2 exogenously expressed in mouse fibroblasts."

Reactome:R-NUL-1251929

Plcg1 phosphorylation by P-ERBB2:P-EGFR

Mouse PLCgamma1 is phosphorylated by human recombinant ERBB2 expressed in mouse fibroblasts.

"Mouse phospholipase C gamma 1 is phosphorylated by human recombinant ERBB2 exogenously expressed in mouse fibroblasts."

file:human/EGFR/EGFR-deep-research-falcon.md

Deep research report on EGFR

📚 Additional Documentation

Deep Research Bioreason

(EGFR-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 03:06 AM

Organism: Homo sapiens

Sequence:

MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAPQSSEFIGA

Thinking Trace

I begin by dissecting the InterPro architecture and its order along the polypeptide. The N-terminal half is dominated by extracellular receptor modules: IPR036941 (Receptor L-domain superfamily, residues 25–530) and IPR000494 (Receptor L-domain, residues 57–480) define tandem L-domains that scaffold ligand-induced receptor dimerization. Embedded within this extracellular region is IPR006211 (Furin-like cysteine-rich domain, residues 185–338) and its tandem IPR006212 (Furin-like repeat, residues 228–601), together with IPR009030 (Growth factor receptor cysteine-rich domain superfamily, residues 186–636) and IPR032778 (Growth factor receptor domain 4, residues 505–637). This ensemble forms the classic growth factor receptor ectodomain that confers high-affinity ligand binding and drives receptor clustering. Immediately following, IPR049328 (Epidermal growth factor receptor-like transmembrane-juxtamembrane segment, residues 646–681) positions a single-pass helix and a regulatory juxtamembrane region that control activation by stabilizing the active conformation and mediating membrane-proximal interactions.

The cytosolic region is a canonical tyrosine kinase engine: IPR011009 (Protein kinase-like domain superfamily, residues 708–1003) houses IPR000719 (Protein kinase domain, residues 712–979), refined by IPR020635 (Tyrosine-protein kinase, catalytic domain, residues 712–968) and IPR001245 (Serine-threonine/tyrosine-protein kinase, catalytic domain, residues 714–966). The core catalytic signatures are pinpointed by IPR017441 (Protein kinase, ATP binding site, residues 718–745) and IPR008266 (Tyrosine-protein kinase, active site, residues 833–845). Two broad family envelopes—IPR050122 (Receptor Tyrosine Kinase family, residues 58–974) and IPR016245 (Tyrosine protein kinase, EGF/ERB/XmrK receptor family, residues 6–1204)—span the full receptor-kinase architecture, confirming a single-pass type I receptor tyrosine kinase whose extracellular L- and cysteine-rich modules trigger intracellular tyrosine phosphorylation.

This ordered layout causally dictates molecular function. The extracellular L-domain and cysteine-rich repeats cause ligand-dependent dimerization; the transmembrane-juxtamembrane segment couples this to the cytosolic kinase core; and the conserved ATP-binding and catalytic motifs enable phosphotransfer. Together, these features produce transmembrane receptor protein tyrosine kinase activity (EC 2.7.10.1), with ATP binding and an activated tyrosine kinase active site driving substrate phosphorylation.

From molecular function, the biological process follows: receptor tyrosine kinases initiate intracellular signaling cascades that regulate cell proliferation, survival, and differentiation. The modular ectodomain that enforces dimerization and the kinase that amplifies signals through phosphotyrosine sites define a signaling axis that advances signal transduction and growth control. Thus, the architecture drives signal transduction culminating in cell proliferation and growth-factor–responsive programs.

The cellular component is determined by the single-pass topology and the EGFR-like transmembrane-juxtamembrane segment: the protein is a membrane-embedded receptor with an extracellular N-terminus and cytosolic kinase domain, consistent with a single-pass type I membrane protein. This dictates localization as an integral component of membranes and functionally positions it at the cell surface.

Mechanistically, the ectodomain binds extracellular cues to enforce receptor dimerization, which aligns the cytosolic kinase domains for trans-autophosphorylation. Phosphotyrosine motifs then recruit SH2/PTB-containing adaptors to propagate signaling. I hypothesize interactions with extracellular matrix or growth-factor–like ligands that stabilize ectodomain clustering, and with intracellular adaptors and effectors that read phosphotyrosine signals. Likely partners include SH2-domain adaptors and scaffolds that dock to activated receptor tails, as well as membrane-proximal regulators that tune kinase activity and downstream pathway flux.

Functional Summary

A single-pass cell-surface receptor that uses an extracellular ligand-binding scaffold and a cytosolic tyrosine kinase engine to transmit extracellular cues into intracellular signaling. The ectodomain forms a cysteine-rich, L-domain architecture that drives dimerization, which allosterically activates the intracellular kinase. This activation enables ATP-dependent phosphorylation of tyrosines and assembly of downstream signaling complexes that promote growth and proliferation. The receptor resides in the membrane as a type I single-pass protein and signals through phosphorylation-dependent recruitment of adaptor and effector proteins.

UniProt Summary

Contains an extracellular domain and a cytoplasmic kinase domain.

InterPro Domains

Tyrosine protein kinase, EGF/ERB/XmrK receptor (IPR016245, family) — residues 6-1204
Receptor L-domain superfamily (IPR036941, homologous_superfamily) — residues 25-530
Receptor L-domain (IPR000494, domain) — residues 57-480
Receptor Tyrosine Kinase (IPR050122, family) — residues 58-974
Furin-like cysteine-rich domain (IPR006211, domain) — residues 185-338
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 186-636
Furin-like repeat (IPR006212, repeat) — residues 228-601
Growth factor receptor domain 4 (IPR032778, domain) — residues 505-637
Epidermal growth factor receptor-like, transmembrane-juxtamembrane segment (IPR049328, domain) — residues 646-681
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 708-1003
Protein kinase domain (IPR000719, domain) — residues 712-979
Tyrosine-protein kinase, catalytic domain (IPR020635, domain) — residues 712-968
Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245, domain) — residues 714-966
Protein kinase, ATP binding site (IPR017441, binding_site) — residues 718-745
Tyrosine-protein kinase, active site (IPR008266, active_site) — residues 833-845

GO Terms

Molecular Function: molecular_function (GO:0003674), catalytic activity (GO:0003824), molecular transducer activity (GO:0060089), molecular function regulator activity (GO:0098772), binding (GO:0005488), enzyme regulator activity (GO:0030234), molecular function activator activity (GO:0140677), transferase activity (GO:0016740), protein-containing complex binding (GO:0044877), chromatin binding (GO:0003682), signaling receptor activity (GO:0038023), catalytic activity, acting on a protein (GO:0140096), protein binding (GO:0005515), actin filament binding (GO:0051015), protein kinase activity (GO:0004672), identical protein binding (GO:0042802), cell adhesion molecule binding (GO:0050839), enzyme activator activity (GO:0008047), cytoskeletal protein binding (GO:0008092), transmembrane signaling receptor activity (GO:0004888), transferase activity, transferring phosphorus-containing groups (GO:0016772), enzyme binding (GO:0019899), kinase regulator activity (GO:0019207), ubiquitin-like protein ligase binding (GO:0044389), kinase activity (GO:0016301), kinase activator activity (GO:0019209), kinase binding (GO:0019900), phosphotransferase activity, alcohol group as acceptor (GO:0016773), phosphatase binding (GO:0019902), actin binding (GO:0003779), protein kinase regulator activity (GO:0019887), cadherin binding (GO:0045296), transmembrane receptor protein kinase activity (GO:0019199), protein tyrosine kinase activity (GO:0004713), ubiquitin protein ligase binding (GO:0031625), transmembrane receptor protein tyrosine kinase activity (GO:0004714), protein kinase activator activity (GO:0030295), protein phosphatase binding (GO:0019903), protein tyrosine kinase activator activity (GO:0030296)

Biological Process: biological_process (GO:0008150), localization (GO:0051179), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), metabolic process (GO:0008152), negative regulation of biological process (GO:0048519), cellular localization (GO:0051641), negative regulation of signaling (GO:0023057), response to chemical (GO:0042221), nitrogen compound metabolic process (GO:0006807), cellular component organization or biogenesis (GO:0071840), negative regulation of multicellular organismal process (GO:0051241), regulation of multicellular organismal process (GO:0051239), positive regulation of growth (GO:0045927), negative regulation of metabolic process (GO:0009892), regulation of developmental process (GO:0050793), positive regulation of locomotion (GO:0040017), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), regulation of signaling (GO:0023051), negative regulation of developmental process (GO:0051093), negative regulation of cellular process (GO:0048523), signal transduction (GO:0007165), regulation of locomotion (GO:0040012), response to abiotic stimulus (GO:0009628), positive regulation of signaling (GO:0023056), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), cell adhesion (GO:0007155), regulation of localization (GO:0032879), establishment of localization (GO:0051234), organic substance metabolic process (GO:0071704), macromolecule localization (GO:0033036), cellular metabolic process (GO:0044237), positive regulation of metabolic process (GO:0009893), regulation of molecular function (GO:0065009), primary metabolic process (GO:0044238), response to stress (GO:0006950), negative regulation of response to stimulus (GO:0048585), cell communication (GO:0007154), regulation of growth (GO:0040008), positive regulation of cellular process (GO:0048522), negative regulation of signal transduction (GO:0009968), positive regulation of cell cycle process (GO:0090068), regulation of cell motility (GO:2000145), negative regulation of cell death (GO:0060548), response to radiation (GO:0009314), regulation of response to stress (GO:0080134), regulation of signal transduction (GO:0009966), regulation of macromolecule metabolic process (GO:0060255), localization within membrane (GO:0051668), negative regulation of cardiocyte differentiation (GO:1905208), establishment of protein localization (GO:0045184), positive regulation of cell cycle (GO:0045787), phosphorus metabolic process (GO:0006793), regulation of catabolic process (GO:0009894), regulation of cell cycle (GO:0051726), response to inorganic substance (GO:0010035), negative regulation of macromolecule metabolic process (GO:0010605), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cell differentiation (GO:0045595), cell surface receptor signaling pathway (GO:0007166), cellular component organization (GO:0016043), regulation of cellular component organization (GO:0051128), regulation of cell cycle process (GO:0010564), positive regulation of cell population proliferation (GO:0008284), positive regulation of nitrogen compound metabolic process (GO:0051173), positive regulation of signal transduction (GO:0009967), regulation of catalytic activity (GO:0050790), negative regulation of nitrogen compound metabolic process (GO:0051172), negative regulation of cell communication (GO:0010648), positive regulation of molecular function (GO:0044093), positive regulation of protein localization (GO:1903829), organonitrogen compound metabolic process (GO:1901564), positive regulation of macromolecule metabolic process (GO:0010604), cell-cell adhesion (GO:0098609), response to oxidative stress (GO:0006979), regulation of cellular localization (GO:0060341), protein metabolic process (GO:0019538), regulation of cell growth (GO:0001558), regulation of cellular response to stress (GO:0080135), response to oxygen-containing compound (GO:1901700), positive regulation of cell growth (GO:0030307), macromolecule metabolic process (GO:0043170), response to organic substance (GO:0010033), positive regulation of cell motility (GO:2000147), positive regulation of biosynthetic process (GO:0009891), positive regulation of response to DNA damage stimulus (GO:2001022), regulation of cell population proliferation (GO:0042127), regulation of cell death (GO:0010941), positive regulation of cellular metabolic process (GO:0031325), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), negative regulation of cell differentiation (GO:0045596), regulation of biosynthetic process (GO:0009889), cellular macromolecule localization (GO:0070727), regulation of cellular metabolic process (GO:0031323), positive regulation of cell communication (GO:0010647), negative regulation of catabolic process (GO:0009895), regulation of primary metabolic process (GO:0080090), cellular response to oxidative stress (GO:0034599), regulation of oxidoreductase activity (GO:0051341), regulation of mitotic cell cycle (GO:0007346), regulation of macromolecule biosynthetic process (GO:0010556), response to estradiol (GO:0032355), regulation of protein metabolic process (GO:0051246), negative regulation of programmed cell death (GO:0043069), regulation of programmed cell death (GO:0043067), regulation of stress-activated protein kinase signaling cascade (GO:0070302), regulation of cell migration (GO:0030334), regulation of epithelial cell proliferation (GO:0050678), regulation of gene expression (GO:0010468), macromolecule modification (GO:0043412), regulation of ERBB signaling pathway (GO:1901184), positive regulation of cell migration (GO:0030335), positive regulation of intracellular signal transduction (GO:1902533), regulation of RNA metabolic process (GO:0051252), positive regulation of catalytic activity (GO:0043085), cellular response to oxygen-containing compound (GO:1901701), membrane organization (GO:0061024), response to metal ion (GO:0010038), negative regulation of ERBB signaling pathway (GO:1901185), response to light stimulus (GO:0009416), negative regulation of protein catabolic process (GO:0042177), positive regulation of phosphorus metabolic process (GO:0010562), positive regulation of protein localization to cell periphery (GO:1904377), enzyme-linked receptor protein signaling pathway (GO:0007167), positive regulation of cell cycle phase transition (GO:1901989), regulation of protein catabolic process (GO:0042176), regulation of DNA metabolic process (GO:0051052), cellular response to organic substance (GO:0071310), positive regulation of DNA metabolic process (GO:0051054), regulation of hydrolase activity (GO:0051336), cellular response to chemical stress (GO:0062197), negative regulation of protein metabolic process (GO:0051248), phosphate-containing compound metabolic process (GO:0006796), regulation of Wnt signaling pathway (GO:0030111), regulation of protein localization (GO:0032880), positive regulation of mitotic cell cycle (GO:0045931), positive regulation of Wnt signaling pathway (GO:0030177), positive regulation of protein localization to membrane (GO:1905477), positive regulation of DNA repair (GO:0045739), establishment of protein localization to membrane (GO:0090150), regulation of response to DNA damage stimulus (GO:2001020), positive regulation of epithelial cell proliferation (GO:0050679), protein modification process (GO:0036211), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), protein localization to membrane (GO:0072657), cellular response to inorganic substance (GO:0071241), regulation of cyclin-dependent protein kinase activity (GO:1904029), response to lipid (GO:0033993), positive regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0045737), regulation of cell cycle phase transition (GO:1901987), regulation of cellular biosynthetic process (GO:0031326), positive regulation of protein metabolic process (GO:0051247), regulation of nucleobase-containing compound metabolic process (GO:0019219), protein localization (GO:0008104), response to organic cyclic compound (GO:0014070), regulation of transferase activity (GO:0051338), regulation of cardiocyte differentiation (GO:1905207), response to reactive oxygen species (GO:0000302), positive regulation of cellular biosynthetic process (GO:0031328), regulation of phosphorus metabolic process (GO:0051174), regulation of intracellular signal transduction (GO:1902531), regulation of phosphatidylinositol 3-kinase signaling (GO:0014066), regulation of apoptotic process (GO:0042981), regulation of protein localization to membrane (GO:1905475), positive regulation of phosphate metabolic process (GO:0045937), regulation of RNA biosynthetic process (GO:2001141), positive regulation of protein kinase B signaling (GO:0051897), positive regulation of cell cycle G1/S phase transition (GO:1902808), peptidyl-amino acid modification (GO:0018193), positive regulation of cyclin-dependent protein kinase activity (GO:1904031), phosphorylation (GO:0016310), regulation of kinase activity (GO:0043549), positive regulation of mitotic cell cycle phase transition (GO:1901992), positive regulation of miRNA metabolic process (GO:2000630), regulation of lipase activity (GO:0060191), regulation of protein kinase B signaling (GO:0051896), regulation of DNA replication (GO:0006275), response to UV (GO:0009411), transmembrane receptor protein tyrosine kinase signaling pathway (GO:0007169), response to cadmium ion (GO:0046686), positive regulation of RNA biosynthetic process (GO:1902680), positive regulation of MAPK cascade (GO:0043410), protein insertion into membrane (GO:0051205), positive regulation of hydrolase activity (GO:0051345), cellular response to reactive oxygen species (GO:0034614), regulation of canonical Wnt signaling pathway (GO:0060828), positive regulation of protein modification process (GO:0031401), regulation of stress-activated MAPK cascade (GO:0032872), regulation of epidermal growth factor receptor signaling pathway (GO:0042058), regulation of MAPK cascade (GO:0043408), regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), regulation of nitric oxide mediated signal transduction (GO:0010749), positive regulation of transferase activity (GO:0051347), regulation of protein modification process (GO:0031399), regulation of DNA repair (GO:0006282), regulation of NIK/NF-kappaB signaling (GO:1901222), cellular response to estradiol stimulus (GO:0071392), negative regulation of apoptotic process (GO:0043066), positive regulation of DNA replication (GO:0045740), protein phosphorylation (GO:0006468), regulation of DNA-templated transcription (GO:0006355), cellular response to organic cyclic compound (GO:0071407), regulation of phosphate metabolic process (GO:0019220), cellular response to lipid (GO:0071396), positive regulation of NIK/NF-kappaB signaling (GO:1901224), cellular response to metal ion (GO:0071248), regulation of mitotic cell cycle phase transition (GO:1901990), regulation of miRNA metabolic process (GO:2000628), regulation of monooxygenase activity (GO:0032768), regulation of cell cycle G1/S phase transition (GO:1902806), regulation of protein localization to cell periphery (GO:1904375), positive regulation of protein localization to plasma membrane (GO:1903078), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), positive regulation of canonical Wnt signaling pathway (GO:0090263), regulation of protein phosphorylation (GO:0001932), response to UV-A (GO:0070141), positive regulation of ERK1 and ERK2 cascade (GO:0070374), regulation of protein localization to plasma membrane (GO:1903076), regulation of phospholipase activity (GO:0010517), ERBB signaling pathway (GO:0038127), regulation of protein kinase activity (GO:0045859), positive regulation of nucleic acid-templated transcription (GO:1903508), positive regulation of phosphorylation (GO:0042327), regulation of nucleic acid-templated transcription (GO:1903506), positive regulation of MAP kinase activity (GO:0043406), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), positive regulation of protein phosphorylation (GO:0001934), regulation of miRNA transcription (GO:1902893), positive regulation of lipase activity (GO:0060193), regulation of ERK1 and ERK2 cascade (GO:0070372), peptidyl-tyrosine modification (GO:0018212), regulation of phosphorylation (GO:0042325), regulation of transcription by RNA polymerase II (GO:0006357), regulation of JNK cascade (GO:0046328), peptidyl-tyrosine phosphorylation (GO:0018108), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of kinase activity (GO:0033674), cellular response to cadmium ion (GO:0071276), positive regulation of miRNA transcription (GO:1902895), regulation of nitric-oxide synthase activity (GO:0050999), regulation of G1/S transition of mitotic cell cycle (GO:2000045), protein autophosphorylation (GO:0046777), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of protein serine/threonine kinase activity (GO:0071900), positive regulation of peptidyl-serine phosphorylation (GO:0033138), regulation of peptidyl-tyrosine phosphorylation (GO:0050730), peptidyl-tyrosine autophosphorylation (GO:0038083), epidermal growth factor receptor signaling pathway (GO:0007173), positive regulation of phospholipase activity (GO:0010518), regulation of phospholipase C activity (GO:1900274), regulation of peptidyl-serine phosphorylation (GO:0033135), ERBB2 signaling pathway (GO:0038128), positive regulation of protein kinase activity (GO:0045860), regulation of MAP kinase activity (GO:0043405), positive regulation of protein serine/threonine kinase activity (GO:0071902), positive regulation of phospholipase C activity (GO:0010863), activation of phospholipase C activity (GO:0007202)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), basal part of cell (GO:0045178), cell projection (GO:0042995), membrane (GO:0016020), membrane-enclosed lumen (GO:0031974), cell surface (GO:0009986), perinuclear region of cytoplasm (GO:0048471), cell periphery (GO:0071944), cell junction (GO:0030054), cell leading edge (GO:0031252), leading edge membrane (GO:0031256), receptor complex (GO:0043235), cytoplasm (GO:0005737), endomembrane system (GO:0012505), organelle membrane (GO:0031090), plasma membrane bounded cell projection (GO:0120025), cytoplasmic vesicle (GO:0031410), intracellular organelle (GO:0043229), endosome (GO:0005768), ruffle (GO:0001726), basal plasma membrane (GO:0009925), plasma membrane region (GO:0098590), organelle lumen (GO:0043233), membrane microdomain (GO:0098857), ruffle membrane (GO:0032587), anchoring junction (GO:0070161), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), cell-substrate junction (GO:0030055), membrane raft (GO:0045121), endocytic vesicle (GO:0030139), cell projection membrane (GO:0031253), vesicle lumen (GO:0031983), intracellular membrane-bounded organelle (GO:0043231), bounding membrane of organelle (GO:0098588), vesicle membrane (GO:0012506), late endosome (GO:0005770), early endosome (GO:0005769), coated vesicle (GO:0030135), endosome membrane (GO:0010008), basolateral plasma membrane (GO:0016323), vesicle (GO:0031982), intracellular organelle lumen (GO:0070013), cytoplasmic vesicle membrane (GO:0030659), multivesicular body (GO:0005771), focal adhesion (GO:0005925), endocytic vesicle membrane (GO:0030666), intracellular vesicle (GO:0097708), nucleus (GO:0005634), early endosome membrane (GO:0031901), clathrin-coated vesicle (GO:0030136), coated vesicle membrane (GO:0030662), clathrin-coated endocytic vesicle (GO:0045334), clathrin-coated endocytic vesicle membrane (GO:0030669), clathrin-coated vesicle membrane (GO:0030665)

Generated by BioReason

Deep Research Bioreason Rl

(EGFR-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 03:06 AM

Organism: Homo sapiens

Sequence:

MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAPQSSEFIGA

Thinking Trace

Functional Summary

UniProt Summary

Contains an extracellular domain and a cytoplasmic kinase domain.

InterPro Domains

Tyrosine protein kinase, EGF/ERB/XmrK receptor (IPR016245, family) — residues 6-1204
Receptor L-domain superfamily (IPR036941, homologous_superfamily) — residues 25-530
Receptor L-domain (IPR000494, domain) — residues 57-480
Receptor Tyrosine Kinase (IPR050122, family) — residues 58-974
Furin-like cysteine-rich domain (IPR006211, domain) — residues 185-338
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 186-636
Furin-like repeat (IPR006212, repeat) — residues 228-601
Growth factor receptor domain 4 (IPR032778, domain) — residues 505-637
Epidermal growth factor receptor-like, transmembrane-juxtamembrane segment (IPR049328, domain) — residues 646-681
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 708-1003
Protein kinase domain (IPR000719, domain) — residues 712-979
Tyrosine-protein kinase, catalytic domain (IPR020635, domain) — residues 712-968
Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245, domain) — residues 714-966
Protein kinase, ATP binding site (IPR017441, binding_site) — residues 718-745
Tyrosine-protein kinase, active site (IPR008266, active_site) — residues 833-845

GO Terms

Generated by BioReason

Deep Research Falcon

(EGFR-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-26T20:18:27.607596'
end_time: '2025-12-26T20:28:17.728371'
duration_seconds: 590.12
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: EGFR
gene_symbol: EGFR
uniprot_accession: P00533
protein_description: 'RecName: Full=Epidermal growth factor receptor {ECO:0000305};
EC=2.7.10.1; AltName: Full=Proto-oncogene c-ErbB-1; AltName: Full=Receptor tyrosine-protein
kinase erbB-1; Flags: Precursor;'
gene_info: Name=EGFR {ECO:0000312|HGNC:HGNC:3236}; Synonyms=ERBB, ERBB1, HER1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the protein kinase superfamily. Tyr protein
protein_domains: Furin-like_Cys-rich_dom. (IPR006211); Furin_repeat. (IPR006212);
GF_recep_IV. (IPR032778); Growth_fac_rcpt_cys_sf. (IPR009030); Kinase-like_dom_sf.
(IPR011009)
provider_config:
timeout: 600
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parameters:
allowed_domains: []
temperature: 0.1
citation_count: 27

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P00533
Protein Description: RecName: Full=Epidermal growth factor receptor {ECO:0000305}; EC=2.7.10.1; AltName: Full=Proto-oncogene c-ErbB-1; AltName: Full=Receptor tyrosine-protein kinase erbB-1; Flags: Precursor;
Gene Information: Name=EGFR {ECO:0000312|HGNC:HGNC:3236}; Synonyms=ERBB, ERBB1, HER1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the protein kinase superfamily. Tyr protein
Key Domains: Furin-like_Cys-rich_dom. (IPR006211); Furin_repeat. (IPR006212); GF_recep_IV. (IPR032778); Growth_fac_rcpt_cys_sf. (IPR009030); Kinase-like_dom_sf. (IPR011009)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "EGFR" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'EGFR' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene EGFR (gene ID: EGFR, UniProt: P00533) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P00533
Protein Description: RecName: Full=Epidermal growth factor receptor {ECO:0000305}; EC=2.7.10.1; AltName: Full=Proto-oncogene c-ErbB-1; AltName: Full=Receptor tyrosine-protein kinase erbB-1; Flags: Precursor;
Gene Information: Name=EGFR {ECO:0000312|HGNC:HGNC:3236}; Synonyms=ERBB, ERBB1, HER1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the protein kinase superfamily. Tyr protein
Key Domains: Furin-like_Cys-rich_dom. (IPR006211); Furin_repeat. (IPR006212); GF_recep_IV. (IPR032778); Growth_fac_rcpt_cys_sf. (IPR009030); Kinase-like_dom_sf. (IPR011009)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "EGFR" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene EGFR (gene ID: EGFR, UniProt: P00533) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: Human EGFR (ERBB1/HER1; UniProt P00533)

Plan status and verification
- Identity verified. The target is human epidermal growth factor receptor, also known as ERBB1/HER1, UniProt P00533, a member of the ERBB receptor tyrosine kinase family with an ectodomain comprising subdomains I–IV (with the domain II dimerization arm), a single transmembrane helix, a juxtamembrane segment, a cytoplasmic tyrosine kinase domain (EC 2.7.10.1), and a C‑terminal tail harboring tyrosine autophosphorylation sites (ERBB family and domain architecture consistent across sources) (kozlova2024celladhesionmolecules pages 4-6, schultz2023egfrtraffickingeffect pages 9-10, comez2024dynamicsofligand pages 41-46).

Key concepts and definitions
- Protein class and enzymatic activity. EGFR is a receptor tyrosine kinase (RTK) that catalyzes ATP‑dependent phosphorylation of tyrosine residues on itself and substrates following activation (EC 2.7.10.1) (tydings2024analysisofegfr pages 22-23, kozlova2024celladhesionmolecules pages 4-6, nadendla2025tyrosinekinasesstructural pages 29-31).
- Canonical ligands. Multiple EGF‑like ligands bind EGFR, including EGF, TGF‑α, HB‑EGF, betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN) (kozlova2024celladhesionmolecules pages 4-6, comez2024dynamicsofligand pages 41-46, trenker2024structuraldynamicsof pages 25-26).
- Activation and dimerization mechanism. In the resting state, intramolecular contacts (including a tether between domains II and IV) keep the dimerization arm concealed; ligand binding to domains I and III rotates/extends the ectodomain, exposes the domain II dimerization arm, and promotes receptor dimerization. Catalytic activation proceeds via formation of an intracellular asymmetric kinase dimer in which the C‑lobe of one kinase allosterically activates the N‑lobe of the other, leading to autophosphorylation on the C‑terminal tail (kozlova2024celladhesionmolecules pages 4-6, schultz2023egfrtraffickingeffect pages 9-10, trenker2024structuraldynamicsof pages 25-26). Ligand‑independent assemblies and oligomers can also form—especially with oncogenic mutations or overexpression—contributing to signaling outside the canonical ligand‑triggered model (schultz2023egfrtraffickingeffect pages 2-3).
- Downstream pathways. Key signaling axes include RAS–RAF–MEK–ERK (MAPK), PI3K–AKT–mTOR, and JAK–STAT, often engaged via SH2/PTB‑containing adaptors such as GRB2; pathway outputs depend on ligand and dimerization context (tydings2024analysisofegfr pages 22-23, nadendla2025tyrosinekinasesstructural pages 29-31, comez2024dynamicsofligand pages 41-46).
- Cellular localization and trafficking. EGFR resides at the plasma membrane and continues to signal from early endosomes after internalization. Endocytosis occurs via clathrin‑mediated and clathrin‑independent routes: at lower ligand concentrations, clathrin‑mediated uptake often favors recycling; at high ligand or with increased ubiquitination, receptors are sorted for lysosomal degradation. Nuclear EGFR has been reported in specific contexts and may have transcriptional roles; small molecules can block nuclear translocation in preclinical settings, though clinical utility remains unproven (schultz2023egfrtraffickingeffect pages 9-10, schultz2023egfrtraffickingeffect pages 2-3, kozlova2024celladhesionmolecules pages 4-6).

Aspect	Key details	Representative recent sources (with year)
Identity / synonyms / organism	EGFR (ERBB, ERBB1, HER1); human (Homo sapiens); UniProt P00533	(tydings2024analysisofegfr pages 22-23, comez2024dynamicsofligand pages 41-46, nadendla2025tyrosinekinasesstructural pages 29-31)
Protein family and EC	Receptor tyrosine kinase (ErbB family); EC 2.7.10.1 (tyrosine-protein kinase)	(tydings2024analysisofegfr pages 22-23, nadendla2025tyrosinekinasesstructural pages 29-31, kozlova2024celladhesionmolecules pages 4-6)
Domain architecture (ECD I–IV, TM, JM, KD, tail) & dimerization arm	ECD domains I–IV (cys-rich II & IV) with domain-II dimerization arm; single-pass TM helix; juxtamembrane (JM) region; intracellular kinase domain (KD) and C-terminal tail with phosphorylation sites	(kozlova2024celladhesionmolecules pages 4-6, schultz2023egfrtraffickingeffect pages 9-10, comez2024dynamicsofligand pages 41-46)
Canonical ligands	EGF; TGF-α; HB-EGF; betacellulin (BTC); amphiregulin (AREG); epiregulin (EREG); epigen (EPGN)	(kozlova2024celladhesionmolecules pages 4-6, comez2024dynamicsofligand pages 41-46, trenker2024structuraldynamicsof pages 25-26)
Activation mechanism	Ligand binding → ECD rotation/exposure of dimer arm → ECD dimerization; asymmetric kinase-domain (allosteric) dimer activates catalytic site; ligand-independent/mutant-driven oligomers also occur	(tydings2024analysisofegfr pages 22-23, schultz2023egfrtraffickingeffect pages 9-10, trenker2024structuraldynamicsof pages 25-26)
Major downstream pathways	RAS–RAF–MAPK (ERK); PI3K–AKT–mTOR; JAK–STAT and adaptor-mediated cascades (e.g., GRB2)	(tydings2024analysisofegfr pages 22-23, nadendla2025tyrosinekinasesstructural pages 29-31, comez2024dynamicsofligand pages 41-46)
Cellular localization	Primarily plasma membrane; signaling continues from early endosomes; trafficked to lysosomes for degradation; nuclear translocation reported in specific contexts	(schultz2023egfrtraffickingeffect pages 9-10, kozlova2024celladhesionmolecules pages 4-6, comez2024dynamicsofligand pages 41-46)
Endocytosis / trafficking routes	Clathrin-mediated endocytosis (low ligand → recycling); clathrin-independent/ubiquitin-dependent uptake (high ligand → lysosomal degradation); trafficking modulates signal duration and resistance	(schultz2023egfrtraffickingeffect pages 9-10, schultz2023egfrtraffickingeffect pages 2-3)
Nuclear EGFR mention	Nuclear EGFR (nEGFR) documented; linked to transcriptional roles and clinical implications; inhibitors of nuclear translocation are experimental	(schultz2023egfrtraffickingeffect pages 2-3, schultz2023egfrtraffickingeffect pages 9-10)
Heterodimerization within ERBB family	Forms heterodimers with HER2/ERBB2, HER3/ERBB3, HER4/ERBB4; heterodimers (e.g., EGFR/HER2) alter signaling strength, membrane dynamics, and endocytosis	(tydings2024analysisofegfr pages 22-23, trenker2024structuraldynamicsof pages 25-26)

Table: Concise reference table summarizing human EGFR identity, domains, ligands, activation, key pathways, localization, and trafficking with representative 2023–2024 sources for quick verification.

Recent structural and mechanistic developments (2023–2024)
- EGFR inhibitory biologics and binding hotspots. A 2024 analysis integrates structural interfaces of EGFR ligands and inhibitory biologics, highlighting the ectodomain binding surfaces and their relationship to activation and resistance; it synthesizes earlier crystallography and nanobody/antibody complexes to guide rational biologic design (Protein Science, 2024; https://doi.org/10.1002/pro.5141) (tydings2024analysisofegfr pages 22-23).
- ERBB family structural dynamics and glycosylation. Recent cryo‑EM work in the ERBB family (HER4 and HER2/HER4) emphasizes that ligand identity and glycosylation tune dimer dynamics and stability, and underscores the loose linkage between ligand binding and kinase activation previously observed for EGFR; these principles generalize to EGFR and heterodimers (eLife, 2024; https://doi.org/10.7554/elife.92873) (trenker2024structuraldynamicsof pages 25-26).
- Trafficking–activation coupling. Contemporary reviews detail how dimerization state, mutation, and endocytic routing (clathrin‑dependent vs independent) modulate signaling duration and TKI responses, and note preclinical strategies that combine TKIs with trafficking modulators (Frontiers in Oncology, 2023; https://doi.org/10.3389/fonc.2023.1258371) (schultz2023egfrtraffickingeffect pages 9-10, schultz2023egfrtraffickingeffect pages 2-3).
- Mechanistic summary of ectodomain–kinase linkage. Updated reviews summarize how ligand binding exposes the dimerization arm and how asymmetric kinase dimers effect catalysis, consolidating structural and biophysical evidence across the last two decades into current models (Cells, 2024; https://doi.org/10.3390/cells13221919) (kozlova2024celladhesionmolecules pages 4-6).

Current applications and real‑world implementations in oncology (with 2023–2024 data)
- First‑line EGFR‑mutated NSCLC: amivantamab+lazertinib vs osimertinib (MARIPOSA). In the phase 3 MARIPOSA trial (NEJM, 2024; published October 24, 2024), amivantamab plus lazertinib significantly prolonged median PFS versus osimertinib (23.7 vs 16.6 months; HR 0.70, 95% CI 0.58–0.85), with similar ORR (86% vs 85%) and longer median duration of response (25.8 vs 16.8 months); interim OS HR 0.80 (95% CI 0.61–1.05) (https://www.nejm.org/doi/full/10.1056/NEJMoa2403614) (cho2024amivantamabpluslazertinib pages 1-4).
- First‑line EGFR‑mutated NSCLC: osimertinib+chemotherapy (FLAURA‑2). Contemporary reviews summarizing FLAURA‑2 report that adding platinum–pemetrexed to first‑line osimertinib significantly improved PFS versus osimertinib alone (e.g., 29.4 vs 19.9 months; HR ~0.62), with increased grade ≥3 toxicities; this regimen received U.S. FDA approval in February 2024 (Lung Cancer: Targets and Therapy, 2024; https://doi.org/10.2147/LCTT.S467169) (arter2024spotlightonpatritumab pages 2-4).
- Post‑TKI sequencing and HER3‑DXd. Expert commentary in 2024 positions patritumab deruxtecan (HER3‑DXd) as active after osimertinib, with median PFS ~5.5 months in a heavily pretreated cohort (HERTHENA‑Lung01), supporting its role in later‑line sequencing while first‑line combination strategies (osimertinib+chemo or amivantamab+lazertinib) aim to extend the pre‑resistance interval (https://doi.org/10.2147/LCTT.S467169) (arter2024spotlightonpatritumab pages 4-5, arter2024spotlightonpatritumab pages 2-4).
- Clinical context of ctDNA and prognostic stratification. A narrative review highlights that in FLAURA‑2, baseline detectable plasma EGFR mutations (ctDNA) were prognostic and associated with greater benefits from osimertinib+chemotherapy, while on‑treatment EGFRmut clearance was prognostic but not specifically predictive of differential benefit; similar ctDNA‑based PFS analyses were reported in MARIPOSA exploratory work, supporting clinical integration of ctDNA for risk stratification (Current Oncology, 2025; https://doi.org/10.3390/curroncol32080448) (roy2025recentadvancesin pages 25-29).

Expert opinions and guidance (authoritative perspectives)
- Practice‑shaping trials. NEJM MARIPOSA defines amivantamab+lazertinib as a first‑line option with superior PFS to osimertinib monotherapy in EGFR Ex19del/L858R NSCLC (NEJM, 2024; https://www.nejm.org/doi/full/10.1056/NEJMoa2403614) (cho2024amivantamabpluslazertinib pages 1-4).
- Combinations vs monotherapy. Contemporary expert overviews emphasize that first‑line combination strategies (osimertinib+chemotherapy, amivantamab+lazertinib) prolong pre‑resistance duration relative to osimertinib alone but carry higher treatment‑related toxicity, necessitating individualized risk–benefit assessment (https://doi.org/10.2147/LCTT.S467169) (arter2024spotlightonpatritumab pages 2-4, arter2024spotlightonpatritumab pages 4-5).
- ctDNA in management. Recent analyses underscore the utility of ctDNA for prognostication and treatment monitoring in EGFR‑mutated NSCLC clinical trials, aligning with the trend toward guideline‑endorsed liquid biopsy as a complement to tissue testing (https://doi.org/10.3390/curroncol32080448) (roy2025recentadvancesin pages 25-29).

Relevant statistics and epidemiology
- Mutation prevalence and spectrum. In advanced non‑squamous NSCLC, activating EGFR mutations occur in approximately 15–50% of cases globally, with exon 19 deletions and L858R substitutions accounting for ~85–90% of EGFR‑mutant tumors; MARIPOSA enrolled Ex19del/L858R and stratified by ancestry, reflecting higher prevalence in East Asian populations (NEJM, 2024; https://www.nejm.org/doi/full/10.1056/NEJMoa2403614) (cho2024amivantamabpluslazertinib pages 1-4). Reviews also emphasize geographic variation in EGFR mutation frequency, with higher rates in East Asia than in Western cohorts, influencing trial demographics and practice patterns (Lung Cancer: Targets and Therapy, 2024; https://doi.org/10.2147/LCTT.S467169) (arter2024spotlightonpatritumab pages 2-4).

Focused functional annotation of EGFR (mechanism and site of action)
- Molecular function. EGFR’s primary biochemical function is receptor‑mediated tyrosine phosphorylation of its own C‑terminal tail and of recruited substrates following ligand binding and dimerization, initiating downstream signaling cascades controlling proliferation, survival, and differentiation (tydings2024analysisofegfr pages 22-23, kozlova2024celladhesionmolecules pages 4-6).
- Substrate specificity. Substrate recognition is largely indirect, via recruitment of SH2/PTB‑containing adaptors (e.g., GRB2) to phosphotyrosine motifs on EGFR, which in turn engage downstream effectors (RAS–RAF–MEK–ERK; PI3K–AKT–mTOR; JAK–STAT) (tydings2024analysisofegfr pages 22-23, nadendla2025tyrosinekinasesstructural pages 29-31, comez2024dynamicsofligand pages 41-46).
- Cellular compartment and dynamics. EGFR functions primarily at the plasma membrane and in early endosomes; clathrin‑mediated endocytosis usually favors recycling and sustained signaling, whereas clathrin‑independent uptake coupled to ubiquitination promotes lysosomal degradation. Nuclear translocation has been described in some contexts and is under investigation pharmacologically (schultz2023egfrtraffickingeffect pages 9-10, schultz2023egfrtraffickingeffect pages 2-3, kozlova2024celladhesionmolecules pages 4-6).

Expert analysis and synthesis
- Alignment with domain/family expectations. The domain architecture, activation modality via asymmetric kinase dimer, and integration into canonical RTK pathways collectively confirm that human EGFR (ERBB1/HER1) matches UniProt P00533 descriptions and ERBB family paradigms, fulfilling the ambiguity checks required before analysis (kozlova2024celladhesionmolecules pages 4-6, schultz2023egfrtraffickingeffect pages 9-10, comez2024dynamicsofligand pages 41-46).
- Translational trajectory (2023–2024). Two pivotal strategies advanced first‑line care: (1) vertical intensification with osimertinib+platinum–pemetrexed (FLAURA‑2) and (2) receptor‑level dual targeting (amivantamab EGFR–MET bispecific) plus a brain‑penetrant TKI (lazertinib) in MARIPOSA. Both improve PFS over osimertinib alone but present distinct safety profiles; patient selection may be influenced by baseline disease burden, comorbidities, and ctDNA‑based risk stratification patterns observed in exploratory analyses (cho2024amivantamabpluslazertinib pages 1-4, arter2024spotlightonpatritumab pages 2-4, roy2025recentadvancesin pages 25-29).
- Open questions. Optimizing sequencing after first‑line combination therapy, integrating HER3‑directed ADCs, and exploiting trafficking‑dependent vulnerabilities remain active areas; mechanistic insights into ligand‑independent oligomerization and heterodimer dynamics (with HER2/HER3/HER4) continue to inform next‑generation inhibitor and biologic design (schultz2023egfrtraffickingeffect pages 9-10, trenker2024structuraldynamicsof pages 25-26, tydings2024analysisofegfr pages 22-23).

URLs and publication dates (selected)
- NEJM MARIPOSA: Amivantamab+lazertinib vs osimertinib first‑line; published October 24, 2024; https://www.nejm.org/doi/full/10.1056/NEJMoa2403614 (cho2024amivantamabpluslazertinib pages 1-4).
- FLAURA‑2 overview and FDA approval context: Lung Cancer: Targets and Therapy; July 2024; https://doi.org/10.2147/LCTT.S467169 (arter2024spotlightonpatritumab pages 2-4, arter2024spotlightonpatritumab pages 4-5).
- EGFR inhibitory biologics interfaces: Protein Science; September 2024; https://doi.org/10.1002/pro.5141 (tydings2024analysisofegfr pages 22-23).
- ERBB structural dynamics and glycosylation (HER4/HER2): eLife; March 2024; https://doi.org/10.7554/eLife.92873 (trenker2024structuraldynamicsof pages 25-26).
- EGFR trafficking and dimerization/mutation review: Frontiers in Oncology; September 2023; https://doi.org/10.3389/fonc.2023.1258371 (schultz2023egfrtraffickingeffect pages 9-10, schultz2023egfrtraffickingeffect pages 2-3).
- Cell adhesion molecules modulating EGFR: Cells; November 2024; https://doi.org/10.3390/cells13221919 (kozlova2024celladhesionmolecules pages 4-6).
- ctDNA prognostic utility in trial contexts: Current Oncology; August 2025; https://doi.org/10.3390/curroncol32080448 (roy2025recentadvancesin pages 25-29).

Limitations and scope note
- Where explicit guideline text (e.g., NCCN/ESMO/ASCO) and some real‑world datasets were not directly accessible in the current context, we cited high‑quality trial reports and recent peer‑reviewed syntheses capturing the 2023–2024 practice changes and ctDNA‑related findings. All claims are restricted to the evidence listed above.

References

(kozlova2024celladhesionmolecules pages 4-6): Irina Kozlova and Vladimir Sytnyk. Cell adhesion molecules as modulators of the epidermal growth factor receptor. Cells, 13:1919, Nov 2024. URL: https://doi.org/10.3390/cells13221919, doi:10.3390/cells13221919. This article has 11 citations and is from a poor quality or predatory journal.
(schultz2023egfrtraffickingeffect pages 9-10): Destiny F. Schultz, Daniel D. Billadeau, and Seetharama D. Jois. Egfr trafficking: effect of dimerization, dynamics, and mutation. Frontiers in Oncology, Sep 2023. URL: https://doi.org/10.3389/fonc.2023.1258371, doi:10.3389/fonc.2023.1258371. This article has 25 citations and is from a poor quality or predatory journal.
(comez2024dynamicsofligand pages 41-46): D Comez. Dynamics of ligand and nanobody binding at cxcr4/egfr complexes. Unknown journal, 2024.
(tydings2024analysisofegfr pages 22-23): Claiborne W. Tydings, Bhuminder Singh, Adam W. Smith, Kaitlyn V. Ledwitch, Benjamin P. Brown, Christine M. Lovly, Allison S. Walker, and Jens Meiler. Analysis of egfr binding hotspots for design of new egfr inhibitory biologics. Protein Science : A Publication of the Protein Society, Sep 2024. URL: https://doi.org/10.1002/pro.5141, doi:10.1002/pro.5141. This article has 6 citations.
(nadendla2025tyrosinekinasesstructural pages 29-31): Eswar Kumar Nadendla, Gangadhar P Vadla, Manohar Radhakrishnan, and Raghavendra Sashi Krishna Nagampalli. Tyrosine kinases: structural insights and mechanistic roles in cancer progression and therapeutics. May 2025. URL: https://doi.org/10.20944/preprints202505.0180.v1, doi:10.20944/preprints202505.0180.v1.
(trenker2024structuraldynamicsof pages 25-26): Raphael Trenker, Devan Diwanji, Tanner Bingham, Kliment A Verba, and Natalia Jura. Structural dynamics of the active her4 and her2/her4 complexes is finely tuned by different growth factors and glycosylation. eLife, Mar 2024. URL: https://doi.org/10.7554/elife.92873, doi:10.7554/elife.92873. This article has 17 citations and is from a domain leading peer-reviewed journal.
(schultz2023egfrtraffickingeffect pages 2-3): Destiny F. Schultz, Daniel D. Billadeau, and Seetharama D. Jois. Egfr trafficking: effect of dimerization, dynamics, and mutation. Frontiers in Oncology, Sep 2023. URL: https://doi.org/10.3389/fonc.2023.1258371, doi:10.3389/fonc.2023.1258371. This article has 25 citations and is from a poor quality or predatory journal.
(cho2024amivantamabpluslazertinib pages 1-4): Byoung C. Cho, Shun Lu, Enriqueta Felip, Alexander I. Spira, Nicolas Girard, Jong-Seok Lee, Se-Hoon Lee, Yurii Ostapenko, Pongwut Danchaivijitr, Baogang Liu, Adlinda Alip, Ernesto Korbenfeld, Josiane Mourão Dias, Benjamin Besse, Ki-Hyeong Lee, Hailin Xiong, Soon-Hin How, Ying Cheng, Gee-Chen Chang, Hiroshige Yoshioka, James C.-H. Yang, Michael Thomas, Danny Nguyen, Sai-Hong I. Ou, Sanjay Mukhedkar, Kumar Prabhash, Manolo D’Arcangelo, Jorge Alatorre-Alexander, Juan C. Vázquez Limón, Sara Alves, Daniil Stroyakovskiy, Marina Peregudova, Mehmet A.N. Şendur, Ozan Yazici, Raffaele Califano, Vanesa Gutiérrez Calderón, Filippo de Marinis, Antonio Passaro, Sang-We Kim, Shirish M. Gadgeel, John Xie, Tao Sun, Melissa Martinez, Mariah Ennis, Elizabeth Fennema, Mahesh Daksh, Dawn Millington, Isabelle Leconte, Ryota Iwasawa, Patricia Lorenzini, Mahadi Baig, Sujay Shah, Joshua M. Bauml, S. Martin Shreeve, Seema Sethi, Roland E. Knoblauch, and Hidetoshi Hayashi. Amivantamab plus lazertinib in previously untreated egfr -mutated advanced nsclc. New England Journal of Medicine, 391:1486-1498, Oct 2024. URL: https://doi.org/10.1056/nejmoa2403614, doi:10.1056/nejmoa2403614. This article has 343 citations and is from a highest quality peer-reviewed journal.
(arter2024spotlightonpatritumab pages 2-4): Zhaohui Arter and Misako Nagasaka. Spotlight on patritumab deruxtecan (her3-dxd) from herthena lung01. is a median pfs of 5.5 months enough in light of flaura-2 and mariposa? Lung Cancer: Targets and Therapy, 15:115-121, Jul 2024. URL: https://doi.org/10.2147/lctt.s467169, doi:10.2147/lctt.s467169. This article has 4 citations.
(arter2024spotlightonpatritumab pages 4-5): Zhaohui Arter and Misako Nagasaka. Spotlight on patritumab deruxtecan (her3-dxd) from herthena lung01. is a median pfs of 5.5 months enough in light of flaura-2 and mariposa? Lung Cancer: Targets and Therapy, 15:115-121, Jul 2024. URL: https://doi.org/10.2147/lctt.s467169, doi:10.2147/lctt.s467169. This article has 4 citations.
(roy2025recentadvancesin pages 25-29): Prabhat Gautam Roy, Davida Reingold, Neha Pathak, Saurav Verma, Aarushi Gupta, N. Meti, C. Moltó, P. Malik, Geordie Linford, and A. Mittal. Recent advances in the management of egfr-mutated advanced non-small cell lung cancer—a narrative review. Current Oncology, Aug 2025. URL: https://doi.org/10.3390/curroncol32080448, doi:10.3390/curroncol32080448. This article has 4 citations and is from a poor quality or predatory journal.

Citations

schultz2023egfrtraffickingeffect pages 2-3
tydings2024analysisofegfr pages 22-23
trenker2024structuraldynamicsof pages 25-26
kozlova2024celladhesionmolecules pages 4-6
cho2024amivantamabpluslazertinib pages 1-4
arter2024spotlightonpatritumab pages 2-4
roy2025recentadvancesin pages 25-29
schultz2023egfrtraffickingeffect pages 9-10
comez2024dynamicsofligand pages 41-46
nadendla2025tyrosinekinasesstructural pages 29-31
arter2024spotlightonpatritumab pages 4-5
https://doi.org/10.1002/pro.5141
https://doi.org/10.7554/elife.92873
https://doi.org/10.3389/fonc.2023.1258371
https://doi.org/10.3390/cells13221919
https://www.nejm.org/doi/full/10.1056/NEJMoa2403614
https://doi.org/10.2147/LCTT.S467169
https://doi.org/10.3390/curroncol32080448
https://doi.org/10.7554/eLife.92873
https://doi.org/10.3390/cells13221919,
https://doi.org/10.3389/fonc.2023.1258371,
https://doi.org/10.1002/pro.5141,
https://doi.org/10.20944/preprints202505.0180.v1,
https://doi.org/10.7554/elife.92873,
https://doi.org/10.1056/nejmoa2403614,
https://doi.org/10.2147/lctt.s467169,
https://doi.org/10.3390/curroncol32080448,

Deep Research Perplexity

(EGFR-deep-research-perplexity.md)

provider: perplexity
model: sonar-deep-research
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start_time: '2025-12-29T11:49:48.033706'
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template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: EGFR
gene_symbol: EGFR
uniprot_accession: P00533
protein_description: 'RecName: Full=Epidermal growth factor receptor {ECO:0000305};
EC=2.7.10.1; AltName: Full=Proto-oncogene c-ErbB-1; AltName: Full=Receptor tyrosine-protein
kinase erbB-1; Flags: Precursor;'
gene_info: Name=EGFR {ECO:0000312|HGNC:HGNC:3236}; Synonyms=ERBB, ERBB1, HER1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the protein kinase superfamily. Tyr protein
protein_domains: Furin-like_Cys-rich_dom. (IPR006211); Furin_repeat. (IPR006212);
GF_recep_IV. (IPR032778); Growth_fac_rcpt_cys_sf. (IPR009030); Kinase-like_dom_sf.
(IPR011009)
provider_config:
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parameters:
allowed_domains: []
reasoning_effort: medium
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return_citations: true
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citation_count: 60

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P00533
Protein Description: RecName: Full=Epidermal growth factor receptor {ECO:0000305}; EC=2.7.10.1; AltName: Full=Proto-oncogene c-ErbB-1; AltName: Full=Receptor tyrosine-protein kinase erbB-1; Flags: Precursor;
Gene Information: Name=EGFR {ECO:0000312|HGNC:HGNC:3236}; Synonyms=ERBB, ERBB1, HER1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the protein kinase superfamily. Tyr protein
Key Domains: Furin-like_Cys-rich_dom. (IPR006211); Furin_repeat. (IPR006212); GF_recep_IV. (IPR032778); Growth_fac_rcpt_cys_sf. (IPR009030); Kinase-like_dom_sf. (IPR011009)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "EGFR" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene EGFR (gene ID: EGFR, UniProt: P00533) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Output

Let me carefully read through the user's query. They want a comprehensive research report on the EGFR gene (UniProt: P00533) from Homo sapiens (Human). The gene product is the Epidermal growth factor receptor, a receptor tyrosine-protein kinase.

Let me verify first:
- Gene symbol: EGFR
- UniProt Accession: P00533
- Protein: Epidermal growth factor receptor
- Organism: Homo sapiens (Human)
- Type: Receptor tyrosine kinase (EC=2.7.10.1)
- Domains: Growth factor receptor with extracellular domain, transmembrane domain, kinase domain

The search results provided are all highly relevant to EGFR, covering:
1. Structure and function (transmembrane receptor, tyrosine kinase)
2. Ligand binding (EGF, TGF-α, and other ligands)
3. Activation mechanisms (ligand-induced dimerization, asymmetric kinase domain dimers)
4. Signaling pathways (MAPK/ERK, PI3K/AKT, PLCγ, STAT, JAK/STAT)
5. Phosphorylation sites and substrates
6. Endocytosis and trafficking
7. Nuclear localization and function
8. Role in development, wound healing, and disease
9. Mutations and cancer

This is a very rich set of sources. I need to write a 10,000+ word report covering:
1. Primary function (receptor tyrosine kinase for growth factor signaling)
2. Substrate specificity (what it phosphorylates)
3. Localization (plasma membrane, endosomes, nucleus)
4. Signaling pathways
5. Biological processes
6. Structure and mechanism

Let me organize this into a comprehensive report with proper section structure and citations.

The Epidermal Growth Factor Receptor: Structure, Function, and Signal Transduction Mechanisms

The epidermal growth factor receptor (EGFR), also known as ErbB-1 or HER1, is a prototypical member of the ErbB family of receptor tyrosine kinases (RTKs) that serves as a critical molecular bridge between extracellular growth factor signals and intracellular signal transduction cascades[1][2]. This transmembrane protein represents one of the most extensively characterized signaling receptors in human biology, with fundamental importance in cellular processes ranging from proliferation and differentiation to migration and survival. The receptor's dysregulation is implicated in numerous human diseases, particularly in carcinogenesis, making it a major target for therapeutic intervention[1][3]. This report provides a comprehensive analysis of EGFR's molecular architecture, enzymatic function, substrate specificity, subcellular localization, and the complex signaling networks it orchestrates.

Molecular Architecture and Structural Organization

Overall Receptor Structure

The human EGFR is a single-pass transmembrane glycoprotein with a molecular mass of approximately 170 kilodaltons that consists of several functionally distinct domains[2][25]. The receptor adopts a multi-domain architecture comprising an extracellular ligand-binding region, a single transmembrane α-helical domain, a short juxtamembrane (JM) segment, a cytoplasmic tyrosine kinase domain, and a carboxyl-terminal regulatory tail containing multiple tyrosine autophosphorylation sites[1][2][25]. This modular organization permits the coupling of ligand recognition at the cell surface to catalytic activation within the intracellular compartment, enabling rapid translation of external stimuli into biochemical signals[3].

The extracellular domain comprises approximately 620 amino acids organized into four distinct subdomains: domains I and III form the primary ligand-binding sites and are characterized by β-solenoid structures, while domains II and IV are cysteine-rich regions structurally similar to laminin repeats that contain disulfide-bonded modules[5][28]. The fundamental architecture of these domains is conserved across the entire ErbB family, yet specific sequence variations confer ligand selectivity and binding affinity distinctions among family members[28]. The transmembrane domain is a single hydrophobic α-helix that serves as both a structural anchor and, increasingly, as recognized through structural studies, an important mediator of receptor dimerization through specific GxxxG motifs[5].

The intracellular region is remarkably complex, consisting of the juxtamembrane domain (approximately 38 amino acids), the tyrosine kinase domain (approximately 280 amino acids), and a carboxy-terminal tail of approximately 230 amino acids[5][31]. Unusually among RTKs, the juxtamembrane region of EGFR functions in an activating rather than autoinhibitory capacity, directly stabilizing the asymmetric kinase domain dimer required for catalytic activation[31]. The carboxy-terminal tail is substantially larger than in many other kinases and contains multiple autophosphorylation sites that serve as docking platforms for downstream signaling proteins[1][2].

The Extracellular Ligand-Binding Domain

High-resolution crystal structures have revealed that EGFR's ligand-binding mechanism is fundamentally different from many other RTKs and represents a paradigm of allosteric regulation[25][28]. In the ligand-free state, the extracellular domain adopts an autoinhibited "tethered" conformation in which subdomain IV directly contacts subdomain II, effectively burying the dimerization interface and preventing unliganded receptor aggregation[25][28]. The conserved disulfide bond between cysteine residues 582 and 591 (or 558 and 567 in the mature, proteolytically processed form) in the "tethering arm" of subdomain IV is critical for stabilizing this inactive configuration, and disruption of this bond entirely abrogates negative cooperativity in EGF binding[25].

Upon ligand binding, the extracellular domain undergoes a substantial conformational transition to an "extended" conformation[25]. Ligands such as epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) bind within a cleft formed between subdomains I and III in a clamping mechanism[28]. This ligand-induced repositioning pulls subdomains I and III together, breaking the domain II/IV tether and exposing a second protein-protein interaction surface on subdomain II that serves as the dimerization interface[25][28]. The ligand does not directly participate in dimer formation; rather, ligand binding allosterically promotes a conformational change that makes the receptor competent for receptor-receptor contact. This represents an important distinction from many other growth factor receptors where the ligand itself provides cross-linking between two receptor molecules[5][28].

Six conserved cysteine residues within each EGFR ligand share a characteristic EGF-like motif forming three disulfide-bonded loops that provide structural rigidity[28]. Molecular dynamics simulations have identified that glutamine 16 of EGFR forms consistent hydrogen bonds with the backbones of the fourth and fifth conserved cysteines across multiple ligand species, and that salt bridge formation between the ligand and EGFR receptor contributes substantially to binding affinity, with higher-affinity ligands forming more stable salt bridges than lower-affinity variants[28]. The non-conserved residue between the fourth and fifth cysteine in different ligands provides varying contributions to binding energy, ranging from 1.94 to −4.32 kcal/mol, demonstrating that ligand specificity is not solely determined by conserved structural elements but depends critically on sequence variation in non-conserved positions[28].

Different EGFR ligands exhibit substantial differences in binding kinetics and affinity. EGF and transforming growth factor alpha (TGF-α), the canonical ligands, have relatively different receptor affinities and induce distinct receptor trafficking and signaling outcomes despite utilizing the same receptor[29]. EGF binding is relatively stable at the acidic pH of endosomal compartments, whereas TGF-α rapidly dissociates under these conditions[29]. This pH-dependent ligand stability has profound consequences for receptor sorting, with EGF-bound receptors undergoing sustained ubiquitination and lysosomal degradation, while TGF-α-bound receptors become de-ubiquitinated and recycled to the plasma membrane[29]. Additional ligands including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, betacellulin, epiregulin, and epigen activate EGFR with varying efficiencies, and the connective tissue growth factor (CTGF/CCN2) has recently been identified as a novel EGFR ligand with particular relevance in renal pathology[55].

The Transmembrane Domain and Juxtamembrane Region

The transmembrane domain consists of a single hydrophobic α-helix that transverses the cell membrane[2]. Early structural and biochemical investigations suggested that the transmembrane domain functioned primarily as a passive anchor; however, more recent evidence demonstrates that it actively participates in receptor dimerization through specific sequence motifs[5]. The transmembrane helix contains two GxxxG motifs characteristic of helix-helix interaction surfaces, with the amino-terminal motif supporting EGFR transmembrane domain dimerization and the carboxy-terminal motif being particularly critical[5]. According to NMR-guided structural models, the amino-terminal GxxxG region mediates transmembrane helical dimerization, as confirmed by mutagenesis studies in which alterations of residues at positions 675, 680, or 682 disrupt the asymmetric kinase domain dimer essential for activation[5].

Upon ligand binding to the extracellular domain, ligand-induced rotation of the transmembrane domains parallel to the plane of the cell membrane occurs through approximately a 140-degree rotation, as determined through structural studies of receptor dimers[25]. This mechanical coupling represents the physical means by which the extracellular ligand-binding event is transmitted through the membrane to alter intracellular kinase domain orientation. The transmembrane domain thus functions as a transducer converting extracellular conformational changes into altered intracellular architecture[25].

The juxtamembrane region, spanning approximately 38 amino acids in humans (residues R645-I682 in the intracellular region), exhibits an unusual structural and functional role among RTKs[31]. Crystallographic analysis of the EGFR kinase domain extended to include the entire JM region reveals that the JM segment of the "acceptor" kinase domain in an asymmetric dimer makes extensive contacts with the carboxy-terminal lobe of the "donor" kinase, effectively cradling the activation lobe of its dimerization partner[31]. Comprehensive alanine-scanning mutagenesis demonstrates that specific residues within the JM region, particularly in the C-terminal 19 amino acids, are essential for EGFR activation; mutation of these residues completely abolishes ligand-induced activation[31]. This stands in marked contrast to several other growth factor receptors where the juxtamembrane domain exerts inhibitory constraints that must be relieved for kinase activation. The activation function of the EGFR JM domain is stabilized through allosteric interactions with the kinase domain, and the ordered N-terminal helix visible in crystallographic structures may coexist with transient interactions involving calmodulin or negatively-charged membrane surfaces[31].

Mechanism of Ligand-Induced Dimerization and Kinase Activation

The Two-Step Allosteric Model

Contemporary structural and biophysical evidence supports a sophisticated two-step allosteric model for EGFR activation[38][41][45]. This model describes two separate but structurally coupled allosteric activation events that occur across the plasma membrane: an extracellular ligand-dependent event leading to receptor dimerization, followed by an intracellular dimer-dependent event resulting in tyrosine kinase domain activation[38]. In the basal state, EGFR exists in equilibrium between monomeric and preformed dimeric inactive states; modern evidence suggests that a substantial fraction of EGFR molecules (estimated at 40-100% depending on experimental methodology and cell line) spontaneously adopt a preformed dimeric structure prior to ligand binding[41][45]. These preformed inactive dimers stabilize each other through interactions of the intracellular kinase domains in an autoinhibited symmetric back-to-back orientation, with the AP-2 helix and "electrostatic hook" playing crucial roles in stabilizing these inactive dimeric complexes[41][45].

Upon ligand binding to the extracellular domain, the population of EGFR molecules shifts toward an active conformation through a series of coordinated conformational changes[38]. The ligand-induced extended conformation of the extracellular domain propagates structural changes through the transmembrane helix, promoting a reorientation of the transmembrane domains from a C-terminal-cross interaction to a near N-terminal-cross arrangement[38]. This transmembrane reorientation couples to a rearrangement of the juxtamembrane helical segments and ultimately to a transition of the intracellular kinase domains from an inactive symmetric configuration to an active asymmetric dimer[38]. In this asymmetric arrangement, the kinase domain from one receptor (the "activator") makes extensive allosteric contacts with the kinase domain of a second receptor (the "receiver"), inducing conformational changes in the receiver that stabilize its catalytically active state[13][25].

Full kinase activation may require higher-order complex formation; evidence suggests that in vivo, EGFR dimers may further assemble into tetrameric complexes in a ligand-dependent manner through interactions within subdomain IV of the extracellular region[25][27]. These higher-order structures appear to be functionally important, as a previously selected RNA aptamer that disrupts tetramer formation while preserving dimer formation and receptor phosphorylation selectively inhibits MAPK signaling while leaving PI3K/AKT signaling partially intact[27]. This functional segregation suggests that different downstream pathways may emanate preferentially from different quaternary EGFR assemblies[27].

The Asymmetric Kinase Domain Dimer

The mechanism of kinase domain activation in EGFR fundamentally differs from the activation-loop phosphorylation mechanism utilized by most other kinases[2][5][13]. Crystal structures of inactive EGFR kinase domains reveal a symmetric back-to-back orientation in which the two kinase domains interact symmetrically, stabilized by the AP-2 helix of each protomer[31][41]. Upon ligand-induced dimerization, the kinase domains undergo a dramatic reorientation to form an asymmetric dimer in which the carboxy-terminal lobe of the activator kinase makes contact with the amino-terminal lobe of the receiver kinase[5][13][31]. This allosteric interaction induces several critical conformational changes in the receiver kinase: rotation of the αC helix from an "out" position to an "in" position adjacent to the ATP-binding site, stabilization of the activation loop in an active conformation maintaining the β9 strand and permitting substrate binding, and overall stabilization of a catalytically competent active state[13][16].

The carboxy-terminal lobe of the activator kinase domain interacts with a surface on the amino-terminal lobe of the receiver created by elements including the αC helix, the β4/β5 loop, and an N-terminal extension of the N-lobe that includes part of the juxtamembrane segment[31]. The extended juxtamembrane segment of the receiver effectively "cradles" the carboxy-terminal lobe of the donor, with specific residues such as V665, L679, and others making critical contacts that stabilize the asymmetric dimer interface[31]. Crystal structures of constitutively active EGFR variants with oncogenic mutations (such as the L858R point mutation in the kinase domain or various in-frame deletions in exon 19) demonstrate that these mutations promote conformational changes that favor the active asymmetric dimer state even in the absence of ligand-induced external domain rearrangement, explaining their oncogenic properties[50].

Molecular dynamics simulations have illuminated the conformational dynamics of the EGFR kinase domain and have revealed the existence of additional conformational states beyond those captured in crystallographic structures[16]. These simulations demonstrate that the active state of an isolated EGFR monomer is highly unstable, consistent with experimental observations that EGFR kinase is activated only in the context of an asymmetric dimer. The simulations have identified a "Src-like" inactive conformation characterized by an outward rotation of the αC helix and remodeling of the activation loop into a two-turn helix, an intermediate state in the transition toward a DFG-out inactive conformation, and a "detached" conformation in which the activation loop assumes an extended conformation away from the kinase body[16]. These simulations reveal extraordinary conformational flexibility of the activation loop, with activation loop rearrangements exceeding 20 Å RMSD even during seemingly local conformational transitions such as the DFG flip[16].

Substrate Specificity and Autophosphorylation Mechanisms

Identification of Autophosphorylation Sites

Upon activation through ligand-induced dimerization and asymmetric kinase domain formation, EGFR catalyzes trans-autophosphorylation of multiple tyrosine residues within its own carboxy-terminal tail[1][2][7]. The major autophosphorylation sites include tyrosines 992, 1045, 1068, 1086, 1148, and 1173, with Y1068, Y1148, and Y1173 being quantitatively the most prominent[7][43]. These tyrosine residues, once phosphorylated, become docking sites for intracellular proteins containing Src homology 2 (SH2) domains or phosphotyrosine-binding (PTB) domains, thereby coupling receptor activation to downstream signal transduction[1][2][43].

Detailed phosphokinetic analysis employing synthetic peptides demonstrates that EGFR exhibits a remarkable and previously unappreciated substrate specificity preference: the kinase preferentially phosphorylates substrates that contain a phosphotyrosine residue at the +1 position relative to the target tyrosine[10]. This represents a fundamentally different recognition principle than the well-characterized preference for acidic residues N-terminal to the phosphorylation site that was previously considered the primary determinant of EGFR substrate specificity[10]. The crystal structure of the EGFR kinase domain in complex with a "primed" Shc1 peptide phosphorylated at tyrosine 240 reveals the structural basis for this substrate specificity: the phosphate of the phosphotyrosine at the +1 position makes major sequence-specific interactions with the EGFR kinase active site, occupying a recognition pocket and forming hydrogen bonds with basic residues in the kinase[10].

This preference for phosphotyrosine-primed substrates has important functional implications. Several cellular substrates including Shc1 (Src homology 2 domain containing collagen-related protein) contain tyrosine pairs in positions 239 and 240 that correspond to the consensus substrate motif, where phosphorylation at tyrosine 239 creates a priming substrate for subsequent phosphorylation of tyrosine 240. The MET receptor tyrosine kinase similarly contains phosphorylation sites with tyrosine at the +1 position that are preferentially phosphorylated by EGFR[10]. This specificity mechanism appears to function in coordinating multi-site phosphorylation of substrates and may serve to impose temporal ordering on phosphorylation events, with prior phosphorylation at one site enhancing phosphorylation at downstream sites within the same protein[10].

The Kinase Domain Active Site and Catalytic Mechanism

The EGFR kinase domain, like all protein tyrosine kinases, catalyzes the phosphoryl transfer reaction through a two-metal-ion catalytic mechanism utilizing aspartate residues to coordinate metal ions (typically magnesium or manganese) that position and activate the ATP γ-phosphate for transfer to the hydroxyl group of the target tyrosine residue[1][2]. The ATP-binding pocket is situated in a cleft between the amino-terminal and carboxy-terminal lobes of the kinase domain, with the adenine ring making stacking interactions with the highly conserved "gatekeeper" residue threonine 854[1].

The catalytic loop (residues 861-876) contains the essential aspartate 863 that coordinates metal ions and positions the substrate's target tyrosine for phosphorylation[1]. The carboxy-terminal activation loop (residues 936-964) undergoes substantial conformational changes during activation; in the inactive state, the loop is disordered or assumes a catalytically incompetent conformation, while in the active state it adopts a β-strand conformation and positions alongside the catalytic residues to form a peptide-binding groove that accommodates substrate[1][13][16]. In the inactive state, the activation loop can fold back onto the substrate-binding site (an autoinhibitory conformation), physically occluding substrate access and preventing catalysis[16].

The alpha-C helix, a critical structural element in the amino-terminal lobe, moves from an "out" position adjacent to the ATP site in inactive kinases to an "in" position where it makes direct contacts with ATP in the active state[13][16]. This αC helix movement is coupled to stabilization of the activation loop in an active conformation and together these changes create a catalytically competent active site[13][16]. The asymmetric dimer interface appears to stabilize the receiver kinase's αC-in conformation through allosteric interactions, thereby promoting the catalytically active state[13].

Substrate Specificity for Downstream Signaling Proteins

While EGFR readily autophosphorylates on its own tyrosine residues, its activity toward downstream signaling proteins varies considerably depending on the substrate and cellular context[7][10][43]. The major downstream adaptor proteins that are phosphorylated by EGFR include the growth factor receptor-bound protein 2 (GRB2)-associated binder 1 (Gab1) protein, the Src homology 2 domain and collagen-containing protein (Shc), phospholipase C gamma 1 (PLCγ1), and signal transducer and activator of transcription proteins (STATs)[2][3][43].

Comprehensive kinetic analysis of EGFR-catalyzed phosphorylation reveals that EGF stimulation increases the catalytic-center activity of the kinase without substantially affecting substrate binding affinity toward major EGFR autophosphorylation sites[7]. This suggests that ligand effects on substrate specificity are exerted primarily through modulation of the kinase's catalytic efficiency toward different substrates rather than through differential substrate binding[7]. Interestingly, peptides representing phosphorylation sites in other ErbB family members (ErbB2, ErbB3, ErbB4) are phosphorylated by EGFR with efficiencies that correlate well with the presence of favorable residues at the −1 position (acidic residues) and at the +3 position (hydrophobic residues)[7]. However, not all identified or predicted phosphorylation sites in ErbB3 are efficiently phosphorylated by EGFR in oligomeric receptor complexes, suggesting that steric constraints within assembled receptor complexes may limit kinase accessibility to certain sites, and that direct phosphorylation by ErbB2 or ErbB4 kinases (which retain catalytic activity) may be required for some sites[7].

Subcellular Localization and Signal Compartmentalization

Plasma Membrane Signaling

The primary site of EGFR activation is the plasma membrane, where ligand-receptor interactions occur and where the receptor's extracellular domain is accessible to growth factors in the extracellular space[1][3][12]. At the plasma membrane, EGFR forms clusters or punctate accumulations that correspond to ligand-saturated receptor dimers and higher-order oligomers; visualization of receptors with fluorescent ligands reveals concentration into discrete spots with patterns reminiscent of clathrin-coated pits even in the early moments after EGF binding[9].

Significantly, EGFR signaling through the canonical Ras/ERK pathway occurs preferentially or exclusively from the plasma membrane[9]. Live-cell imaging experiments employing gene-edited cells expressing endogenous H-Ras labeled with fluorescent proteins have demonstrated that although activated EGFR is rapidly internalized into early endosomes following ligand stimulation, the membrane-anchored Ras protein exhibits minimal colocalization with internalized EGFR[9]. Quantitative analysis reveals that less than 1% of total cellular H-Ras overlaps with internalized EGF-bound EGFR at 15 minutes post-stimulation, despite robust Ras-GTP activation at this time point[9]. This spatial segregation indicates that EGFR recruits and activates its downstream Ras effectors specifically at the plasma membrane, and that endocytosis of EGFR serves to separate the activated receptor from Ras, thereby attenuating Ras signaling[9]. Furthermore, approximately 20% of phosphorylated EGFR remains surface-active at 15 minutes post-stimulation, providing a pool of activated receptors that is likely sufficient to sustain the Ras-ERK signaling cascade observed during continuous endocytosis[9].

Endosomal Trafficking and Signal Attenuation

Following ligand binding and activation, EGFR undergoes rapid clathrin-mediated endocytosis that internalizes the activated receptor complex into early endosomes within 5-15 minutes[3][6][9][12]. This endocytic process is essential for signal termination and is mediated through the recruitment of the ubiquitin ligase Casitas B-lineage lymphoma (Cbl) protein, which binds to the phosphorylated tyrosine 1045 residue of EGFR through its SH2 domain and catalyzes the covalent attachment of polyubiquitin chains to lysine residues in the receptor[1][3][6][26]. The ubiquitination process requires the adapter protein GRB2, whose SH2 domain binds to phosphorylated EGFR while its SH3 domains interact with the proline-rich regions of Cbl, effectively bridging the receptor to the ubiquitin ligase[14].

The fate of internalized EGFR depends critically on the nature of the bound ligand and the resulting duration of receptor phosphorylation and ubiquitination[29]. EGF maintains its binding to EGFR at the acidic pH of endosomal compartments (pH approximately 5.5), and receptors bound to EGF remain continuously phosphorylated and ubiquitinated as they traffic through the endosomal system[29]. This persistent ubiquitination targets the receptors for transport to multivesicular bodies and ultimately to lysosomes, where the receptors undergo proteolytic degradation[29]. In contrast, TGF-α rapidly dissociates from EGFR at acidic pH, permitting dephosphorylation and de-ubiquitination of the receptor[29]. Once de-ubiquitinated, these receptors are sorted away from degradative pathways and instead are recycled back to the plasma membrane, where they resume signaling capacity[29]. Amphiregulin similarly permits complete receptor recycling without lysosomal degradation, while other ligands produce intermediate trafficking patterns[29].

GRB2 plays a central regulatory role in both EGFR endocytosis and in coupling the internalized receptor to downstream signaling machinery[14]. GRB2 is recruited to activated EGFR through direct binding of its SH2 domain to phosphorylated tyrosine residues (particularly Y1068 and Y1086 as primary sites, with Y1173 serving as a secondary binding site), and can also bind indirectly to EGFR through interaction with phosphorylated Shc[14][17]. The dynamic localization of GRB2 shifts from a dispersed cytosolic and nuclear distribution in unstimulated cells to concentrated accumulation in endocytic compartments following EGF stimulation[14][17]. Detailed FRET (Förster resonance energy transfer) analysis demonstrates substantial colocalization of GRB2 and Shc in endosomes, and that GRB2 can be recruited to endosomes either through direct interaction with phosphorylated EGFR or indirectly through binding to Shc protein[14][17]. The SH3 domain of GRB2 mediates binding to proline-rich regions of Cbl, and this interaction is essential for rapid clathrin-mediated endocytosis of EGFR[14]. Mutant GRB2 proteins lacking functional SH3 domains impede stimulus-dependent internalization of EGFR despite normal plasma membrane translocation, confirming the critical role of GRB2's SH3-mediated interactions in coordinating receptor internalization[14].

The ubiquitin ligase Cbl controls not only EGFR ubiquitination and degradation but also regulates endosomal maturation and the fusion of early endosomes that traffic EGFR to lysosomes[26]. Cbl accomplishes this through tyrosine-phosphorylation-dependent interactions with the hepatocyte growth factor-regulated tyrosine kinase substrate protein (Hrs), a key regulator of endosomal trafficking[26]. Specific amino acid residues within Cbl's RING finger domain contribute differentially to these processes: while some residues control ubiquitination and receptor down-regulation, others regulate dephosphorylation of Hrs and early endosome fusion[26].

Nuclear Translocation of EGFR

In addition to signaling from the plasma membrane and endosomes, a substantial and functionally important pool of EGFR undergoes translocation to the cell nucleus[6][15][18][20][23]. Nuclear accumulation of EGFR has been observed in cancer cells and correlates with malignancy, increased proliferation rates, and therapy resistance[6][18]. The nuclear translocation of EGFR is mediated through the classical nuclear import machinery involving the Importin α/β1 complex[15]. EGFR contains a tripartite nuclear localization sequence (NLS) within its juxtamembrane domain that serves as the cargo signal recognized by Importin proteins; mutation or deletion of this NLS markedly reduces nuclear accumulation of EGFR[15][18].

Nuclear EGFR enters through the nuclear pore complex in a manner dependent on Importin β1, and this process is enhanced by ligand binding and EGFR activation[15]. Prostaglandin E2 (PGE2) provides a particularly robust stimulus for EGFR nuclear translocation and appears to promote internalization through both clathrin-dependent and caveolin-mediated endocytic pathways, with dynamin playing a critical role[15]. Within the nucleus, EGFR localizes to specific promoter regions and functions as a transcriptional coactivator, forming complexes with transcription factors including the signal transducer and activator of transcription 3 (STAT3), STAT5, and E2F1[6][15][18][20].

The mechanism of nuclear EGFR action differs fundamentally from classical transcription factors; EGFR lacks a DNA-binding domain and instead operates through protein-protein interactions with other nuclear proteins that provide DNA-binding capacity[6][18][20]. EGFR has been recruited to the AT-rich sequence (ATRS) motifs of multiple gene promoters through interaction with STAT3, and this interaction is essential for EGFR-dependent induction of cyclin D1 (CCND1), inducible nitric oxide synthase (iNOS/NOS2), cyclooxygenase-2 (COX-2/PTGS2), and c-Myc (MYC) genes[6][15][18][20]. The interaction between nuclear EGFR and STAT5 similarly regulates Aurora-A kinase expression, which has implications for centrosome amplification and chromosomal instability[18].

Nuclear EGFR also participates in calcium signaling within the nucleus[20][23]. EGF stimulation triggers nuclear calcium signals through a mechanism distinct from classical cytosolic calcium signaling; EGF induces calcium release from intranuclear calcium stores through a pathway mediated by the nuclear isoform of phospholipase C, PLCδ4 (not the cytosolic PLCγ1)[20][23]. EGFR appears to promote hydrolysis of nuclear phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) by PLCδ4, generating inositol 1,4,5-trisphosphate (InsP3) that binds to inositol 1,4,5-trisphosphate receptors located on the nuclear envelope or nucleoplasmic reticulum[20][23]. This releases calcium from intranuclear stores, a process that activates protein kinase C (PKC) within the nucleus and regulates cell cycle progression through modulation of cyclin A and cyclin B1 expression[20][23].

Signal Transduction Pathways Downstream of EGFR Activation

The MAPK/ERK Cascade

The mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) pathway represents the most canonical and well-characterized downstream effector of EGFR signaling and is essential for ligand-induced cell proliferation[3][6][35][54]. Activation of this pathway begins with the recruitment of the adaptor protein GRB2 to phosphorylated tyrosine residues Y1068 and Y1086 on the activated EGFR, either through direct SH2 domain-EGFR interaction or indirectly through binding to phosphorylated Shc protein[3][17][35][54]. GRB2 is constitutively associated with the guanine nucleotide exchange factor SOS (Son of Sevenless) through interactions between the GRB2 SH3 domains and proline-rich regions of SOS[3][35][54].

When the GRB2-SOS complex is recruited to the plasma membrane by association with activated EGFR, SOS becomes activated and catalyzes the exchange of GDP for GTP on membrane-anchored Ras proteins (predominantly H-Ras or K-Ras in response to EGFR stimulation)[3][35][54]. Ras-GTP subsequently recruits and activates the RAF kinase family member (predominantly RAF-1/C-RAF in epithelial cells) through direct binding to the Ras-binding domain in RAF's amino-terminal region[3][54]. RAF-1 undergoes phosphorylation at multiple sites including S338 and Y341 in the catalytic region to achieve full activation, and these phosphorylations are catalyzed by distinct kinase pathways: S338 phosphorylation is induced by activated Ras, while Y341 phosphorylation is catalyzed primarily by Src family kinases[49][54].

Activated RAF-1 phosphorylates and activates the dual-specificity kinase MEK1/2 (mitogen-activated protein kinase kinase), which in turn catalyzes activating phosphorylation of ERK1/2 (mitogen-activated protein kinase 1/2, also designated p42/p44 MAPK)[3][35]. Activated ERK1/2 translocates to the nucleus where it phosphorylates multiple transcription factors including Elk1, c-Myc, and c-Jun, leading to induction of genes required for cell cycle progression and proliferation including cyclins (particularly cyclin D1)[3][35][54]. The transcriptional responses to ERK activation include induction of early-immediate genes such as c-FOS and c-JUN, which then form heterodimers to activate additional downstream genes[54].

Importantly, the ERK pathway exhibits temporal dynamics characterized by transient or oscillatory activity patterns rather than sustained activation[35]. Single-cell imaging experiments reveal that EGF-induced ERK activation occurs in stochastic bursts, with the frequency of activation bursts, rather than amplitude alone, encoding information about the strength of the initial signal[35]. Lower EGF concentrations produce lower-frequency bursts of ERK activity, while higher EGF concentrations result in higher-frequency bursts[35]. Integration of the cumulative time cells spend in the ERK-activated state over the course of the cell cycle appears to determine cell proliferation rate, with longer cumulative periods of ERK activity correlating with higher proliferation rates[35].

The PI3K/AKT/mTOR Pathway

In addition to the MAPK pathway, EGFR activation strongly stimulates the phosphatidylinositol 3-kinase (PI3K) pathway, which regulates cell survival, metabolism, and growth[3][6][22][54]. PI3K recruitment to activated EGFR occurs through multiple mechanisms: the regulatory subunit (p85) of PI3K can be recruited indirectly through the adaptor protein GAB1 (Grb2-associated binder 1), whose proline-rich domain interacts with GRB2's SH3 domains, and whose tyrosine residues once phosphorylated by EGFR provide docking sites for the p85 SH2 domain[3][54]. Additionally, overexpressed EGFR with enhanced dimerization can provide direct p85 SH2 domain binding sites on phosphorylated receptor tyrosines[54].

Upon recruitment to the plasma membrane, PI3K catalyzes phosphorylation of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to generate the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3)[3]. PIP3 serves as a membrane-docking site for proteins containing pleckstrin homology (PH) domains, including the serine/threonine kinase protein kinase B (also designated Akt)[3][6]. At the plasma membrane, Akt becomes phosphorylated at critical regulatory sites (threonine 308 by PDK1 and serine 473 by mTORC2) leading to full activation[3][19].

Activated Akt catalyzes phosphorylation of numerous downstream substrates that collectively promote cell survival and growth[3][6][22]. Critical among these is phosphorylation and inactivation of the pro-apoptotic proteins BAD (Bcl2-associated agonist of cell death) and FoxO (forkhead box O) transcription factors, thereby suppressing apoptotic pathways[3][6]. Akt also phosphorylates and partially inhibits GSK3β (glycogen synthase kinase 3 beta), leading to increased protein synthesis through enhanced translation initiation[3]. A major downstream target of Akt is the mammalian target of rapamycin complex 1 (mTORC1), which Akt activates through phosphorylation of the tuberous sclerosis complex 2 (TSC2) subunit, thereby removing the inhibitory effect of the TSC complex on the mTORC1 activator Rheb[3][6][22]. mTORC1 then phosphorylates S6K (ribosomal S6 kinase) and 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1), promoting protein synthesis and cell growth[3][22].

The PI3K/AKT/mTOR pathway is frequently hyperactivated in cancer cells, and approximately 50% of hepatocellular carcinomas exhibit abnormal activation of this cascade[22]. In hepatocellular carcinoma, EGFR overexpression occurs in 68% of cases and correlates with metastasis and poor survival[22]. The pathway is negatively regulated by the phosphatase and tensin homolog (PTEN), which hydrolyzes PIP3 to PI(4,5)P2, thereby reducing plasma membrane recruitment of Akt[22][42][39]. Loss or reduced expression of PTEN, which occurs frequently in cancers, leads to hyperactivation of Akt signaling[39][42].

The PLCγ Pathway and Calcium Signaling

Phospholipase C gamma 1 (PLCγ1) is activated by EGFR through a dual-interaction mechanism in which the SH2 domains of PLCγ1 bind to phosphorylated tyrosine 992 and tyrosine 1173 on the activated EGFR[2][3][43][54]. Following recruitment to the plasma membrane, PLCγ1 becomes tyrosine-phosphorylated by EGFR at residues 771 and 1254, leading to full catalytic activation[3][43]. Activated PLCγ1 catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to generate the second messengers inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol (DAG)[3][6][43].

InsP3 diffuses through the cytoplasm and binds to InsP3 receptors on the endoplasmic reticulum, triggering release of calcium from intracellular stores[3][6][43]. This calcium release is essential for EGF-stimulated cell motility, and mutations or deletions of the EGFR tyrosines that serve as PLCγ1 docking sites (Y992/Y1173) substantially impair chemotactic migration despite only partial reduction of overall PLCγ1 phosphorylation[43]. DAG, as a membrane-associated lipid second messenger, directly activates protein kinase C (PKC) isoforms through binding to their C1 domains[3][6]. Additionally, calcium and DAG together provide the necessary cofactors for full PKC activation[3]. Activated PKC phosphorylates diverse substrates involved in cell migration, gene expression, and cytoskeletal reorganization[3][6][43].

The importance of EGFR-mediated calcium signaling is further underscored by the demonstration that PKC activation occurs not only in the cytosol but also within the nucleus[20][23]. Nuclear PKC activity is specifically triggered by nuclear EGFR through a mechanism distinct from cytosolic signaling, involving nuclear translocation of EGFR and subsequent PLCδ4-mediated PI(4,5)P2 hydrolysis in the nucleus[20][23]. This nuclear calcium signaling pathway participates in regulating cell cycle progression and gene expression[20][23].

STAT Pathway Activation

EGFR directly phosphorylates the signal transducer and activator of transcription proteins (STAT1 and STAT3), in addition to its established role in recruiting STATs through adapter proteins[3][6][21][54]. Direct phosphorylation of STAT proteins at their critical tyrosine residues (Y701 in STAT1 and STAT3) creates docking sites for Src homology 2 domain-containing proteins and facilitates STAT dimerization[3][21]. Phosphorylated STAT dimers translocate to the nucleus where they bind to specific DNA sequences (GAS elements) in gene promoters and activate transcription of target genes[3][21].

EGFR appears to activate STAT proteins through both JAK-dependent and JAK-independent mechanisms[24]. While traditional dogma suggests that JAK kinases mediate most STAT activation downstream of growth factor receptors, recent evidence indicates that EGFR can directly phosphorylate STATs and activate STAT signaling through mechanisms that do not require JAK proteins[24]. Different STAT family members (STAT1, STAT3, STAT5, etc.) exhibit distinct target genes and biological outcomes: STAT3 activation promotes cell proliferation, survival, angiogenesis, and metastasis[21]; STAT1 is more closely associated with growth inhibition and immune responses[21]; and STAT5 cooperates with nuclear EGFR to drive Aurora-A kinase expression[18].

Regulation of EGFR Signaling

Negative Feedback Regulation by ERK

The ERK/MAPK cascade itself provides powerful negative feedback regulation of EGFR signaling, creating a self-limiting mechanism that prevents excessive or sustained receptor activation[32][37]. ERK1/2 catalyzes phosphorylation of EGFR at threonine 669 (T669), a site located in the juxtamembrane region of the receptor[32]. Interestingly, T669 phosphorylation exerts dual effects: it reduces the tyrosine phosphorylation and kinase activity of EGFR, thereby providing negative feedback on the initial receptor activation[32]. However, T669 phosphorylation simultaneously inhibits receptor downregulation and endocytosis, thereby extending the persistence of activated EGFR at the cell surface[32]. These opposing regulatory effects likely arise through distinct mechanisms, with the reduction in kinase activity being direct, while the inhibition of internalization may be indirect through effects on receptor trafficking.

Additional negative feedback mechanisms include ERK1/2-mediated phosphorylation of the Raf kinase, KSR (kinase suppressor of Ras), and other upstream signaling components[32]. ERK directly phosphorylates Raf-1 at multiple sites, and these phosphorylations are associated with reduced Raf activity and prevention of re-activation, thereby limiting the duration of Raf signaling[32]. Phosphorylation of KSR1, a scaffolding protein critical for organizing the Raf-MEK-ERK signaling complex, leads to KSR1 release from the plasma membrane and dissolution of the signaling complex, reducing the efficiency of signal propagation[32].

The Role of Protein Tyrosine Phosphatase SHP2

The protein tyrosine phosphatase SHP2 (also designated PTPN11) functions as both a positive and negative regulator of EGFR signaling[37][40]. SHP2 is activated upon ligand binding through a conformational change that relieves autoinhibition of its catalytic domain[37]. Once activated, SHP2 interacts with phosphorylated EGFR either directly through its SH2 domains or indirectly through adapter proteins, and catalyzes dephosphorylation of specific regulatory phosphorylation sites[37].

A key mechanistic insight is that SHP2 acts upstream of Ras and promotes GTP-Ras accumulation by dephosphorylating Ras GTPase-activating protein (RasGAP) binding sites, particularly Y992 on EGFR, preventing the membrane translocation of RasGAP that is required for its activity[37]. By maintaining high levels of Ras-GTP, SHP2 prolongs and enhances Ras-dependent signaling such as ERK1/2 activation[37]. This represents a positive regulatory function, with dominant-negative SHP2 reducing EGF-stimulated ERK1/2 phosphorylation and preventing sustained Ras-GTP accumulation[37]. However, the dephosphorylation of negative-regulatory sites also occurs, including Y1045 that mediates Cbl-dependent ubiquitination, potentially affecting receptor trafficking and degradation[37].

Cbl-Mediated Ubiquitination and Receptor Degradation

The Cbl ubiquitin ligase family, particularly c-Cbl (CBL proto-oncogene, E3 ubiquitin protein ligase), catalyzes ubiquitination of EGFR at lysine residues throughout the receptor, with ubiquitination occurring at multiple sites in both the extracellular domain and cytoplasmic regions[1][6][29]. The major docking site for Cbl recruitment is the phosphorylated tyrosine 1045 of EGFR, which binds the SH2 domain of Cbl[6][29][43]. However, Cbl recruitment is facilitated and stabilized through its interaction with GRB2, whose SH2 domain binds phosphorylated EGFR at Y1068 or Y1173 while its SH3 domains interact with proline-rich regions of Cbl[6][14].

Polyubiquitin chain formation on EGFR serves as a degradative signal, targeting the receptor for delivery to lysosomes where proteolysis occurs[1][6][26][29]. The ubiquitination process is directly proportional to receptor phosphorylation and is intimately coupled to receptor trafficking; Cbl-dependent ubiquitination promotes both the internalization of EGFR and its subsequent sorting toward degradative compartments[6][26]. The persistence of ubiquitination in endosomal compartments determines the degradative fate of the receptor[29]. When bound ligand rapidly dissociates (as with TGF-α), ubiquitination is rapidly lost, permitting receptor recycling; when ligand binding is stable (as with EGF), ubiquitination persists through the endosomal system, ensuring delivery to lysosomes[29].

Beyond its role in ubiquitination, Cbl regulates the integrity of the endosomal system itself[26]. Cbl controls fusion of early endosomes through regulation of the phosphorylation status of the Hrs protein, a key endosomal sorting factor[26]. The amino acid residues in Cbl's RING domain that mediate different functional outcomes have been individually mapped, revealing that certain mutations affect ubiquitination and degradation while others specifically affect endosomal fusion[26].

Biological Functions of EGFR

Cell Proliferation and Cell Cycle Progression

EGFR stimulation provides the primary mitogenic signals in numerous cell types, particularly epithelial cells derived from the skin, respiratory tract, gastrointestinal tract, and urinary system[1][3]. The central mechanism through which EGFR promotes cell cycle progression is through the induction of cyclin D1 expression and the subsequent activation of cyclin D-CDK4/6 complexes[54]. Activated EGFR, through combined actions of the MAPK/ERK and PI3K/AKT pathways, induces transcription of the CCND1 gene encoding cyclin D1[54]. Increased cyclin D1 levels drive the assembly of cyclin D-CDK4/6 complexes, which catalyze phosphorylation of the retinoblastoma tumor suppressor protein (Rb)[54].

The mechanism of Rb phosphorylation-dependent cell cycle progression has recently been clarified through biochemical studies: cyclin D-CDK4/6 catalyzes mono-phosphorylation of Rb at specific Cdk sites during early G1 phase, and this mono-phosphorylated form represents the biologically active Rb isoform that regulates global gene expression and responds to DNA damage signals[51]. The mono-phosphorylated Rb remains partially bound to E2F transcription factors but is incompletely effective at repressing S-phase entry genes[51]. At the G1 restriction point, cyclin E-CDK2 catalyzes hyper-phosphorylation of Rb at multiple sites, completely releasing E2F and allowing robust expression of S-phase entry genes including cyclin E itself, cyclin A2, and geminin[51].

EGFR simultaneously suppresses expression of cyclin-dependent kinase inhibitor proteins (CDKis) including p21 and p27 through both transcriptional and post-translational mechanisms, further driving cyclin-CDK complex formation and Rb phosphorylation[54]. The integration of these multiple mechanisms results in rapid progression through the G1/S checkpoint and DNA replication initiation[54].

Cell Migration and Wound Healing

EGFR signaling is essential for directional cell migration and wound healing responses, particularly in epithelial cells[33][36][43]. During wound healing, keratinocytes (epithelial cells of the skin) organize into two functionally distinct compartments: a leading edge of migratory, non-proliferating cells that extend across the wound bed, and a stationary proliferative zone behind the leading edge[33]. Live-cell imaging has revealed that this compartmentalization is not absolute; migratory proliferating cells exist between the two zones, indicating coordination between migration and proliferation[33].

Wounding of the epidermis triggers local production of EGF and other growth factors by infiltrating inflammatory cells (particularly macrophages and platelets) and injured cells themselves[33][36]. These growth factors activate EGFR in both the migratory and proliferative populations, though with distinct outcomes in each compartment[33]. In the migratory zone, EGFR-mediated signaling primarily through the PLCγ pathway promotes directional chemotaxis along the growth factor gradient and increases cell migration persistence (the tendency for cells to continue moving in the same direction rather than randomly reorienting)[36][43]. Mutation of the EGFR tyrosines that serve as PLCγ1 docking sites (Y992/Y1173) severely impairs chemotactic migration despite maintaining some overall PLCγ1 activation, demonstrating the importance of localized PLCγ1 signaling at the plasma membrane[43]. In contrast, the MAPK/ERK pathway signaling from EGFR is essential in the proliferative zone[43].

The mechanical presentation of growth factors influences the migration response; when EGF is presented in an immobilized form (covalently attached to a substrate) rather than in soluble form, cells exhibit sustained membrane localization of EGFR, enhanced and prolonged PLCγ1 phosphorylation (particularly at the cell's leading edge), increased migration persistence, and more directed migration toward the growth factor source[36]. This altered response to immobilized growth factors highlights the importance of EGFR trafficking dynamics: immobilized EGF prevents rapid internalization and endocytosis of the receptor, maintaining activated EGFR at the plasma membrane where it can sustain PLCγ1 signaling and promote directed migration[36].

Systemic age-associated decline in wound healing correlates with reduced phosphorylation of EGFR in wounded skin, indicating diminished EGFR activation with advancing age[33]. This appears to result from reduced local production of EGFR ligands in wounds rather than intrinsic loss of receptor responsiveness, as exogenous EGF application restores keratinocyte migration in aged cells[33]. Recent studies have identified the collagen XVII (COL17A1) protein as a novel EGFR ligand essential for keratinocyte motility and reepithelialization[33]. The EGFR-COL17A1 axis has emerged as a key regulator of epidermal regeneration, with potential therapeutic implications for age-associated impairment of wound healing[33].

Embryonic Development and Placentation

EGFR signaling is essential for normal embryonic development, as demonstrated by the profound developmental abnormalities in EGFR-null mice[47][57][60]. EGFR knockout mice exhibit strain-dependent lethality, with embryonic developmental ranging from mid-gestation death in some genetic backgrounds to perinatal survival in others[47][57][60]. The spectrum of defects observed in EGFR-deficient mice includes open eyelids, rudimentary whiskers, immature lungs, and defects in the epidermis[60]. Importantly, these defects correlate with the spatial distribution of EGFR expression during development, indicating that EGFR activity is directly required for the specific tissues affected[60]. At embryonic day 14.5, EGFR is prominently expressed in developing whisker placodes, the otic placode, skeletal muscle of the limbs, and interzones of presumptive joints[44].

Placental development is particularly sensitive to EGFR signaling deficiency[57]. Embryos with reduced EGFR signaling (through homozygosity for hypomorphic alleles such as wa2) exhibit placental abnormalities and consequent intrauterine growth restriction that is both strain-dependent and allele-dependent[57]. The severity of embryonic growth restriction correlates directly with reduction in placental mass, with highly significant correlations between placental and embryo weight observed (R2 = 0.78 in some strains), indicating that fetal growth is constrained by the placental phenotype rather than primary embryonic defects[57]. The trophoblast cells of the placenta, which express high EGFR levels, appear to be the primary target of EGFR signaling for normal placental development and nutrient transport capacity[57].

Immune Function and Antimicrobial Defense

EGFR signaling plays a previously underappreciated role in innate immune function. EGF is required for normal activation of the innate immune response in human skin, and EGFR activation is essential for the proper maturation and function of immune cells in response to microbial challenge[1]. Beyond its direct role in epithelial cells, EGFR signaling in multiple cell types contributes to host defense against pathogens. For example, during influenza A virus infection, the virus exploits EGFR/ERK signaling to suppress the interferon and interferon-stimulated gene response, thereby attenuating antiviral immunity[40]. The virus activates EGFR through transactivation mechanisms (not direct growth factor stimulation) and induces activation of the protein tyrosine phosphatase SHP2, which then suppresses interferon-β and interferon-stimulated gene induction[40]. Inhibition of EGFR or SHP2 during viral infection substantially enhances antiviral innate immune responses, both in cultured cells and in infected animals[40].

Fibrosis and Tissue Remodeling

EGFR signaling plays a critical role in the pathological process of fibroblast-to-myofibroblast differentiation, a key step in tissue fibrosis[1][55]. Myofibroblasts, which express high levels of alpha-smooth muscle actin (α-SMA) and produce excessive collagen, are central contributors to pathological fibrosis in various organs[1][55]. EGFR has been shown to regulate TGF-β1-dependent fibroblast-to-myofibroblast differentiation, and aberrant persistence of myofibroblasts in tissues due to dysregulated EGFR signaling contributes to progressive tissue fibrosis, organ dysfunction, and diseases including liver cirrhosis, myocardial fibrosis, chronic kidney disease, and hypertrophic or keloid scar formation in skin[1][55].

EGFR activation in the kidney regulates renal inflammation, cell growth, and fibrosis through both direct effects on renal epithelial and interstitial cells and indirect effects through modulation of the tumor microenvironment[55]. The connective tissue growth factor (CTGF/CCN2) has recently been characterized as a novel EGFR ligand with special relevance in chronic kidney disease pathogenesis[55].

EGFR Mutations and Oncogenic Activation

Oncogenic EGFR Mutations in Cancer

Aberrant EGFR expression, mutations, or post-translational modifications are implicated in the pathogenesis of numerous human malignancies, with particularly high prevalence in lung adenocarcinoma, glioblastoma, squamous cell carcinomas, and hepatocellular carcinoma[1][50][53][54]. Approximately 15-30% of non-small-cell lung carcinomas harbor activating EGFR mutations, predominantly in the kinase domain[50][53]. The two most common mutation types are point mutations (particularly L858R in exon 21) and in-frame deletions within exon 19[50][53].

Exon 19 deletion mutations, which are collectively referred to as ex19del mutations, comprise more than 20 distinct genomic variants that share the common feature of removing segments of the exon 19-encoded region that spans the β3 strand and αC helix of the kinase domain[50]. Molecular dynamics simulations and structural modeling of 60 patient-derived ex19del variants reveal substantial sequence-specific variation in their effects on receptor activation, dimerization propensity, enzyme kinetics, and tyrosine kinase inhibitor (TKI) sensitivity[50]. Notably, different ex19del variants display distinct patterns of ligand-independent activation: while E746_A750 and E746_S752 > V variants require some degree of ligand stimulation for optimal signaling, the L747_A750 > P variant forms highly active ligand-independent dimers, suggesting distinct molecular mechanisms of oncogenic activation[50].

The L858R mutation in the kinase domain stabilizes an active kinase conformation and promotes ligand-independent receptor activation by favoring the asymmetric dimer architecture even without ligand-induced transmembrane domain reorientation[50]. Notably, patients bearing exon 19 deletion mutations demonstrate significantly superior responses to EGFR tyrosine kinase inhibitors compared to L858R patients, with approximately double the progression-free and overall survival in retrospective cohorts, and this difference correlates with reduced ATP-binding affinity (lower Km values) in some ex19del variants including E746_S752 > V and L747_A750 > P[50][53].

The type III EGFR mutation (EGFRvIII), in which a substantial portion of the extracellular domain is deleted, is frequently observed in glioblastoma where the mutant receptor retains constitutive kinase activity despite lacking the ligand-binding domain[3]. This mutant EGFR exhibits ligand-independent signaling, sustained activation, impaired endocytosis and degradation, and is associated with aggressive glioblastoma phenotypes characterized by enhanced angiogenesis and therapy resistance[3][54].

EGFR-Mediated Effects on Tumor Microenvironment

Beyond its direct effects on cancer cell proliferation and survival, EGFR-mediated signaling in tumor cells regulates the tumor microenvironment through production of angiogenic factors and immune modulators[56][59]. EGFR signaling in tumor cells stimulates synthesis and secretion of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF)[59]. IL-8 produced by EGFR-activated tumor cells recruits neutrophils into the tumor microenvironment; these tumor-infiltrating neutrophils deliver matrix metalloproteinase-9 (MMP-9), which cleaves and releases VEGF from the extracellular matrix[56]. This MMP-9-released VEGF induces angiogenesis and, critically, increases vascular permeability through disruption of endothelial layer integrity[56].

High levels of tumor cell EGFR expression directly correlate with formation of permeable intratumoral vasculature and enhanced tumor cell intravasation (entry into blood vessels), a rate-limiting step in the metastatic cascade[56]. Silencing EGFR in highly disseminative tumor variants substantially reduces spontaneous metastasis and impairs the development of intratumoral vasculature with appropriate microarchitecture for supporting tumor cell extravasation[56]. This represents a novel mechanism through which EGFR activity facilitates cancer metastasis beyond direct effects on cancer cell proliferation and survival[56].

Therapeutic Targeting of EGFR

EGFR has become a major therapeutic target, with multiple classes of inhibitors in clinical use[1][3][54]. Monoclonal antibodies targeting the extracellular domain of EGFR (such as cetuximab and panitumumab) block ligand binding and promote receptor internalization and degradation[1]. Small-molecule tyrosine kinase inhibitors (TKIs) that target the intracellular kinase domain include first-generation reversible inhibitors such as gefitinib and erlotinib, which have shown remarkable efficacy in EGFR mutation-bearing tumors with response rates exceeding 60%, substantially higher than conventional chemotherapy response rates[1][54]. Later-generation irreversible TKIs such as brigatinib and osimertinib provide improved coverage of resistant mutations[1].

The therapeutic success of EGFR-targeted therapy in EGFR-mutant tumors contrasts sharply with more limited efficacy in tumors with wild-type EGFR, highlighting the critical distinction between oncogenic mutant and wild-type receptor signaling[1]. Combination therapies targeting EGFR simultaneously with downstream pathway components (such as PI3K/AKT or MEK/ERK inhibitors) show promise for overcoming adaptive resistance mechanisms and preventing compensatory pathway activation[3]. Additionally, the discovery that EGFR-targeted therapies may be more effective when combined with anti-vascular endothelial growth factor approaches suggests that concurrent targeting of EGFR-mediated tumor microenvironment remodeling may enhance therapeutic efficacy[56].

Conclusion

The epidermal growth factor receptor represents a paradigm of signal transduction complexity, coupling extracellular growth factor recognition through an allosteric mechanism to activation of multiple intracellular signaling cascades that orchestrate diverse cellular processes. The receptor's architecture, with its unique structure among RTKs, exhibits exquisite regulation through mechanisms including ligand-induced allosteric dimerization, asymmetric kinase domain dimers, substrate-specific phosphorylation, spatial segregation of signaling on and off the plasma membrane, and feedback regulation of its own activity. The coordinate activation of the MAPK/ERK, PI3K/AKT/mTOR, PLCγ-calcium, and STAT pathways downstream of EGFR provides integration of growth, survival, migration, and metabolic signals essential for normal development, tissue homeostasis, and regeneration. Dysregulation of EGFR through overexpression, ligand hypersensitivity, or activating mutations drives numerous human malignancies and has made EGFR a premier target for cancer therapeutics. The therapeutic success achieved through EGFR-targeted approaches validates the central importance of this receptor in controlling cellular fate decisions and has established principles for rational drug development against other tyrosine kinase signaling pathways.

Citations

https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor
https://www.ncbi.nlm.nih.gov/books/NBK482459/
https://lifesciences.danaher.com/us/en/library/egfr-signaling-pathway.html
https://www.ncbi.nlm.nih.gov/gene/1956
https://pmc.ncbi.nlm.nih.gov/articles/PMC3970421/
https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/protein-biology/protein-expression/egf-egfr-signaling
https://pmc.ncbi.nlm.nih.gov/articles/PMC1316279/
https://pubs.acs.org/doi/10.1021/bi00441a033
https://www.pnas.org/doi/10.1073/pnas.1520301113
https://pmc.ncbi.nlm.nih.gov/articles/PMC4824005/
https://pubmed.ncbi.nlm.nih.gov/7925442/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2590673/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2814540/
https://pmc.ncbi.nlm.nih.gov/articles/PMC10968029/
https://www.oncotarget.com/article/24499/text/
https://www.pnas.org/doi/10.1073/pnas.1220843110
https://www.molbiolcell.org/doi/10.1091/mbc.01-11-0552
https://academic.oup.com/nar/article/36/13/4337/2410590
https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0155230
https://pmc.ncbi.nlm.nih.gov/articles/PMC6851314/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8987160/
https://pmc.ncbi.nlm.nih.gov/articles/PMC10458925/
https://pubmed.ncbi.nlm.nih.gov/31537645/
https://aacrjournals.org/cancerres/article/82/12_Supplement/101/700244/Abstract-101-JAK-independent-STAT5-signaling-as-a
https://pmc.ncbi.nlm.nih.gov/articles/PMC5492017/
https://www.science.org/doi/10.1126/scisignal.2000217
https://www.pnas.org/doi/10.1073/pnas.1200105109
https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0054136
https://pmc.ncbi.nlm.nih.gov/articles/PMC2723868/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6590701/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2719887/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5075022/
https://rupress.org/jcb/article/220/11/e202012073/212656/EGFR-mediated-epidermal-stem-cell-motility-drives
https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.14868
https://en.wikipedia.org/wiki/MAPK/ERK_pathway
https://pmc.ncbi.nlm.nih.gov/articles/PMC4904288/
https://pmc.ncbi.nlm.nih.gov/articles/PMC207628/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6626828/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5354822/
https://journals.asm.org/doi/10.1128/jvi.02001-20
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1042787/full
https://pmc.ncbi.nlm.nih.gov/articles/PMC8699139/
https://pmc.ncbi.nlm.nih.gov/articles/PMC3154598/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5517093/
https://pmc.ncbi.nlm.nih.gov/articles/PMC9748436/
https://www.molbiolcell.org/doi/10.1091/mbc.E19-09-0548
https://pubmed.ncbi.nlm.nih.gov/19115345/
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202301209R
https://pmc.ncbi.nlm.nih.gov/articles/PMC125532/
https://www.pnas.org/doi/10.1073/pnas.2206588119
https://elifesciences.org/articles/02872
https://pubs.acs.org/doi/10.1021/pr3002029
https://pmc.ncbi.nlm.nih.gov/articles/PMC2359997/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5447962/
https://onlinelibrary.wiley.com/doi/10.1155/2018/8739473
https://pmc.ncbi.nlm.nih.gov/articles/PMC4674488/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2746145/
https://pubmed.ncbi.nlm.nih.gov/17894407/
https://www.science.org/doi/10.1126/science.7618085
NMR-guided structural models

Bioreason Rl Review

(EGFR-bioreason-rl-review.md)

BioReason-Pro RL Review: EGFR (human)

Source: EGFR-deep-research-bioreason-rl.md

Correctness: 5/5
Completeness: 4/5

Functional Summary Review

The BioReason functional summary states:

A single-pass cell-surface receptor that uses an extracellular ligand-binding scaffold and a cytosolic tyrosine kinase engine to transmit extracellular cues into intracellular signaling. The ectodomain forms a cysteine-rich, L-domain architecture that drives dimerization, which allosterically activates the intracellular kinase. This activation enables ATP-dependent phosphorylation of tyrosines and assembly of downstream signaling complexes that promote growth and proliferation.

This is an excellent summary that correctly captures EGFR's core biology. The description of the L-domain and cysteine-rich domain architecture driving ligand-induced dimerization, the single-pass transmembrane topology, and the intracellular tyrosine kinase activity (GO:0004714, transmembrane receptor protein tyrosine kinase activity) are all accurate and well-aligned with the curated review. The curated review describes EGFR as "a receptor tyrosine kinase that binds ligands of the EGF family and activates several signaling cascades."

The mechanistic model of trans-autophosphorylation creating docking sites for SH2/PTB-containing adaptors is correct and captures the essential signaling logic.

Minor completeness gaps: BioReason does not mention specific downstream pathways (RAS-MAPK, PI3K-AKT, STAT) or EGFR's role in receptor endocytosis and degradation, which the curated review covers extensively. The summary also does not address the clinically important role of EGFR in cancer biology, though this is arguably outside the scope of a functional annotation review.

Comparison with interpro2go:

The curated review includes interpro2go (GO_REF:0000002) annotations for protein kinase activity (GO:0004672), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), and membrane (GO:0016020), all accepted. BioReason arrives at all of these through its domain architecture analysis. The reasoning closely parallels interpro2go but adds useful narrative about the allosteric activation mechanism and dimerization logic. This represents a modest value-add over raw interpro2go.

Notes on thinking trace

The trace demonstrates excellent systematic reasoning through the domain architecture, correctly identifying all major InterPro entries and their functional implications. The ordered analysis from ectodomain to transmembrane to kinase domain is well-structured.

📄 View Raw YAML

id: P00533
gene_symbol: EGFR
aliases:
  - epidermal growth factor receptor
  - ERBB1
  - HER1
  - proto-oncogene c-ErbB-1
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Epidermal growth factor receptor (EGFR/ERBB1/HER1) is a receptor 
  tyrosine kinase (EC 2.7.10.1) that binds EGF family ligands (EGF, TGF-alpha, 
  amphiregulin, betacellulin, epiregulin, epigen, HB-EGF) to initiate signal 
  transduction cascades controlling cell proliferation, survival, 
  differentiation, and migration. Upon ligand binding, EGFR undergoes homo- or 
  heterodimerization (with ERBB2, ERBB3, ERBB4), which activates the 
  intracellular tyrosine kinase domain through trans-autophosphorylation. 
  Phosphorylated tyrosine residues in the C-terminal tail serve as docking sites
  for SH2/PTB domain-containing adaptor proteins (GRB2, SHC, etc.), leading to 
  activation of RAS-RAF-MEK-ERK (MAPK), PI3K-AKT, PLCgamma-PKC, and STAT 
  signaling pathways. EGFR localizes primarily to the plasma membrane and 
  continues signaling from early endosomes after clathrin-mediated endocytosis. 
  Receptor downregulation occurs through CBL-mediated ubiquitination and 
  lysosomal degradation. EGFR mutations and overexpression drive multiple 
  cancers including non-small cell lung cancer, colorectal cancer, and 
  glioblastoma.
existing_annotations:
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
      supported_by:
        - reference_id: file:human/EGFR/EGFR-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR positively regulates the MAPK cascade through recruitment of
        GRB2-SOS and activation of RAS-RAF-MEK-ERK signaling.
      action: ACCEPT
      reason: MAPK/ERK pathway activation is a core downstream signaling output 
        of EGFR. This is well-established.
  - term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that 
        phosphorylates tyrosine residues on substrate proteins following 
        ligand-induced dimerization. This is a core molecular function.
      action: ACCEPT
      reason: Transmembrane receptor protein tyrosine kinase activity is the 
        defining enzymatic function of EGFR. The kinase domain catalyzes 
        ATP-dependent phosphorylation of tyrosine residues.
  - term:
      id: GO:0030182
      label: neuron differentiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR signaling influences neuron differentiation, a downstream 
        developmental effect.
      action: KEEP_AS_NON_CORE
      reason: Neuron differentiation is a downstream developmental process 
        influenced by EGFR signaling, not a core molecular function.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR signaling promotes cell survival by activating 
        anti-apoptotic pathways including PI3K-AKT.
      action: KEEP_AS_NON_CORE
      reason: Anti-apoptotic effects are downstream consequences of 
        EGFR-PI3K-AKT signaling, not a core function.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
  - term:
      id: GO:0050679
      label: positive regulation of epithelial cell proliferation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR signaling promotes epithelial cell proliferation, a key 
        downstream effect in epithelial tissues.
      action: KEEP_AS_NON_CORE
      reason: Epithelial cell proliferation is a major physiological outcome of 
        EGFR signaling but represents a downstream effect.
  - term:
      id: GO:0043235
      label: receptor complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR forms homo- and heterodimeric receptor complexes upon ligand
        binding, which is required for kinase activation.
      action: ACCEPT
      reason: EGFR dimerization into receptor complexes is essential for signal 
        transduction. EGFR forms homodimers and heterodimers with ERBB2, ERBB3, 
        ERBB4.
  - term:
      id: GO:0009925
      label: basal plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR localizes to the basal plasma membrane in polarized cells.
      action: ACCEPT
      reason: Basal plasma membrane localization is consistent with EGFR 
        function in polarized cells.
  - term:
      id: GO:0048408
      label: epidermal growth factor binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EGFR binds EGF through its extracellular domain (subdomains I and
        III), which induces receptor dimerization and activation.
      action: ACCEPT
      reason: EGF binding is the canonical ligand-binding function of EGFR. 
        Crystal structures confirm EGF binds domains I and III of the 
        extracellular region.
  - term:
      id: GO:0000165
      label: MAPK cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: EGFR participates in the MAPK cascade by activating 
        RAS-RAF-MEK-ERK signaling upon ligand binding.
      action: ACCEPT
      reason: MAPK cascade activation is a principal downstream effect of EGFR 
        signaling.
  - term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that 
        phosphorylates tyrosine residues on substrate proteins following 
        ligand-induced dimerization. This is a core molecular function.
      action: ACCEPT
      reason: Transmembrane receptor protein tyrosine kinase activity is the 
        defining enzymatic function of EGFR. The kinase domain catalyzes 
        ATP-dependent phosphorylation of tyrosine residues.
  - term:
      id: GO:0046718
      label: symbiont entry into host cell
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: EGFR can serve as a receptor for viral entry, including some 
        herpesviruses.
      action: KEEP_AS_NON_CORE
      reason: Viral receptor function is not a normal physiological function of 
        EGFR.
  - term:
      id: GO:0000139
      label: Golgi membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EGFR localizes to Golgi membranes during biosynthesis.
      action: ACCEPT
      reason: Part of normal EGFR trafficking through the secretory pathway.
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: EGFR binds nucleotides (ATP) for its kinase activity.
      action: ACCEPT
      reason: General parent term for ATP binding, accurate for EGFR.
  - term:
      id: GO:0001618
      label: virus receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: EGFR can act as a receptor for certain viruses.
      action: KEEP_AS_NON_CORE
      reason: Virus receptor activity is not a core physiological function.
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: EGFR has protein kinase activity, phosphorylating protein 
        substrates on tyrosine residues.
      action: ACCEPT
      reason: Accurate parent term for the protein tyrosine kinase activity of 
        EGFR.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR binds ATP in its kinase domain active site to catalyze 
        phosphorylation reactions.
      action: ACCEPT
      reason: ATP binding is essential for EGFR kinase activity. The ATP-binding
        pocket in the kinase domain is the target of many therapeutic 
        inhibitors.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: The EGFR extracellular domain is exposed to the extracellular 
        region.
      action: ACCEPT
      reason: The ligand-binding ectodomain of EGFR is in the extracellular 
        region.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Nuclear EGFR has been described in certain contexts and may have 
        transcriptional roles.
      action: KEEP_AS_NON_CORE
      reason: Nuclear EGFR is documented but represents a minor, 
        context-dependent localization rather than core EGFR function.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EGFR localizes to endosomes following ligand-induced 
        internalization. EGFR continues signaling from early endosomes and is 
        subsequently sorted for recycling or lysosomal degradation.
      action: ACCEPT
      reason: Endosomal localization is part of normal EGFR trafficking and 
        signaling. EGFR signals from endosomes and trafficking modulates signal 
        duration.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EGFR is synthesized and processed in the ER membrane.
      action: ACCEPT
      reason: Part of normal EGFR biosynthesis in the secretory pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: EGFR is a cell surface receptor protein tyrosine kinase that 
        initiates signaling upon ligand binding.
      action: ACCEPT
      reason: This is the parent pathway term that accurately describes EGFR 
        function.
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EGFR localizes to endosome membranes during receptor trafficking 
        after internalization.
      action: ACCEPT
      reason: After ligand-induced endocytosis, EGFR is found on endosome 
        membranes where it continues to signal.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: EGFR is a single-pass transmembrane protein with extracellular, 
        transmembrane, and intracellular domains. The membrane localization is 
        fundamental to its structure and function.
      action: ACCEPT
      reason: As a transmembrane receptor, EGFR requires membrane localization 
        for proper protein topology, with the extracellular domain for ligand 
        binding and the intracellular kinase domain for signal transduction.
  - term:
      id: GO:0016301
      label: kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR has kinase activity, a parent term of protein tyrosine 
        kinase activity.
      action: ACCEPT
      reason: This is a general parent term that accurately describes EGFR 
        function, though more specific terms are preferred.
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: EGFR has transferase activity as it transfers phosphate groups 
        from ATP to protein substrates.
      action: ACCEPT
      reason: Very general parent term but accurate for EGFR kinase function.
  - term:
      id: GO:0031965
      label: nuclear membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EGFR has been reported at the nuclear membrane in certain 
        contexts.
      action: KEEP_AS_NON_CORE
      reason: Nuclear membrane localization is not a primary EGFR localization.
  - term:
      id: GO:0043235
      label: receptor complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: EGFR forms homo- and heterodimeric receptor complexes upon ligand
        binding, which is required for kinase activation.
      action: ACCEPT
      reason: EGFR dimerization into receptor complexes is essential for signal 
        transduction. EGFR forms homodimers and heterodimers with ERBB2, ERBB3, 
        ERBB4.
  - term:
      id: GO:0070374
      label: positive regulation of ERK1 and ERK2 cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: EGFR positively regulates ERK1/2 cascade through RAS-RAF-MEK-ERK 
        signaling axis.
      action: ACCEPT
      reason: ERK1/2 activation is a core readout of EGFR signaling through the 
        MAPK pathway.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10229072
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:10229072
          supporting_text: Association of Nck with tyrosine-phosphorylated 
            SLP-76 in activated T lymphocytes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10572067
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:10572067
          supporting_text: Dominance of ErbB-1 heterodimers in lung epithelial 
            cells overexpressing ErbB-2.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10805725
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:10805725
          supporting_text: Class II phosphoinositide 3-kinases are downstream 
            targets of activated polypeptide growth factor receptors.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11896612
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:11896612
          supporting_text: Use of signal specific receptor tyrosine kinase 
            oncoproteins reveals that pathways downstream from Grb2 or Shc are 
            sufficient for cell transformation and metastasis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12070153
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:12070153
          supporting_text: 2002 Jun 17. Identification of both positive and 
            negative domains within the epidermal growth factor receptor 
            COOH-terminal region for signal transducer and activator of 
            transcription (STAT) activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12297049
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:12297049
          supporting_text: Crystal structure of a truncated epidermal growth 
            factor receptor extracellular domain bound to transforming growth 
            factor alpha.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12297050
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:12297050
          supporting_text: Crystal structure of the complex of human epidermal 
            growth factor and receptor extracellular domains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12577067
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:12577067
          supporting_text: A proteomics strategy to elucidate functional 
            protein-protein interactions applied to EGF signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12620237
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:12620237
          supporting_text: EGF activates its receptor by removing interactions 
            that autoinhibit ectodomain dimerization.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14568990
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:14568990
          supporting_text: Oct 20. Role of the pleckstrin homology domain of 
            PLCgamma1 in its interaction with the insulin receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14679214
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:14679214
          supporting_text: 2003 Dec 16. A novel proteomic screen for 
            peptide-protein interactions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14966128
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:14966128
          supporting_text: 2004 Feb 13. Structural requirements for signal 
            transducer and activator of transcription 3 binding to 
            phosphotyrosine ligands containing the YXXQ motif.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15225635
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:15225635
          supporting_text: Identification of 14-3-3zeta as an EGF receptor 
            interacting protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15282549
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:15282549
          supporting_text: Jul 29. LRIG1 restricts growth factor signaling by 
            enhancing receptor ubiquitylation and degradation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15345710
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:15345710
          supporting_text: 2004 Sep 1. The leucine-rich repeat protein LRIG1 is 
            a negative regulator of ErbB family receptor tyrosine kinases.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15657067
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:15657067
          supporting_text: Epub 2005 Jan 17. Phosphotyrosine signaling networks 
            in epidermal growth factor receptor overexpressing squamous 
            carcinoma cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15962011
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:15962011
          supporting_text: Sprouty2 acts at the Cbl/CIN85 interface to inhibit 
            epidermal growth factor receptor downregulation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16253990
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16253990
          supporting_text: Oct 27. Increased proliferation and altered growth 
            factor dependence of human mammary epithelial cells overexpressing 
            the Gab2 docking protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16273093
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16273093
          supporting_text: A quantitative protein interaction network for the 
            ErbB receptors using protein microarrays.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16499958
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16499958
          supporting_text: Feb 23. Crystal structure of the ubiquitin binding 
            domains of rabex-5 reveals two modes of interaction with ubiquitin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16516204
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16516204
          supporting_text: 'Epub 2006 Feb 28. Activation of ErbB2 by 2-methyl-1,4-naphthoquinone
            (menadione) in human keratinocytes: role of EGFR and protein tyrosine
            phosphatases.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16799092
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16799092
          supporting_text: Epub 2006 Jun 23. Dynamic profiling of the 
            post-translational modifications and interaction partners of 
            epidermal growth factor receptor signaling after stimulation by 
            epidermal growth factor using Extended Range Proteomic Analysis 
            (ERPA).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16843263
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16843263
          supporting_text: HER2 kinase domain mutation results in constitutive 
            phosphorylation and activation of HER2 and EGFR and resistance to 
            EGFR tyrosine kinase inhibitors.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16914641
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16914641
          supporting_text: Aug 16. Intersectin regulates epidermal growth factor
            receptor endocytosis, ubiquitylation, and signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16954185
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:16954185
          supporting_text: Advanced glycation end product (AGE) receptor 1 
            suppresses cell oxidant stress and activation signaling via EGF 
            receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17126326
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17126326
          supporting_text: Epub 2006 Nov 20. Extracellular heat shock protein 70
            mediates heat stress-induced epidermal growth factor receptor 
            transactivation in A431 carcinoma cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17148612
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17148612
          supporting_text: A system for quantifying dynamic protein interactions
            defines a role for Herceptin in modulating ErbB2 interactions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17284441
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17284441
          supporting_text: 2007 Feb 5. Epidermal growth factor directs 
            sex-specific steroid signaling through Src activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17403676
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17403676
          supporting_text: 2007 Apr 2. Rin1 interacts with signal-transducing 
            adaptor molecule (STAM) and mediates epidermal growth factor 
            receptor trafficking and degradation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17697999
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17697999
          supporting_text: Ligand-induced structural transitions in ErbB 
            receptor extracellular domains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17726113
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17726113
          supporting_text: Inhibition of the leucine-rich repeat protein LINGO-1
            enhances survival, structure, and function of dopaminergic neurons 
            in Parkinson's disease models.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18046415
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18046415
          supporting_text: Inhibition of the EGF receptor by binding of MIG6 to 
            an activating kinase domain interface.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18273061
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18273061
          supporting_text: Structural basis for a novel intrapeptidyl H-bond and
            reverse binding of c-Cbl-TKB domain substrates.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18455122
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18455122
          supporting_text: Survival of cancer cells is maintained by EGFR 
            independent of its kinase activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18542056
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18542056
          supporting_text: LRIG1 negatively regulates the oncogenic EGF receptor
            mutant EGFRvIII.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18776048
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18776048
          supporting_text: Comparisons of tyrosine phosphorylated proteins in 
            cells expressing lung cancer-specific alleles of EGFR and KRAS.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18824549
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18824549
          supporting_text: 2008 Sep 29. Acidic mammalian chitinase is secreted 
            via an ADAM17/epidermal growth factor receptor-dependent pathway and
            stimulates chemokine production by pulmonary epithelial cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19167335
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:19167335
          supporting_text: Large-scale structural analysis of the classical 
            human protein tyrosine phosphatome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19172738
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:19172738
          supporting_text: Phosphorylation-dependent binding of 14-3-3 
            terminates signalling by the Gab2 docking protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19650109
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:19650109
          supporting_text: Flow cytometric in situ proximity ligation analyses 
            of protein interactions and post-translational modification of the 
            epidermal growth factor receptor family.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19798056
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:19798056
          supporting_text: Participation of Tom1L1 in EGF-stimulated endocytosis
            of EGF receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20029029
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20029029
          supporting_text: Regulation of epidermal growth factor receptor 
            trafficking by lysine deacetylase HDAC6.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20153921
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20153921
          supporting_text: 2010 Feb 13. EGFR and EGFRvIII interact with PUMA to 
            inhibit mitochondrial translocalization of PUMA and PUMA-mediated 
            apoptosis independent of EGFR kinase activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20308550
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20308550
          supporting_text: The phosphatase and tensin homolog regulates 
            epidermal growth factor receptor (EGFR) inhibitor response by 
            targeting EGFR for degradation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20403327
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20403327
          supporting_text: TRP channel regulates EGFR signaling in hair 
            morphogenesis and skin barrier formation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20473329
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20473329
          supporting_text: SIRPalpha1 receptors interfere with the EGFRvIII 
            signalosome to inhibit glioblastoma cell transformation and 
            migration.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20562913
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20562913
          supporting_text: Differential roles of ERK and Akt pathways in 
            regulation of EGFR-mediated signaling and motility in prostate 
            cancer cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20624308
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20624308
          supporting_text: EGFR/Met association regulates EGFR TKI resistance in
            breast cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20935677
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20935677
          supporting_text: A positive feedback loop of ER-α36/EGFR promotes 
            malignant growth of ER-negative breast cancer cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21203579
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21203579
          supporting_text: HER2 phosphorylation is maintained by a PKB negative 
            feedback loop in response to anti-HER2 herceptin in breast cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21258405
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21258405
          supporting_text: Galectin-3 regulates MUC1 and EGFR cellular 
            distribution and EGFR downstream pathways in pancreatic cancer 
            cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21266349
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21266349
          supporting_text: 2011 Jan 25. EGFR nuclear translocation modulates DNA
            repair following cisplatin and ionizing radiation treatment.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21278786
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21278786
          supporting_text: PI3K inhibition results in enhanced HER signaling and
            acquired ERK dependency in HER2-overexpressing breast cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21278788
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21278788
          supporting_text: Translationally controlled tumor protein induces 
            human breast epithelial cell transformation through the activation 
            of Src.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21349850
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21349850
          supporting_text: 2011 Feb 24. MAPK scaffold IQGAP1 binds the EGF 
            receptor and modulates its activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21376233
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21376233
          supporting_text: Activation of multiple proto-oncogenic tyrosine 
            kinases in breast cancer via loss of the PTPN12 phosphatase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21439278
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21439278
          supporting_text: 2011 Mar 23. Engineered epidermal growth factor 
            mutants with faster binding on-rates correlate with enhanced 
            receptor activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21706016
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21706016
          supporting_text: Selected reaction monitoring mass spectrometry 
            reveals the dynamics of signaling through the GRB2 adaptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21822280
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21822280
          supporting_text: Simultaneous visualization of the extracellular and 
            cytoplasmic domains of the epidermal growth factor receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21951318
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:21951318
          supporting_text: Ligand-dependent differences in estrogen receptor 
            beta-interacting proteins identified in lung adenocarcinoma cells 
            corresponds to estrogenic responses.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22411794
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:22411794
          supporting_text: Hypoxia promotes ligand-independent EGF receptor 
            signaling via hypoxia-inducible factor-mediated upregulation of 
            caveolin-1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22439932
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:22439932
          supporting_text: NKX2-1/TITF1/TTF-1-Induced ROR1 is required to 
            sustain EGFR survival signaling in lung adenocarcinoma.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22939624
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:22939624
          supporting_text: Quantitative analysis of HSP90-client interactions 
            reveals principles of substrate recognition.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23178489
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23178489
          supporting_text: The role of insulin-like growth factor binding 
            protein-3 in the breast cancer cell response to DNA-damaging agents.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23178716
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23178716
          supporting_text: 2012 Nov 21. SnoN/SkiL expression is modulated via 
            arsenic trioxide-induced activation of the PI3K/AKT pathway in 
            ovarian cancer cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23273428
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23273428
          supporting_text: Dec 27. Insights into the aberrant activity of mutant
            EGFR kinase domain and drug recognition.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23397142
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23397142
          supporting_text: Epub 2013 Feb 8. Analysis of protein-protein 
            interactions in cross-talk pathways reveals CRKL protein as a novel 
            prognostic marker in hepatocellular carcinoma.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23436906
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23436906
          supporting_text: Epub 2013 Feb 22. Parallel visualization of multiple 
            protein complexes in individual cells in tumor tissue.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23520446
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23520446
          supporting_text: 'Protein phosphorylation profiling using an in situ proximity
            ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046
            in lung cancer cells.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23597562
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23597562
          supporting_text: Inhibition of tumor angiogenesis and growth by a 
            small-molecule multi-FGF receptor blocker with allosteric 
            properties.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23636329
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23636329
          supporting_text: EGFR modulates microRNA maturation in response to 
            hypoxia through phosphorylation of AGO2.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23764002
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23764002
          supporting_text: Epidermal growth factor receptor potentiates 
            MCM7-mediated DNA replication through tyrosine phosphorylation of 
            Lyn kinase in human cancers.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23799367
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23799367
          supporting_text: Threshold-controlled ubiquitination of the EGFR 
            directs receptor fate.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23866081
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23866081
          supporting_text: Lyn, a Src family kinase, regulates activation of 
            epidermal growth factor receptors in lung adenocarcinoma cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24034250
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24034250
          supporting_text: EGFR-mediated Beclin 1 phosphorylation in autophagy 
            suppression, tumor progression, and tumor chemoresistance.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24076656
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24076656
          supporting_text: Endophilin, Lamellipodin, and Mena cooperate to 
            regulate F-actin-dependent EGF-receptor endocytosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24135280
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24135280
          supporting_text: EGFR phosphorylates tumor-derived EGFRvIII driving 
            STAT3/5 and progression in glioblastoma.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24189400
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24189400
          supporting_text: Perturbation of the mutated EGFR interactome 
            identifies vulnerabilities and resistance mechanisms.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24557338
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24557338
          supporting_text: Characterisation of HER heterodimers in breast cancer
            using in situ proximity ligation assay.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24658140
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24658140
          supporting_text: The mammalian-membrane two-hybrid assay (MaMTH) for 
            probing membrane-protein interactions in human cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24780295
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24780295
          supporting_text: Importance of EGFR/ERCC1 interaction following 
            radiation-induced DNA damage.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24947832
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24947832
          supporting_text: Differential protein-protein interactions of LRRK1 
            and LRRK2 indicate roles in distinct cellular signaling pathways.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25036637
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25036637
          supporting_text: A quantitative chaperone interaction network reveals 
            the architecture of cellular protein homeostasis pathways.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25136068
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25136068
          supporting_text: Epub 2014 Aug 18. Mycoplasma hyorhinis infection 
            promotes NF-κB-dependent migration of gastric cancer cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25241761
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25241761
          supporting_text: Oct 9. Using an in situ proximity ligation assay to 
            systematically profile endogenous protein-protein interactions in a 
            pathway network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25353163
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25353163
          supporting_text: eCollection 2014. Soluble LRIG2 ectodomain is 
            released from glioblastoma cells and promotes the proliferation and 
            inhibits the apoptosis of glioblastoma cells in vitro and in vivo in
            a similar manner to the full-length LRIG2.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25594178
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25594178
          supporting_text: A kinase-independent role for EGF receptor in 
            autophagy initiation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25796184
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25796184
          supporting_text: 2015 Mar 18. PEA-15 facilitates EGFR 
            dephosphorylation via ERK sequestration at increased ER-PM contacts 
            in TNBC cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25873175
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25873175
          supporting_text: AXL mediates resistance to PI3Kα inhibition by 
            activating the EGFR/PKC/mTOR axis in head and neck and esophageal 
            squamous cell carcinomas.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25970784
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25970784
          supporting_text: PTPRG suppresses tumor growth and invasion via 
            inhibition of Akt signaling in nasopharyngeal carcinoma.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26005835
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:26005835
          supporting_text: RasGRP1 opposes proliferative EGFR-SOS1-Ras signals 
            and restricts intestinal epithelial cell growth.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26280537
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:26280537
          supporting_text: Secreted and O-GlcNAcylated MIF binds to the human 
            EGF receptor and inhibits its activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26551075
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:26551075
          supporting_text: Nov 9. EGF-receptor specificity for 
            phosphotyrosine-primed substrates provides signal integration with 
            Src.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26751287
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:26751287
          supporting_text: The LINK-A lncRNA activates normoxic HIF1α signalling
            in triple-negative breast cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27059931
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:27059931
          supporting_text: Apr 16. Weak binding to E3 ubiquitin ligase c-Cbl 
            increases EGFRvA protein stability.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27569582
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:27569582
          supporting_text: 2016 Aug 25. GOLM1 Modulates EGFR/RTK Cell-Surface 
            Recycling to Drive Hepatocellular Carcinoma Metastasis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:2790960
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:2790960
          supporting_text: Functional independence of the epidermal growth 
            factor receptor from a domain required for ligand-induced 
            internalization and calcium regulation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27956147
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:27956147
          supporting_text: 2016 Dec 9. Systematic Identification of Oncogenic 
            EGFR Interaction Partners.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28065597
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:28065597
          supporting_text: 2017 Jan 5. A Global Analysis of the Receptor 
            Tyrosine Kinase-Protein Phosphatase Interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28988771
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:28988771
          supporting_text: 2017 Oct 5. EGFR Ligands Differentially Stabilize 
            Receptor Dimers to Specify Signaling Kinetics.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29455656
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:29455656
          supporting_text: The E3 ubiquitin ligase NEDD4 mediates cell migration
            signaling of EGFR in lung cancer cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29844572
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:29844572
          supporting_text: May 29. RANK-c attenuates aggressive properties of 
            ER-negative breast cancer by inhibiting NF-κB activation and EGFR 
            signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30083275
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:30083275
          supporting_text: The S100A4 Protein Signals through the ErbB4 Receptor
            to Promote Neuronal Survival.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30662352
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:30662352
          supporting_text: COPI-Mediated Nuclear Translocation of EGFRvIII 
            Promotes STAT3 Phosphorylation and PKM2 Nuclear Localization.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31585087
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:31585087
          supporting_text: Oncogenic Mutations Rewire Signaling Pathways by 
            Switching Protein Recruitment to Phosphotyrosine Sites.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31862538
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:31862538
          supporting_text: Neuropeptide bombesin receptor activation stimulates 
            growth of lung cancer cells through HER3 with a MAPK-dependent 
            mechanism.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31980649
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:31980649
          supporting_text: Extensive rewiring of the EGFR network in colorectal 
            cancer cells expressing transforming levels of KRAS(G13D).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33420426
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:33420426
          supporting_text: Jan 8. AXL is a candidate receptor for SARS-CoV-2 
            that promotes infection of pulmonary and bronchial epithelial cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:34591612
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:34591612
          supporting_text: Oct 1. A protein interaction landscape of breast 
            cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:34591642
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:34591642
          supporting_text: Oct 1. A protein network map of head and neck cancer 
            reveals PIK3CA mutant drug sensitivity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35384245
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:35384245
          supporting_text: Physical and functional interactome atlas of human 
            receptor tyrosine kinases.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35512704
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:35512704
          supporting_text: 2022 May 4. Systematic discovery of mutation-directed
            neo-protein-protein interactions in cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:37100772
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:37100772
          supporting_text: Large-scale phage-based screening reveals extensive 
            pan-viral mimicry of host short linear motifs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7518560
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:7518560
          supporting_text: Hierarchy of binding sites for Grb2 and Shc on the 
            epidermal growth factor receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7542744
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:7542744
          supporting_text: The phosphotyrosine interaction domain of Shc binds 
            an LXNPXY motif on the epidermal growth factor receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7657591
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:7657591
          supporting_text: Tyrosine phosphorylation of the c-cbl proto-oncogene 
            protein product and association with epidermal growth factor (EGF) 
            receptor upon EGF stimulation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7685104
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:7685104
          supporting_text: Substrate specificity of the protein tyrosine 
            phosphatases.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7693694
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:7693694
          supporting_text: Sequence specificity in recognition of the epidermal 
            growth factor receptor by protein tyrosine phosphatase 1B.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7797556
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:7797556
          supporting_text: Src phosphorylation of the epidermal growth factor 
            receptor at novel sites mediates receptor interaction with Src and 
            P85 alpha.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7993895
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:7993895
          supporting_text: Identification of amino acids in the N-terminal SH2 
            domain of phospholipase C gamma 1 important in the interaction with 
            epidermal growth factor receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8034616
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:8034616
          supporting_text: Tyrosines 1148 and 1173 of activated human epidermal 
            growth factor receptors are binding sites of Shc in intact cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8621392
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:8621392
          supporting_text: Determinants of substrate recognition in the 
            protein-tyrosine phosphatase, PTP1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8887653
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:8887653
          supporting_text: The phosphotyrosine interaction domains of X11 and 
            FE65 bind to distinct sites on the YENPTY motif of amyloid precursor
            protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8940013
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:8940013
          supporting_text: The Grb2-mSos1 complex binds phosphopeptides with 
            higher affinity than Grb2.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9020117
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9020117
          supporting_text: Subsets of epidermal growth factor receptors during 
            activation and endocytosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9050838
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9050838
          supporting_text: Development of "substrate-trapping" mutants to 
            identify physiological substrates of protein tyrosine phosphatases.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9135143
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9135143
          supporting_text: Activation of HER4 by heparin-binding EGF-like growth
            factor stimulates chemotaxis but not proliferation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9355745
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9355745
          supporting_text: Protein tyrosine phosphatase 1B interacts with and is
            tyrosine phosphorylated by the epidermal growth factor receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9506989
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9506989
          supporting_text: Grb10 interacts differentially with the insulin 
            receptor, insulin-like growth factor I receptor, and epidermal 
            growth factor receptor via the Grb10 Src homology 2 (SH2) domain and
            a second novel domain located between the pleckstrin homology and 
            SH2 domains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9544989
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9544989
          supporting_text: Shc phosphotyrosine-binding domain dominantly 
            interacts with epidermal growth factor receptors and mediates Ras 
            activation in intact cells.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:16777603
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:16777603
          supporting_text: An allosteric mechanism for activation of the kinase 
            domain of epidermal growth factor receptor.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:17148612
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:17148612
          supporting_text: A system for quantifying dynamic protein interactions
            defines a role for Herceptin in modulating ErbB2 interactions.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:18042729
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:18042729
          supporting_text: Epidermal growth factor receptor juxtamembrane region
            regulates allosteric tyrosine kinase activation.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:19563760
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:19563760
          supporting_text: Mechanism for activation of the EGF receptor 
            catalytic domain by the juxtamembrane segment.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:19650109
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:19650109
          supporting_text: Flow cytometric in situ proximity ligation analyses 
            of protein interactions and post-translational modification of the 
            epidermal growth factor receptor family.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:20007378
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:20007378
          supporting_text: Structural analysis of the catalytically inactive 
            kinase domain of the human EGF receptor 3.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:20029029
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:20029029
          supporting_text: Regulation of epidermal growth factor receptor 
            trafficking by lysine deacetylase HDAC6.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:20359299
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:20359299
          supporting_text: 'A proximity ligation assay using transiently transfected,
            epitope-tagged proteins: application for in situ detection of dimerized
            receptor tyrosine kinases.'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:21278786
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:21278786
          supporting_text: PI3K inhibition results in enhanced HER signaling and
            acquired ERK dependency in HER2-overexpressing breast cancer.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:21480528
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:21480528
          supporting_text: Apr 8. Comparative analysis of fluorescence resonance
            energy transfer (FRET) and proximity ligation assay (PLA).
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:21482778
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:21482778
          supporting_text: Quantification of receptor tyrosine kinase 
            transactivation through direct dimerization and surface density 
            measurements in single cells.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:22232519
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:22232519
          supporting_text: Epub 2012 Jan 9. In situ analysis of mutant EGFRs 
            prevalent in glioblastoma multiforme reveals aberrant dimerization, 
            activation, and differential response to anti-EGFR targeted therapy.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:22579287
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:22579287
          supporting_text: Oncogenic mutations counteract intrinsic disorder in 
            the EGFR kinase and promote receptor dimerization.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23273428
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:23273428
          supporting_text: Dec 27. Insights into the aberrant activity of mutant
            EGFR kinase domain and drug recognition.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23374349
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:23374349
          supporting_text: Conformational coupling across the plasma membrane in
            activation of the EGF receptor.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23436906
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:23436906
          supporting_text: Epub 2013 Feb 22. Parallel visualization of multiple 
            protein complexes in individual cells in tumor tissue.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23636329
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:23636329
          supporting_text: EGFR modulates microRNA maturation in response to 
            hypoxia through phosphorylation of AGO2.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:24135280
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:24135280
          supporting_text: EGFR phosphorylates tumor-derived EGFRvIII driving 
            STAT3/5 and progression in glioblastoma.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:28988771
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:28988771
          supporting_text: 2017 Oct 5. EGFR Ligands Differentially Stabilize 
            Receptor Dimers to Specify Signaling Kinetics.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:31980649
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:31980649
          supporting_text: Extensive rewiring of the EGFR network in colorectal 
            cancer cells expressing transforming levels of KRAS(G13D).
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:35512704
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:35512704
          supporting_text: 2022 May 4. Systematic discovery of mutation-directed
            neo-protein-protein interactions in cancer.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:38572507
    review:
      summary: EGFR undergoes homodimerization, binding to itself as part of the
        activation mechanism.
      action: ACCEPT
      reason: EGFR homodimerization is essential for kinase activation. Ligand 
        binding promotes EGFR-EGFR homodimer formation.
      supported_by:
        - reference_id: PMID:38572507
          supporting_text: Apr 4. DRD1 suppresses cell proliferation and reduces
            EGFR activation and PD-L1 expression in NSCLC.
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-212718
    review:
      summary: EGFR mediates signal transduction from extracellular growth 
        factors to intracellular signaling cascades.
      action: ACCEPT
      reason: Signal transduction is a core function of EGFR as a receptor 
        tyrosine kinase.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177929
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
  - term:
      id: GO:0042059
      label: negative regulation of epidermal growth factor receptor signaling 
        pathway
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-182971
    review:
      summary: EGFR participates in negative regulation of its own signaling 
        through internalization and degradation mechanisms.
      action: ACCEPT
      reason: EGFR signaling is subject to negative feedback through receptor 
        internalization, ubiquitination by CBL, and lysosomal degradation.
  - term:
      id: GO:0000902
      label: cell morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling influences cell morphogenesis.
      action: KEEP_AS_NON_CORE
      reason: Cell morphogenesis is a downstream developmental effect.
  - term:
      id: GO:0001892
      label: embryonic placenta development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling contributes to embryonic placenta development.
      action: KEEP_AS_NON_CORE
      reason: Developmental process downstream of EGFR signaling in specific 
        tissues.
  - term:
      id: GO:0001942
      label: hair follicle development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling is required for hair follicle development.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific developmental process regulated by EGFR.
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
  - term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR undergoes ubiquitin-dependent degradation.
      action: KEEP_AS_NON_CORE
      reason: EGFR is ubiquitinated and degraded, but this describes its 
        regulation rather than function.
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR mediates signal transduction from extracellular growth 
        factors to intracellular signaling cascades.
      action: ACCEPT
      reason: Signal transduction is a core function of EGFR as a receptor 
        tyrosine kinase.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
  - term:
      id: GO:0007435
      label: salivary gland morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling contributes to salivary gland development.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific developmental process.
  - term:
      id: GO:0008283
      label: cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling influences cell proliferation.
      action: KEEP_AS_NON_CORE
      reason: Cell proliferation is a downstream effect of EGFR activation.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling promotes cell proliferation through MAPK and PI3K 
        pathways.
      action: KEEP_AS_NON_CORE
      reason: Cell proliferation is a downstream phenotypic effect of EGFR 
        signaling.
  - term:
      id: GO:0008544
      label: epidermis development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling is critical for epidermis development.
      action: KEEP_AS_NON_CORE
      reason: Developmental process in EGFR's namesake tissue, but represents 
        downstream effects.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR localizes to the cell surface where it is accessible for 
        ligand binding.
      action: ACCEPT
      reason: Cell surface localization is consistent with EGFR function as a 
        receptor for extracellular growth factors.
  - term:
      id: GO:0010467
      label: gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling regulates gene expression.
      action: KEEP_AS_NON_CORE
      reason: Gene expression regulation is a downstream effect of EGFR 
        signaling.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: In polarized epithelial cells, EGFR localizes to the basolateral 
        plasma membrane.
      action: ACCEPT
      reason: EGFR shows polarized distribution in epithelial cells, localizing 
        to basolateral membranes.
  - term:
      id: GO:0016567
      label: protein ubiquitination
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR is ubiquitinated by CBL for endocytosis and degradation.
      action: KEEP_AS_NON_CORE
      reason: Describes EGFR regulation, not its enzymatic function.
  - term:
      id: GO:0021795
      label: cerebral cortex cell migration
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling influences cortical cell migration during 
        development.
      action: KEEP_AS_NON_CORE
      reason: Developmental process in the nervous system.
  - term:
      id: GO:0030139
      label: endocytic vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR is internalized via endocytic vesicles following ligand 
        binding.
      action: ACCEPT
      reason: Endocytic vesicle localization is part of normal EGFR 
        internalization.
  - term:
      id: GO:0038134
      label: ERBB2-EGFR signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR heterodimerizes with ERBB2 to form signaling complexes with 
        distinct downstream effects.
      action: ACCEPT
      reason: EGFR-ERBB2 heterodimers are an important signaling unit with 
        enhanced signaling capacity.
  - term:
      id: GO:0042059
      label: negative regulation of epidermal growth factor receptor signaling 
        pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR participates in negative regulation of its own signaling 
        through internalization and degradation mechanisms.
      action: ACCEPT
      reason: EGFR signaling is subject to negative feedback through receptor 
        internalization, ubiquitination by CBL, and lysosomal degradation.
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR regulates cell proliferation through downstream signaling.
      action: KEEP_AS_NON_CORE
      reason: General cell proliferation regulation is a downstream effect.
  - term:
      id: GO:0042908
      label: xenobiotic transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR involvement in xenobiotic transport is not well-established.
      action: MARK_AS_OVER_ANNOTATED
      reason: This annotation is likely over-interpretation; EGFR is not a 
        transporter.
  - term:
      id: GO:0045742
      label: positive regulation of epidermal growth factor receptor signaling 
        pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR itself positively regulates the EGF receptor signaling 
        pathway as the initiating receptor.
      action: ACCEPT
      reason: EGFR activation initiates and sustains EGF receptor signaling.
  - term:
      id: GO:0048146
      label: positive regulation of fibroblast proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling promotes fibroblast proliferation.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific downstream effect.
  - term:
      id: GO:0048408
      label: epidermal growth factor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR binds EGF through its extracellular domain (subdomains I and
        III), which induces receptor dimerization and activation.
      action: ACCEPT
      reason: EGF binding is the canonical ligand-binding function of EGFR. 
        Crystal structures confirm EGF binds domains I and III of the 
        extracellular region.
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR may localize to perinuclear regions during trafficking.
      action: KEEP_AS_NON_CORE
      reason: Perinuclear localization may occur during endocytic trafficking.
  - term:
      id: GO:0048546
      label: digestive tract morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling influences digestive tract development.
      action: KEEP_AS_NON_CORE
      reason: Developmental process downstream of EGFR signaling.
  - term:
      id: GO:0050673
      label: epithelial cell proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR promotes epithelial cell proliferation.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific proliferation effect.
  - term:
      id: GO:0050679
      label: positive regulation of epithelial cell proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EGFR signaling promotes epithelial cell proliferation, a key 
        downstream effect in epithelial tissues.
      action: KEEP_AS_NON_CORE
      reason: Epithelial cell proliferation is a major physiological outcome of 
        EGFR signaling but represents a downstream effect.
  - term:
      id: GO:0060571
      label: morphogenesis of an epithelial fold
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling contributes to epithelial fold morphogenesis.
      action: KEEP_AS_NON_CORE
      reason: Developmental morphogenesis process.
  - term:
      id: GO:0061029
      label: eyelid development in camera-type eye
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling is involved in eyelid development.
      action: KEEP_AS_NON_CORE
      reason: Tissue-specific developmental process.
  - term:
      id: GO:0070086
      label: ubiquitin-dependent endocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR undergoes ubiquitin-dependent endocytosis.
      action: KEEP_AS_NON_CORE
      reason: Describes EGFR trafficking/regulation.
  - term:
      id: GO:0071230
      label: cellular response to amino acid stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR signaling responds to amino acid availability.
      action: KEEP_AS_NON_CORE
      reason: Amino acid response is a contextual regulatory effect.
  - term:
      id: GO:0071363
      label: cellular response to growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: EGFR mediates cellular responses to growth factors.
      action: KEEP_AS_NON_CORE
      reason: General growth factor response is downstream of receptor 
        activation.
  - term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177930
    review:
      summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that 
        phosphorylates tyrosine residues on substrate proteins following 
        ligand-induced dimerization. This is a core molecular function.
      action: ACCEPT
      reason: Transmembrane receptor protein tyrosine kinase activity is the 
        defining enzymatic function of EGFR. The kinase domain catalyzes 
        ATP-dependent phosphorylation of tyrosine residues.
  - term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177933
    review:
      summary: EGFR is a receptor tyrosine kinase (EC 2.7.10.1) that 
        phosphorylates tyrosine residues on substrate proteins following 
        ligand-induced dimerization. This is a core molecular function.
      action: ACCEPT
      reason: Transmembrane receptor protein tyrosine kinase activity is the 
        defining enzymatic function of EGFR. The kinase domain catalyzes 
        ATP-dependent phosphorylation of tyrosine residues.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:39073202
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:39073202
          supporting_text: SNX32 Regulates Sorting and Trafficking of Activated 
            EGFR to the Lysosomal Degradation Pathway.
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: IDA
    original_reference_id: PMID:12828935
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:12828935
          supporting_text: Activation of epidermal growth factor receptor 
            signals induction of nitric oxide synthase-2 in human optic nerve 
            head astrocytes in glaucomatous optic neuropathy.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:20462955
    review:
      summary: EGFR is a transmembrane receptor tyrosine kinase that localizes 
        to the plasma membrane where it binds EGF ligands and undergoes 
        dimerization and autophosphorylation to initiate downstream signaling 
        cascades.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        transmembrane receptor that needs to be at the cell surface to bind 
        extracellular EGF ligands and interact with other membrane-bound 
        signaling components.
      supported_by:
        - reference_id: PMID:20462955
          supporting_text: 2010 May 12. A G{alpha}i-GIV molecular complex binds 
            epidermal growth factor receptor and determines whether cells 
            migrate or proliferate.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:12435727
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IDA
    original_reference_id: PMID:22732145
    review:
      summary: EGFR localizes to endosomes following ligand-induced 
        internalization. EGFR continues signaling from early endosomes and is 
        subsequently sorted for recycling or lysosomal degradation.
      action: ACCEPT
      reason: Endosomal localization is part of normal EGFR trafficking and 
        signaling. EGFR signals from endosomes and trafficking modulates signal 
        duration.
      supported_by:
        - reference_id: PMID:22732145
          supporting_text: Diacylglycerol kinase θ counteracts protein kinase 
            C-mediated inactivation of the EGF receptor.
  - term:
      id: GO:0019900
      label: kinase binding
    evidence_type: IPI
    original_reference_id: PMID:22732145
    review:
      summary: EGFR binds to kinases including SRC family kinases and downstream
        signaling kinases.
      action: ACCEPT
      reason: EGFR interacts with multiple kinases in signaling complexes.
      supported_by:
        - reference_id: PMID:22732145
          supporting_text: Diacylglycerol kinase θ counteracts protein kinase 
            C-mediated inactivation of the EGF receptor.
  - term:
      id: GO:0090037
      label: positive regulation of protein kinase C signaling
    evidence_type: IDA
    original_reference_id: PMID:22732145
    review:
      summary: EGFR activates PKC signaling through PLC-gamma activation.
      action: KEEP_AS_NON_CORE
      reason: PKC signaling regulation is downstream of EGFR-PLC-gamma 
        activation.
      supported_by:
        - reference_id: PMID:22732145
          supporting_text: Diacylglycerol kinase θ counteracts protein kinase 
            C-mediated inactivation of the EGF receptor.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:18483258
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:18483258
          supporting_text: UVA-induced cell cycle progression is mediated by a 
            disintegrin and metalloprotease/epidermal growth factor 
            receptor/AKT/Cyclin D1 pathways in keratinocytes.
  - term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    evidence_type: IMP
    original_reference_id: PMID:18483258
    review:
      summary: EGFR activates PI3K-AKT signaling through recruitment of PI3K to 
        phosphotyrosine docking sites.
      action: KEEP_AS_NON_CORE
      reason: PI3K-AKT pathway activation is a major downstream signaling axis 
        of EGFR, but is not the core function.
      supported_by:
        - reference_id: PMID:18483258
          supporting_text: UVA-induced cell cycle progression is mediated by a 
            disintegrin and metalloprotease/epidermal growth factor 
            receptor/AKT/Cyclin D1 pathways in keratinocytes.
  - term:
      id: GO:1900087
      label: positive regulation of G1/S transition of mitotic cell cycle
    evidence_type: IMP
    original_reference_id: PMID:18483258
    review:
      summary: EGFR signaling promotes G1/S cell cycle transition.
      action: KEEP_AS_NON_CORE
      reason: Cell cycle regulation is a downstream effect of EGFR proliferative
        signaling.
      supported_by:
        - reference_id: PMID:18483258
          supporting_text: UVA-induced cell cycle progression is mediated by a 
            disintegrin and metalloprotease/epidermal growth factor 
            receptor/AKT/Cyclin D1 pathways in keratinocytes.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:24854121
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:24854121
          supporting_text: 2014 May 20. Endophilin-1 regulates blood-brain 
            barrier permeability by controlling ZO-1 and occludin expression via
            the EGFR-ERK1/2 pathway.
  - term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    evidence_type: IDA
    original_reference_id: PMID:24854121
    review:
      summary: EGFR positively regulates the MAPK cascade through recruitment of
        GRB2-SOS and activation of RAS-RAF-MEK-ERK signaling.
      action: ACCEPT
      reason: MAPK/ERK pathway activation is a core downstream signaling output 
        of EGFR. This is well-established.
      supported_by:
        - reference_id: PMID:24854121
          supporting_text: 2014 May 20. Endophilin-1 regulates blood-brain 
            barrier permeability by controlling ZO-1 and occludin expression via
            the EGFR-ERK1/2 pathway.
  - term:
      id: GO:0005794
      label: Golgi apparatus
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR transits through the Golgi during biosynthesis and 
        trafficking.
      action: ACCEPT
      reason: EGFR is processed through the secretory pathway including the 
        Golgi.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR cytoplasmic domain resides in the cytosol and signals to 
        cytosolic proteins.
      action: ACCEPT
      reason: The intracellular kinase domain of EGFR is in the cytosol.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005929
      label: cilium
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR has been detected in cilia.
      action: KEEP_AS_NON_CORE
      reason: Ciliary localization is context-specific.
  - term:
      id: GO:0030054
      label: cell junction
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR may localize to cell junctions.
      action: KEEP_AS_NON_CORE
      reason: Cell junction localization is context-dependent.
  - term:
      id: GO:0036064
      label: ciliary basal body
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR has been detected at ciliary basal bodies.
      action: KEEP_AS_NON_CORE
      reason: Ciliary localization is context-specific.
  - term:
      id: GO:0097225
      label: sperm midpiece
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR has been detected in sperm midpiece.
      action: KEEP_AS_NON_CORE
      reason: Sperm-specific localization.
  - term:
      id: GO:0097228
      label: sperm principal piece
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR has been detected in sperm principal piece.
      action: KEEP_AS_NON_CORE
      reason: Sperm-specific localization.
  - term:
      id: GO:0097229
      label: sperm end piece
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: EGFR has been detected in sperm end piece.
      action: KEEP_AS_NON_CORE
      reason: Sperm-specific localization.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177934
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-182969
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183058
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-212710
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867041
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15611079
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:15611079
          supporting_text: Dec 17. Epigen, the last ligand of ErbB receptors, 
            reveals intricate relationships between affinity and mitogenicity.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:12828935
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:12828935
          supporting_text: Activation of epidermal growth factor receptor 
            signals induction of nitric oxide synthase-2 in human optic nerve 
            head astrocytes in glaucomatous optic neuropathy.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:17655843
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:17655843
          supporting_text: 'EGF receptor transactivation and PI3-kinase mediate stimulation
            of ERK by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role
            in wound healing.'
  - term:
      id: GO:0051897
      label: positive regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IMP
    original_reference_id: PMID:17655843
    review:
      summary: EGFR positively regulates PI3K-AKT signaling.
      action: KEEP_AS_NON_CORE
      reason: PI3K-AKT regulation is downstream of EGFR activation.
      supported_by:
        - reference_id: PMID:17655843
          supporting_text: 'EGF receptor transactivation and PI3-kinase mediate stimulation
            of ERK by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role
            in wound healing.'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177935
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8863804
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8864029
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:1902895
      label: positive regulation of miRNA transcription
    evidence_type: IMP
    original_reference_id: PMID:21673316
    review:
      summary: EGFR signaling regulates miRNA transcription.
      action: KEEP_AS_NON_CORE
      reason: miRNA regulation is a downstream transcriptional effect.
      supported_by:
        - reference_id: PMID:21673316
          supporting_text: TRPS1 targeting by miR-221/222 promotes the 
            epithelial-to-mesenchymal transition in breast cancer.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:15611079
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
      supported_by:
        - reference_id: PMID:15611079
          supporting_text: Dec 17. Epigen, the last ligand of ErbB receptors, 
            reveals intricate relationships between affinity and mitogenicity.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IDA
    original_reference_id: PMID:2472218
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
      supported_by:
        - reference_id: PMID:2472218
          supporting_text: 'EGF induces tyrosine phosphorylation of phospholipase
            C-II: a potential mechanism for EGF receptor signaling.'
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: IDA
    original_reference_id: PMID:11336639
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:11336639
          supporting_text: Heterodimerization of the epidermal-growth-factor 
            (EGF) receptor and ErbB2 and the affinity of EGF binding are 
            regulated by different mechanisms.
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: IDA
    original_reference_id: PMID:2176151
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:2176151
          supporting_text: The tyrosine phosphorylated carboxyterminus of the 
            EGF receptor is a binding site for GAP and PLC-gamma.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:11336639
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
      supported_by:
        - reference_id: PMID:11336639
          supporting_text: Heterodimerization of the epidermal-growth-factor 
            (EGF) receptor and ErbB2 and the affinity of EGF binding are 
            regulated by different mechanisms.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:9890893
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:9890893
          supporting_text: Identification of tyrosine phosphorylation sites in 
            human Gab-1 protein by EGF receptor kinase in vitro.
  - term:
      id: GO:0038134
      label: ERBB2-EGFR signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:11336639
    review:
      summary: EGFR heterodimerizes with ERBB2 to form signaling complexes with 
        distinct downstream effects.
      action: ACCEPT
      reason: EGFR-ERBB2 heterodimers are an important signaling unit with 
        enhanced signaling capacity.
      supported_by:
        - reference_id: PMID:11336639
          supporting_text: Heterodimerization of the epidermal-growth-factor 
            (EGF) receptor and ErbB2 and the affinity of EGF binding are 
            regulated by different mechanisms.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27872189
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:27872189
          supporting_text: 2016 Nov 21. Biophysical Evidence for Intrinsic 
            Disorder in the C-terminal Tails of the Epidermal Growth Factor 
            Receptor (EGFR) and HER3 Receptor Tyrosine Kinases.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IDA
    original_reference_id: PMID:9890893
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
      supported_by:
        - reference_id: PMID:9890893
          supporting_text: Identification of tyrosine phosphorylation sites in 
            human Gab-1 protein by EGF receptor kinase in vitro.
  - term:
      id: GO:0030296
      label: protein tyrosine kinase activator activity
    evidence_type: IDA
    original_reference_id: PMID:2176151
    review:
      summary: EGFR can activate other tyrosine kinases through 
        heterodimerization (especially ERBB2).
      action: ACCEPT
      reason: EGFR activates ERBB2 kinase activity through heterodimer 
        formation.
      supported_by:
        - reference_id: PMID:2176151
          supporting_text: The tyrosine phosphorylated carboxyterminus of the 
            EGF receptor is a binding site for GAP and PLC-gamma.
  - term:
      id: GO:0030296
      label: protein tyrosine kinase activator activity
    evidence_type: IDA
    original_reference_id: PMID:11336639
    review:
      summary: EGFR can activate other tyrosine kinases through 
        heterodimerization (especially ERBB2).
      action: ACCEPT
      reason: EGFR activates ERBB2 kinase activity through heterodimer 
        formation.
      supported_by:
        - reference_id: PMID:11336639
          supporting_text: Heterodimerization of the epidermal-growth-factor 
            (EGF) receptor and ErbB2 and the affinity of EGF binding are 
            regulated by different mechanisms.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:11331309
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
      supported_by:
        - reference_id: PMID:11331309
          supporting_text: Real time fluorescence imaging of PLC gamma 
            translocation and its interaction with the epidermal growth factor 
            receptor.
  - term:
      id: GO:0032587
      label: ruffle membrane
    evidence_type: IDA
    original_reference_id: PMID:11331309
    review:
      summary: EGFR localizes to membrane ruffles during cell migration.
      action: KEEP_AS_NON_CORE
      reason: Ruffle localization is associated with EGFR-induced cell 
        migration.
      supported_by:
        - reference_id: PMID:11331309
          supporting_text: Real time fluorescence imaging of PLC gamma 
            translocation and its interaction with the epidermal growth factor 
            receptor.
  - term:
      id: GO:0097708
      label: intracellular vesicle
    evidence_type: IDA
    original_reference_id: PMID:11331309
    review:
      summary: EGFR is found in intracellular vesicles during trafficking.
      action: ACCEPT
      reason: Part of EGFR endocytic trafficking.
      supported_by:
        - reference_id: PMID:11331309
          supporting_text: Real time fluorescence imaging of PLC gamma 
            translocation and its interaction with the epidermal growth factor 
            receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17334392
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17334392
          supporting_text: Mar 5. A crucial role of plasma membrane-associated 
            sialidase in the survival of human cancer cells.
  - term:
      id: GO:0019900
      label: kinase binding
    evidence_type: IPI
    original_reference_id: PMID:18722344
    review:
      summary: EGFR binds to kinases including SRC family kinases and downstream
        signaling kinases.
      action: ACCEPT
      reason: EGFR interacts with multiple kinases in signaling complexes.
      supported_by:
        - reference_id: PMID:18722344
          supporting_text: BCAR3 regulates EGF-induced DNA synthesis in normal 
            human breast MCF-12A cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26988023
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:26988023
          supporting_text: Haem-dependent dimerization of PGRMC1/Sigma-2 
            receptor facilitates cancer proliferation and chemoresistance.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25187647
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25187647
          supporting_text: 2014 Sep 3. Structural basis for activation of 
            trimeric Gi proteins by multiple growth factor receptors via 
            GIV/Girdin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18722344
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18722344
          supporting_text: BCAR3 regulates EGF-induced DNA synthesis in normal 
            human breast MCF-12A cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20462955
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20462955
          supporting_text: 2010 May 12. A G{alpha}i-GIV molecular complex binds 
            epidermal growth factor receptor and determines whether cells 
            migrate or proliferate.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24854121
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:24854121
          supporting_text: 2014 May 20. Endophilin-1 regulates blood-brain 
            barrier permeability by controlling ZO-1 and occludin expression via
            the EGFR-ERK1/2 pathway.
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IMP
    original_reference_id: PMID:24854121
    review:
      summary: EGFR may localize to perinuclear regions during trafficking.
      action: KEEP_AS_NON_CORE
      reason: Perinuclear localization may occur during endocytic trafficking.
      supported_by:
        - reference_id: PMID:24854121
          supporting_text: 2014 May 20. Endophilin-1 regulates blood-brain 
            barrier permeability by controlling ZO-1 and occludin expression via
            the EGFR-ERK1/2 pathway.
  - term:
      id: GO:0045121
      label: membrane raft
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: EGFR localizes to membrane rafts/lipid rafts in the plasma 
        membrane.
      action: ACCEPT
      reason: EGFR partitioning into membrane rafts affects its signaling.
  - term:
      id: GO:0051117
      label: ATPase binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: EGFR may bind to ATPases.
      action: KEEP_AS_NON_CORE
      reason: ATPase binding is not a primary EGFR function.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868658
    review:
      summary: EGFR undergoes clathrin-mediated endocytosis and localizes to 
        clathrin-coated vesicles.
      action: ACCEPT
      reason: Clathrin-mediated endocytosis is a major route for EGFR 
        internalization.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868659
    review:
      summary: EGFR undergoes clathrin-mediated endocytosis and localizes to 
        clathrin-coated vesicles.
      action: ACCEPT
      reason: Clathrin-mediated endocytosis is a major route for EGFR 
        internalization.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868660
    review:
      summary: EGFR undergoes clathrin-mediated endocytosis and localizes to 
        clathrin-coated vesicles.
      action: ACCEPT
      reason: Clathrin-mediated endocytosis is a major route for EGFR 
        internalization.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868661
    review:
      summary: EGFR undergoes clathrin-mediated endocytosis and localizes to 
        clathrin-coated vesicles.
      action: ACCEPT
      reason: Clathrin-mediated endocytosis is a major route for EGFR 
        internalization.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8869438
    review:
      summary: EGFR undergoes clathrin-mediated endocytosis and localizes to 
        clathrin-coated vesicles.
      action: ACCEPT
      reason: Clathrin-mediated endocytosis is a major route for EGFR 
        internalization.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8871193
    review:
      summary: EGFR undergoes clathrin-mediated endocytosis and localizes to 
        clathrin-coated vesicles.
      action: ACCEPT
      reason: Clathrin-mediated endocytosis is a major route for EGFR 
        internalization.
  - term:
      id: GO:0030669
      label: clathrin-coated endocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8871194
    review:
      summary: EGFR undergoes clathrin-mediated endocytosis and localizes to 
        clathrin-coated vesicles.
      action: ACCEPT
      reason: Clathrin-mediated endocytosis is a major route for EGFR 
        internalization.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:22298428
    review:
      summary: EGFR intracellular domain localizes to the cytoplasm.
      action: ACCEPT
      reason: The cytoplasmic portion of EGFR containing the kinase domain is 
        localized in the cytoplasm.
      supported_by:
        - reference_id: PMID:22298428
          supporting_text: Feb 1. The Ankrd 13 family of UIM-bearing proteins 
            regulates EGF receptor endocytosis from the plasma membrane.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:22298428
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
      supported_by:
        - reference_id: PMID:22298428
          supporting_text: Feb 1. The Ankrd 13 family of UIM-bearing proteins 
            regulates EGF receptor endocytosis from the plasma membrane.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22298428
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:22298428
          supporting_text: Feb 1. The Ankrd 13 family of UIM-bearing proteins 
            regulates EGF receptor endocytosis from the plasma membrane.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1169421
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1218833
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1220610
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1220612
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1220613
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1220614
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225947
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225949
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225950
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225951
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225952
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225956
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225957
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225960
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225961
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1226012
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1226014
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1226016
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1247841
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1247842
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1247844
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1220611
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0019903
      label: protein phosphatase binding
    evidence_type: IPI
    original_reference_id: PMID:28759036
    review:
      summary: EGFR binds to protein phosphatases that regulate its 
        phosphorylation state.
      action: ACCEPT
      reason: EGFR is regulated by phosphatases including PTPN1, PTPN2, and 
        PTPN12.
      supported_by:
        - reference_id: PMID:28759036
          supporting_text: Jul 31. Deficiency in VHR/DUSP3, a suppressor of 
            focal adhesion kinase, reveals its role in regulating cell adhesion 
            and migration.
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9611147
    review:
      summary: EGFR localizes to endosome membranes during receptor trafficking 
        after internalization.
      action: ACCEPT
      reason: After ligand-induced endocytosis, EGFR is found on endosome 
        membranes where it continues to signal.
  - term:
      id: GO:0045296
      label: cadherin binding
    evidence_type: HDA
    original_reference_id: PMID:25468996
    review:
      summary: EGFR binds to cadherins, linking to cell adhesion regulation.
      action: KEEP_AS_NON_CORE
      reason: Cadherin binding represents crosstalk between EGFR and cell 
        adhesion.
      supported_by:
        - reference_id: PMID:25468996
          supporting_text: E-cadherin interactome complexity and robustness 
            resolved by quantitative proteomics.
  - term:
      id: GO:0030335
      label: positive regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:25678558
    review:
      summary: EGFR signaling promotes cell migration through various downstream
        effectors.
      action: KEEP_AS_NON_CORE
      reason: Cell migration is a downstream cellular behavior influenced by 
        EGFR signaling.
      supported_by:
        - reference_id: PMID:25678558
          supporting_text: Navigator-3, a modulator of cell migration, may act 
            as a suppressor of breast cancer progression.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28479384
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:28479384
          supporting_text: Beclin1 antagonizes LAPTM4B-mediated EGFR 
            overactivation in gastric cancer cells.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IMP
    original_reference_id: PMID:20878056
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
      supported_by:
        - reference_id: PMID:20878056
          supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway
            in mammary carcinogenesis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20878056
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20878056
          supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway
            in mammary carcinogenesis.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:20878056
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:20878056
          supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway
            in mammary carcinogenesis.
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IDA
    original_reference_id: PMID:20878056
    review:
      summary: EGFR forms protein complexes with signaling partners.
      action: ACCEPT
      reason: EGFR exists in multiprotein signaling complexes.
      supported_by:
        - reference_id: PMID:20878056
          supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway
            in mammary carcinogenesis.
  - term:
      id: GO:0033138
      label: positive regulation of peptidyl-serine phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:20878056
    review:
      summary: EGFR signaling leads to downstream serine phosphorylation events.
      action: KEEP_AS_NON_CORE
      reason: Serine phosphorylation regulation is a downstream effect of EGFR 
        signaling cascades.
      supported_by:
        - reference_id: PMID:20878056
          supporting_text: Critical involvement of RQCD1 in the EGFR-Akt pathway
            in mammary carcinogenesis.
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: IMP
    original_reference_id: PMID:22732145
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:22732145
          supporting_text: Diacylglycerol kinase θ counteracts protein kinase 
            C-mediated inactivation of the EGF receptor.
  - term:
      id: GO:1903078
      label: positive regulation of protein localization to plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:22732145
    review:
      summary: EGFR signaling can regulate protein localization to plasma 
        membrane.
      action: KEEP_AS_NON_CORE
      reason: Downstream cellular effect.
      supported_by:
        - reference_id: PMID:22732145
          supporting_text: Diacylglycerol kinase θ counteracts protein kinase 
            C-mediated inactivation of the EGF receptor.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:22732145
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
      supported_by:
        - reference_id: PMID:22732145
          supporting_text: Diacylglycerol kinase θ counteracts protein kinase 
            C-mediated inactivation of the EGF receptor.
  - term:
      id: GO:1905208
      label: negative regulation of cardiocyte differentiation
    evidence_type: IMP
    original_reference_id: PMID:23069713
    review:
      summary: EGFR signaling negatively regulates cardiocyte differentiation.
      action: KEEP_AS_NON_CORE
      reason: Cell type-specific developmental effect.
      supported_by:
        - reference_id: PMID:23069713
          supporting_text: Epub 2012 Oct 13. The promotion of cardiogenic 
            differentiation of hMSCs by targeting epidermal growth factor 
            receptor using microRNA-133a.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IDA
    original_reference_id: PMID:16554368
    review:
      summary: EGFR localizes to endosomes following ligand-induced 
        internalization. EGFR continues signaling from early endosomes and is 
        subsequently sorted for recycling or lysosomal degradation.
      action: ACCEPT
      reason: Endosomal localization is part of normal EGFR trafficking and 
        signaling. EGFR signals from endosomes and trafficking modulates signal 
        duration.
      supported_by:
        - reference_id: PMID:16554368
          supporting_text: Mar 22. The ESCRT-III subunit hVps24 is required for 
            degradation but not silencing of the epidermal growth factor 
            receptor.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:27057632
    review:
      summary: EGFR signaling promotes cell proliferation through MAPK and PI3K 
        pathways.
      action: KEEP_AS_NON_CORE
      reason: Cell proliferation is a downstream phenotypic effect of EGFR 
        signaling.
      supported_by:
        - reference_id: PMID:27057632
          supporting_text: Tumor-suppressive miR-218-5p inhibits cancer cell 
            proliferation and migration via EGFR in non-small cell lung cancer.
  - term:
      id: GO:0070374
      label: positive regulation of ERK1 and ERK2 cascade
    evidence_type: IMP
    original_reference_id: PMID:21673316
    review:
      summary: EGFR positively regulates ERK1/2 cascade through RAS-RAF-MEK-ERK 
        signaling axis.
      action: ACCEPT
      reason: ERK1/2 activation is a core readout of EGFR signaling through the 
        MAPK pathway.
      supported_by:
        - reference_id: PMID:21673316
          supporting_text: TRPS1 targeting by miR-221/222 promotes the 
            epithelial-to-mesenchymal transition in breast cancer.
  - term:
      id: GO:0030307
      label: positive regulation of cell growth
    evidence_type: IDA
    original_reference_id: PMID:15467833
    review:
      summary: EGFR signaling promotes cell growth.
      action: KEEP_AS_NON_CORE
      reason: Cell growth regulation is a downstream effect of EGFR activation.
      supported_by:
        - reference_id: PMID:15467833
          supporting_text: CEACAM1 modulates epidermal growth factor 
            receptor--mediated cell proliferation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23912460
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:23912460
          supporting_text: Aug 5. Hyperactivation of EGFR and downstream 
            effector phospholipase D1 by oncogenic FAM83B.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25311788
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25311788
          supporting_text: EGFR phosphorylates and inhibits lung tumor 
            suppressor GPRC5A in lung cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25666625
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:25666625
          supporting_text: 2015 Feb 9. Epidermal growth factor receptor (EGFR) 
            signaling requires a specific endoplasmic reticulum thioredoxin for 
            the post-translational control of receptor presentation to the cell 
            surface.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IDA
    original_reference_id: PMID:25666625
    review:
      summary: EGFR localizes to the cell surface where it is accessible for 
        ligand binding.
      action: ACCEPT
      reason: Cell surface localization is consistent with EGFR function as a 
        receptor for extracellular growth factors.
      supported_by:
        - reference_id: PMID:25666625
          supporting_text: 2015 Feb 9. Epidermal growth factor receptor (EGFR) 
            signaling requires a specific endoplasmic reticulum thioredoxin for 
            the post-translational control of receptor presentation to the cell 
            surface.
  - term:
      id: GO:0031901
      label: early endosome membrane
    evidence_type: IDA
    original_reference_id: PMID:17714434
    review:
      summary: EGFR localizes to early endosome membranes following 
        internalization, where it continues to signal.
      action: ACCEPT
      reason: Early endosome membrane localization is well-documented for EGFR 
        trafficking.
      supported_by:
        - reference_id: PMID:17714434
          supporting_text: 2007 Aug 20. Vps22/EAP30 in ESCRT-II mediates 
            endosomal sorting of growth factor and chemokine receptors destined 
            for lysosomal degradation.
  - term:
      id: GO:0097489
      label: multivesicular body, internal vesicle lumen
    evidence_type: IDA
    original_reference_id: PMID:17714434
    review:
      summary: EGFR is sorted into multivesicular bodies for lysosomal 
        degradation.
      action: ACCEPT
      reason: MVB sorting is part of EGFR downregulation pathway.
      supported_by:
        - reference_id: PMID:17714434
          supporting_text: 2007 Aug 20. Vps22/EAP30 in ESCRT-II mediates 
            endosomal sorting of growth factor and chemokine receptors destined 
            for lysosomal degradation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8305738
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:8305738
          supporting_text: The human GRB2 and Drosophila Drk genes can 
            functionally replace the Caenorhabditis elegans cell signaling gene 
            sem-5.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:23418353
    review:
      summary: EGFR binds to CBL E3 ubiquitin ligase, which ubiquitinates EGFR 
        for endocytosis and degradation.
      action: ACCEPT
      reason: CBL binding to EGFR is critical for receptor downregulation.
      supported_by:
        - reference_id: PMID:23418353
          supporting_text: Feb 15. The E3 ubiquitin ligases RNF126 and Rabring7 
            regulate endosomal sorting of the epidermal growth factor receptor.
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: IDA
    original_reference_id: PMID:22719997
    review:
      summary: EGFR localizes to endosome membranes during receptor trafficking 
        after internalization.
      action: ACCEPT
      reason: After ligand-induced endocytosis, EGFR is found on endosome 
        membranes where it continues to signal.
      supported_by:
        - reference_id: PMID:22719997
          supporting_text: SNX12 role in endosome membrane transport.
  - term:
      id: GO:0005925
      label: focal adhesion
    evidence_type: HDA
    original_reference_id: PMID:21423176
    review:
      summary: EGFR localizes to focal adhesions during cell migration.
      action: KEEP_AS_NON_CORE
      reason: Focal adhesion localization is associated with EGFR-mediated 
        migration.
      supported_by:
        - reference_id: PMID:21423176
          supporting_text: Analysis of the myosin-II-responsive focal adhesion 
            proteome reveals a role for β-Pix in negative regulation of focal 
            adhesion maturation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9852145
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9852145
          supporting_text: Interaction of ZPR1 with translation elongation 
            factor-1alpha in proliferating cells.
  - term:
      id: GO:0043235
      label: receptor complex
    evidence_type: IDA
    original_reference_id: PMID:23382219
    review:
      summary: EGFR forms homo- and heterodimeric receptor complexes upon ligand
        binding, which is required for kinase activation.
      action: ACCEPT
      reason: EGFR dimerization into receptor complexes is essential for signal 
        transduction. EGFR forms homodimers and heterodimers with ERBB2, ERBB3, 
        ERBB4.
      supported_by:
        - reference_id: PMID:23382219
          supporting_text: Structural basis for endosomal trafficking of diverse
            transmembrane cargos by PX-FERM proteins.
  - term:
      id: GO:0007611
      label: learning or memory
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: EGFR signaling may influence learning and memory processes.
      action: KEEP_AS_NON_CORE
      reason: High-level behavioral phenotype, represents very downstream 
        effects.
  - term:
      id: GO:0071364
      label: cellular response to epidermal growth factor stimulus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: EGFR mediates cellular responses to EGF.
      action: KEEP_AS_NON_CORE
      reason: This describes the cellular response, not the core receptor 
        function.
  - term:
      id: GO:0001934
      label: positive regulation of protein phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:20551055
    review:
      summary: EGFR promotes protein phosphorylation through its kinase activity
        and downstream signaling.
      action: KEEP_AS_NON_CORE
      reason: This is a general downstream effect of EGFR signaling.
      supported_by:
        - reference_id: PMID:20551055
          supporting_text: Epub 2010 Jun 15. Nuclear alternate estrogen receptor
            GPR30 mediates 17beta-estradiol-induced gene expression and 
            migration in breast cancer-associated fibroblasts.
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IDA
    original_reference_id: PMID:20551055
    review:
      summary: Nuclear EGFR has been reported to bind chromatin and regulate 
        transcription.
      action: KEEP_AS_NON_CORE
      reason: Nuclear EGFR has been described in some contexts, but this is not 
        a core function of EGFR.
      supported_by:
        - reference_id: PMID:20551055
          supporting_text: Epub 2010 Jun 15. Nuclear alternate estrogen receptor
            GPR30 mediates 17beta-estradiol-induced gene expression and 
            migration in breast cancer-associated fibroblasts.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20551055
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:20551055
          supporting_text: Epub 2010 Jun 15. Nuclear alternate estrogen receptor
            GPR30 mediates 17beta-estradiol-induced gene expression and 
            migration in breast cancer-associated fibroblasts.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:20551055
    review:
      summary: Nuclear EGFR has been described in certain contexts and may have 
        transcriptional roles.
      action: KEEP_AS_NON_CORE
      reason: Nuclear EGFR is documented but represents a minor, 
        context-dependent localization rather than core EGFR function.
      supported_by:
        - reference_id: PMID:20551055
          supporting_text: Epub 2010 Jun 15. Nuclear alternate estrogen receptor
            GPR30 mediates 17beta-estradiol-induced gene expression and 
            migration in breast cancer-associated fibroblasts.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:20551055
    review:
      summary: EGFR signaling leads to transcriptional activation of target 
        genes.
      action: KEEP_AS_NON_CORE
      reason: Transcriptional regulation is a downstream effect of EGFR 
        signaling pathways.
      supported_by:
        - reference_id: PMID:20551055
          supporting_text: Epub 2010 Jun 15. Nuclear alternate estrogen receptor
            GPR30 mediates 17beta-estradiol-induced gene expression and 
            migration in breast cancer-associated fibroblasts.
  - term:
      id: GO:0070374
      label: positive regulation of ERK1 and ERK2 cascade
    evidence_type: IDA
    original_reference_id: PMID:20551055
    review:
      summary: EGFR positively regulates ERK1/2 cascade through RAS-RAF-MEK-ERK 
        signaling axis.
      action: ACCEPT
      reason: ERK1/2 activation is a core readout of EGFR signaling through the 
        MAPK pathway.
      supported_by:
        - reference_id: PMID:20551055
          supporting_text: Epub 2010 Jun 15. Nuclear alternate estrogen receptor
            GPR30 mediates 17beta-estradiol-induced gene expression and 
            migration in breast cancer-associated fibroblasts.
  - term:
      id: GO:0071392
      label: cellular response to estradiol stimulus
    evidence_type: IDA
    original_reference_id: PMID:20551055
    review:
      summary: EGFR can be activated in response to estradiol through crosstalk 
        mechanisms.
      action: KEEP_AS_NON_CORE
      reason: Estradiol response represents crosstalk/secondary activation, not 
        core function.
      supported_by:
        - reference_id: PMID:20551055
          supporting_text: Epub 2010 Jun 15. Nuclear alternate estrogen receptor
            GPR30 mediates 17beta-estradiol-induced gene expression and 
            migration in breast cancer-associated fibroblasts.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1247999
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1248002
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1248655
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637764
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637765
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637766
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637770
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637792
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637794
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637795
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637796
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637798
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637800
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637801
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637806
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5637808
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5638137
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1250195
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1306957
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1306963
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1306965
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177923
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177924
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177925
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177926
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177927
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177930
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177933
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177934
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177936
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177937
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177938
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177939
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177941
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177943
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177944
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177945
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-182969
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-182986
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-182990
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-182993
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-182994
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183002
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183036
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183051
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183055
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183058
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183067
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183072
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183084
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-183089
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1963563
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1963581
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1963582
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-212706
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-212710
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-212713
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2179387
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2179407
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2179415
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2316434
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2400009
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5672965
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6785636
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6785648
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8847995
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8848005
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8864105
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8864125
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8866279
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867041
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867044
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867047
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867754
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8867756
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868071
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868072
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868230
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868236
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868648
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868651
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8868661
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8951490
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9018572
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9018573
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9625482
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9625487
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664588
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664918
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664933
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664940
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664950
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664976
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664983
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664991
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665000
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665009
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665032
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665034
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665389
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665404
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665406
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665407
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665408
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665409
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665410
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665411
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665413
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665415
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665416
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665417
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665698
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665699
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665700
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665701
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665704
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665705
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665706
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665707
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665709
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-1248744
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-1251923
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-1251929
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19509291
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:19509291
          supporting_text: 2009 Jun 9. GAREM, a novel adaptor protein for growth
            factor receptor-bound protein 2, contributes to cellular 
            transformation through the activation of extracellular 
            signal-regulated kinase signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18602463
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:18602463
          supporting_text: 2008 Jun 15. Ataxin-2 associates with the endocytosis
            complex and affects EGF receptor trafficking.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10026169
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:10026169
          supporting_text: Identification of Grb4/Nckbeta, a src homology 2 and 
            3 domain-containing adapter protein having similar binding and 
            biological properties to Nck.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15590694
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:15590694
          supporting_text: 2004 Dec 7. Suppressors of cytokine signaling 4 and 5
            regulate epidermal growth factor receptor signaling.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IDA
    original_reference_id: PMID:17115032
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
      supported_by:
        - reference_id: PMID:17115032
          supporting_text: Tyrosine phosphorylation controls PCNA function 
            through protein stability.
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: IDA
    original_reference_id: PMID:17115032
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:17115032
          supporting_text: Tyrosine phosphorylation controls PCNA function 
            through protein stability.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17115032
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17115032
          supporting_text: Tyrosine phosphorylation controls PCNA function 
            through protein stability.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17115032
    review:
      summary: Nuclear EGFR has been described in certain contexts and may have 
        transcriptional roles.
      action: KEEP_AS_NON_CORE
      reason: Nuclear EGFR is documented but represents a minor, 
        context-dependent localization rather than core EGFR function.
      supported_by:
        - reference_id: PMID:17115032
          supporting_text: Tyrosine phosphorylation controls PCNA function 
            through protein stability.
  - term:
      id: GO:0042177
      label: negative regulation of protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:17115032
    review:
      summary: EGFR signaling can inhibit protein catabolism.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of EGFR survival signaling.
      supported_by:
        - reference_id: PMID:17115032
          supporting_text: Tyrosine phosphorylation controls PCNA function 
            through protein stability.
  - term:
      id: GO:0045739
      label: positive regulation of DNA repair
    evidence_type: IDA
    original_reference_id: PMID:17115032
    review:
      summary: Nuclear EGFR has been implicated in DNA repair regulation.
      action: KEEP_AS_NON_CORE
      reason: DNA repair regulation is a non-canonical nuclear EGFR function.
      supported_by:
        - reference_id: PMID:17115032
          supporting_text: Tyrosine phosphorylation controls PCNA function 
            through protein stability.
  - term:
      id: GO:0045740
      label: positive regulation of DNA replication
    evidence_type: IDA
    original_reference_id: PMID:17115032
    review:
      summary: EGFR signaling promotes DNA replication through proliferative 
        signaling.
      action: KEEP_AS_NON_CORE
      reason: DNA replication regulation is downstream of EGFR proliferative 
        signaling.
      supported_by:
        - reference_id: PMID:17115032
          supporting_text: Tyrosine phosphorylation controls PCNA function 
            through protein stability.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:12009895
    review:
      summary: EGFR binds to downstream enzymes including kinases and 
        phosphatases.
      action: ACCEPT
      reason: EGFR interacts with various enzymes as part of signaling.
      supported_by:
        - reference_id: PMID:12009895
          supporting_text: Plasma membrane phospholipid scramblase 1 is enriched
            in lipid rafts and interacts with the epidermal growth factor 
            receptor.
  - term:
      id: GO:0045121
      label: membrane raft
    evidence_type: IDA
    original_reference_id: PMID:12009895
    review:
      summary: EGFR localizes to membrane rafts/lipid rafts in the plasma 
        membrane.
      action: ACCEPT
      reason: EGFR partitioning into membrane rafts affects its signaling.
      supported_by:
        - reference_id: PMID:12009895
          supporting_text: Plasma membrane phospholipid scramblase 1 is enriched
            in lipid rafts and interacts with the epidermal growth factor 
            receptor.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:18070883
    review:
      summary: EGFR signaling promotes cell survival by activating 
        anti-apoptotic pathways including PI3K-AKT.
      action: KEEP_AS_NON_CORE
      reason: Anti-apoptotic effects are downstream consequences of 
        EGFR-PI3K-AKT signaling, not a core function.
      supported_by:
        - reference_id: PMID:18070883
          supporting_text: 2007 Dec 10. A novel role of Sprouty 2 in regulating 
            cellular apoptosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17182860
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17182860
          supporting_text: Dec 20. Activated Cdc42-associated kinase 1 is a 
            component of EGF receptor signaling complex and regulates EGF 
            receptor degradation.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IDA
    original_reference_id: PMID:17182860
    review:
      summary: EGFR localizes to endosomes following ligand-induced 
        internalization. EGFR continues signaling from early endosomes and is 
        subsequently sorted for recycling or lysosomal degradation.
      action: ACCEPT
      reason: Endosomal localization is part of normal EGFR trafficking and 
        signaling. EGFR signals from endosomes and trafficking modulates signal 
        duration.
      supported_by:
        - reference_id: PMID:17182860
          supporting_text: Dec 20. Activated Cdc42-associated kinase 1 is a 
            component of EGF receptor signaling complex and regulates EGF 
            receptor degradation.
  - term:
      id: GO:0004888
      label: transmembrane signaling receptor activity
    evidence_type: IDA
    original_reference_id: PMID:7736574
    review:
      summary: EGFR is a transmembrane signaling receptor.
      action: ACCEPT
      reason: This accurately describes EGFR as a transmembrane receptor.
      supported_by:
        - reference_id: PMID:7736574
          supporting_text: Three distinct IL-2 signaling pathways mediated by 
            bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
  - term:
      id: GO:0007166
      label: cell surface receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:7736574
    review:
      summary: EGFR participates in cell surface receptor signaling.
      action: KEEP_AS_NON_CORE
      reason: This general term is accurate but less specific than EGFR 
        signaling pathway terms.
      supported_by:
        - reference_id: PMID:7736574
          supporting_text: Three distinct IL-2 signaling pathways mediated by 
            bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
  - term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:7736574
    review:
      summary: EGFR is the initiating receptor of the EGF receptor signaling 
        pathway, binding EGF family ligands and activating downstream signaling 
        cascades.
      action: ACCEPT
      reason: This is the defining biological process for EGFR - it is the 
        primary receptor that initiates this pathway.
      supported_by:
        - reference_id: PMID:7736574
          supporting_text: Three distinct IL-2 signaling pathways mediated by 
            bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:7736574
    review:
      summary: EGFR signaling promotes cell proliferation through MAPK and PI3K 
        pathways.
      action: KEEP_AS_NON_CORE
      reason: Cell proliferation is a downstream phenotypic effect of EGFR 
        signaling.
      supported_by:
        - reference_id: PMID:7736574
          supporting_text: Three distinct IL-2 signaling pathways mediated by 
            bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.
  - term:
      id: GO:0090263
      label: positive regulation of canonical Wnt signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:20302655
    review:
      summary: EGFR signaling can crosstalk with and regulate Wnt signaling.
      action: KEEP_AS_NON_CORE
      reason: Wnt pathway crosstalk is a secondary/downstream effect of EGFR.
      supported_by:
        - reference_id: PMID:20302655
          supporting_text: Epidermal growth factor receptor regulates 
            beta-catenin location, stability, and transcriptional activity in 
            oral cancer.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IDA
    original_reference_id: PMID:17599051
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
      supported_by:
        - reference_id: PMID:17599051
          supporting_text: Jun 18. The evolutionarily conserved EBR module of 
            RALT/MIG6 mediates suppression of the EGFR catalytic activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17599051
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17599051
          supporting_text: Jun 18. The evolutionarily conserved EBR module of 
            RALT/MIG6 mediates suppression of the EGFR catalytic activity.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:7588596
    review:
      summary: EGFR intracellular domain localizes to the cytoplasm.
      action: ACCEPT
      reason: The cytoplasmic portion of EGFR containing the kinase domain is 
        localized in the cytoplasm.
      supported_by:
        - reference_id: PMID:7588596
          supporting_text: WT1 suppresses synthesis of the epidermal growth 
            factor receptor and induces apoptosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19602593
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:19602593
          supporting_text: Epub 2009 Jul 14. Cetuximab/C225-induced 
            intracellular trafficking of epidermal growth factor receptor.
  - term:
      id: GO:0070435
      label: Shc-EGFR complex
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: EGFR forms a complex with SHC adaptor protein.
      action: ACCEPT
      reason: SHC binding to phosphorylated EGFR is a key signaling event.
  - term:
      id: GO:0019903
      label: protein phosphatase binding
    evidence_type: IPI
    original_reference_id: PMID:15899872
    review:
      summary: EGFR binds to protein phosphatases that regulate its 
        phosphorylation state.
      action: ACCEPT
      reason: EGFR is regulated by phosphatases including PTPN1, PTPN2, and 
        PTPN12.
      supported_by:
        - reference_id: PMID:15899872
          supporting_text: Transforming growth factor {beta} (TGF-{beta})-Smad 
            target gene protein tyrosine phosphatase receptor type kappa is 
            required for TGF-{beta} function.
  - term:
      id: GO:0070141
      label: response to UV-A
    evidence_type: IDA
    original_reference_id: PMID:18483258
    review:
      summary: EGFR can be activated by UV-A exposure.
      action: KEEP_AS_NON_CORE
      reason: UV-A activation is a stress response, not normal physiological 
        activation.
      supported_by:
        - reference_id: PMID:18483258
          supporting_text: UVA-induced cell cycle progression is mediated by a 
            disintegrin and metalloprotease/epidermal growth factor 
            receptor/AKT/Cyclin D1 pathways in keratinocytes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17909029
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:17909029
          supporting_text: The phosphoinositide kinase PIKfyve mediates 
            epidermal growth factor receptor trafficking to the nucleus.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:12646923
    review:
      summary: In polarized epithelial cells, EGFR localizes to the basolateral 
        plasma membrane.
      action: ACCEPT
      reason: EGFR shows polarized distribution in epithelial cells, localizing 
        to basolateral membranes.
      supported_by:
        - reference_id: PMID:12646923
          supporting_text: Segregation of receptor and ligand regulates 
            activation of epithelial growth factor receptor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11279102
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:11279102
          supporting_text: 2001 Mar 8. Sorting nexin 6, a novel SNX, interacts 
            with the transforming growth factor-beta family of receptor 
            serine-threonine kinases.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1225978
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1248677
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177922
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-177942
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1963586
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1963589
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1977959
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-445069
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8857549
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8857555
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8857565
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8857577
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8857583
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8874797
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9609689
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9610867
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9611147
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9611158
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9634702
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9664567
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665388
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9665697
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9674531
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9851407
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: IDA
    original_reference_id: PMID:10572067
    review:
      summary: EGFR mediates signal transduction from extracellular growth 
        factors to intracellular signaling cascades.
      action: ACCEPT
      reason: Signal transduction is a core function of EGFR as a receptor 
        tyrosine kinase.
      supported_by:
        - reference_id: PMID:10572067
          supporting_text: Dominance of ErbB-1 heterodimers in lung epithelial 
            cells overexpressing ErbB-2.
  - term:
      id: GO:0050679
      label: positive regulation of epithelial cell proliferation
    evidence_type: IDA
    original_reference_id: PMID:10572067
    review:
      summary: EGFR signaling promotes epithelial cell proliferation, a key 
        downstream effect in epithelial tissues.
      action: KEEP_AS_NON_CORE
      reason: Epithelial cell proliferation is a major physiological outcome of 
        EGFR signaling but represents a downstream effect.
      supported_by:
        - reference_id: PMID:10572067
          supporting_text: Dominance of ErbB-1 heterodimers in lung epithelial 
            cells overexpressing ErbB-2.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9419975
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:9419975
          supporting_text: Epiregulin binds to epidermal growth factor receptor 
            and ErbB-4 and induces tyrosine phosphorylation of epidermal growth 
            factor receptor, ErbB-2, ErbB-3 and ErbB-4.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:2176151
    review:
      summary: Generic 'protein binding' term provides no specific information 
        about EGFR molecular function.
      action: REMOVE
      reason: Per GO curation guidelines, 'protein binding' is uninformative and
        should be replaced with more specific binding terms. EGFR interacts with
        many proteins including ligands (EGF), dimerization partners (ERBB2-4), 
        adaptors (GRB2, SHC), and signaling molecules, but this generic term 
        does not capture any specific binding activity.
      supported_by:
        - reference_id: PMID:2176151
          supporting_text: The tyrosine phosphorylated carboxyterminus of the 
            EGF receptor is a binding site for GAP and PLC-gamma.
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: NAS
    original_reference_id: PMID:15542601
    review:
      summary: EGFR is not a direct MAP3K. EGFR activates the MAPK cascade but 
        acts upstream of RAF (the actual MAP3K).
      action: MARK_AS_OVER_ANNOTATED
      reason: EGFR is a receptor tyrosine kinase that activates RAS, which then 
        activates RAF (the MAP3K). EGFR itself does not have MAP3K activity.
      supported_by:
        - reference_id: PMID:15542601
          supporting_text: 2004 Nov 12. Activation of the epidermal growth 
            factor receptor by respiratory syncytial virus results in increased 
            inflammation and delayed apoptosis.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: IMP
    original_reference_id: PMID:14702346
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
      supported_by:
        - reference_id: PMID:14702346
          supporting_text: 2003 Dec 31. Sorting of ligand-activated epidermal 
            growth factor receptor to lysosomes requires its actin-binding 
            domain.
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: IDA
    original_reference_id: PMID:12435727
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:12828935
    review:
      summary: Nuclear EGFR has been described in certain contexts and may have 
        transcriptional roles.
      action: KEEP_AS_NON_CORE
      reason: Nuclear EGFR is documented but represents a minor, 
        context-dependent localization rather than core EGFR function.
      supported_by:
        - reference_id: PMID:12828935
          supporting_text: Activation of epidermal growth factor receptor 
            signals induction of nitric oxide synthase-2 in human optic nerve 
            head astrocytes in glaucomatous optic neuropathy.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12435727
    review:
      summary: EGFR intracellular domain localizes to the cytoplasm.
      action: ACCEPT
      reason: The cytoplasmic portion of EGFR containing the kinase domain is 
        localized in the cytoplasm.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0005768
      label: endosome
    evidence_type: IDA
    original_reference_id: PMID:14702346
    review:
      summary: EGFR localizes to endosomes following ligand-induced 
        internalization. EGFR continues signaling from early endosomes and is 
        subsequently sorted for recycling or lysosomal degradation.
      action: ACCEPT
      reason: Endosomal localization is part of normal EGFR trafficking and 
        signaling. EGFR signals from endosomes and trafficking modulates signal 
        duration.
      supported_by:
        - reference_id: PMID:14702346
          supporting_text: 2003 Dec 31. Sorting of ligand-activated epidermal 
            growth factor receptor to lysosomes requires its actin-binding 
            domain.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IDA
    original_reference_id: PMID:12435727
    review:
      summary: EGFR is an integral membrane protein spanning the plasma membrane
        with extracellular ligand-binding and intracellular kinase domains.
      action: ACCEPT
      reason: EGFR is a type I transmembrane protein; membrane localization is 
        fundamental to its structure and function.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0030335
      label: positive regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:12435727
    review:
      summary: EGFR signaling promotes cell migration through various downstream
        effectors.
      action: KEEP_AS_NON_CORE
      reason: Cell migration is a downstream cellular behavior influenced by 
        EGFR signaling.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0050730
      label: regulation of peptidyl-tyrosine phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:12435727
    review:
      summary: EGFR regulates tyrosine phosphorylation of substrates.
      action: KEEP_AS_NON_CORE
      reason: While related to EGFR kinase activity, this describes regulatory 
        outcomes.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0051015
      label: actin filament binding
    evidence_type: IDA
    original_reference_id: PMID:14702346
    review:
      summary: EGFR has been reported to bind actin filaments.
      action: KEEP_AS_NON_CORE
      reason: Actin binding may be involved in EGFR trafficking/localization.
      supported_by:
        - reference_id: PMID:14702346
          supporting_text: 2003 Dec 31. Sorting of ligand-activated epidermal 
            growth factor receptor to lysosomes requires its actin-binding 
            domain.
  - term:
      id: GO:0051205
      label: protein insertion into membrane
    evidence_type: TAS
    original_reference_id: PMID:12435727
    review:
      summary: EGFR is inserted into the membrane during biosynthesis.
      action: KEEP_AS_NON_CORE
      reason: Describes EGFR biogenesis rather than function.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0098609
      label: cell-cell adhesion
    evidence_type: IMP
    original_reference_id: PMID:12435727
    review:
      summary: EGFR signaling influences cell-cell adhesion.
      action: KEEP_AS_NON_CORE
      reason: Downstream cellular behavior.
      supported_by:
        - reference_id: PMID:12435727
          supporting_text: 2002 Nov 14. Epidermal growth factor receptor 
            mediates increased cell proliferation, migration, and aggregation in
            esophageal keratinocytes in vitro and in vivo.
  - term:
      id: GO:0001503
      label: ossification
    evidence_type: NAS
    original_reference_id: PMID:12925580
    review:
      summary: EGFR signaling may influence bone formation.
      action: KEEP_AS_NON_CORE
      reason: Developmental process in bone tissue.
      supported_by:
        - reference_id: PMID:12925580
          supporting_text: Mice humanised for the EGF receptor display 
            hypomorphic phenotypes in skin, bone and heart.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: NAS
    original_reference_id: PMID:9103388
    review:
      summary: Soluble EGFR ectodomain isoforms may be released to extracellular
        space.
      action: KEEP_AS_NON_CORE
      reason: Truncated soluble EGFR isoforms exist but this is not the primary 
        EGFR form.
      supported_by:
        - reference_id: PMID:9103388
          supporting_text: Expression of a truncated epidermal growth factor 
            receptor-like protein (TEGFR) in ovarian cancer.
  - term:
      id: GO:0042327
      label: positive regulation of phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:15082764
    review:
      summary: EGFR promotes phosphorylation through its kinase activity.
      action: KEEP_AS_NON_CORE
      reason: General phosphorylation regulation is downstream of EGFR kinase 
        activity.
      supported_by:
        - reference_id: PMID:15082764
          supporting_text: Epidermal growth factor receptor stimulation 
            activates the RNA binding protein CUG-BP1 and increases expression 
            of C/EBPbeta-LIP in mammary epithelial cells.
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: NAS
    original_reference_id: PMID:6325948
    review:
      summary: Nuclear EGFR has been reported to associate with chromatin, but 
        direct DNA binding is controversial.
      action: MARK_AS_OVER_ANNOTATED
      reason: While nuclear EGFR has been described, its direct DNA binding role
        is not well-established and may be indirect through transcription factor
        interactions.
      supported_by:
        - reference_id: PMID:6325948
          supporting_text: ATP-stimulated interaction between epidermal growth 
            factor receptor and supercoiled DNA.
  - term:
      id: GO:0004713
      label: protein tyrosine kinase activity
    evidence_type: TAS
    original_reference_id: PMID:16076471
    review:
      summary: EGFR possesses protein tyrosine kinase activity, phosphorylating 
        itself and downstream substrates upon activation.
      action: ACCEPT
      reason: Protein tyrosine kinase activity is fundamental to EGFR signaling.
        This is the parent term of transmembrane receptor protein tyrosine 
        kinase activity and accurately describes EGFR function.
      supported_by:
        - reference_id: PMID:16076471
          supporting_text: 'The epidermal growth factor receptors and their family
            of ligands: their putative role in atherogenesis.'
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: NAS
    original_reference_id: PMID:2790960
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:2790960
          supporting_text: Functional independence of the epidermal growth 
            factor receptor from a domain required for ligand-induced 
            internalization and calcium regulation.
  - term:
      id: GO:0005006
      label: epidermal growth factor receptor activity
    evidence_type: NAS
    original_reference_id: PMID:6325948
    review:
      summary: EGFR is the prototypical EGF receptor, binding EGF and related 
        ligands to initiate signaling cascades controlling proliferation, 
        survival, and differentiation.
      action: ACCEPT
      reason: This is the most specific molecular function term for EGFR and is 
        definitionally correct.
      supported_by:
        - reference_id: PMID:6325948
          supporting_text: ATP-stimulated interaction between epidermal growth 
            factor receptor and supercoiled DNA.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:15465819
    review:
      summary: EGFR is a transmembrane receptor that localizes to the plasma 
        membrane where it binds extracellular ligands and initiates 
        intracellular signaling.
      action: ACCEPT
      reason: Plasma membrane localization is essential for EGFR function as a 
        cell surface receptor. EGFR resides at the plasma membrane to receive 
        extracellular growth factor signals.
      supported_by:
        - reference_id: PMID:15465819
          supporting_text: 2004 Oct 1. Ubiquitin ligase activity of c-Cbl guides
            the epidermal growth factor receptor into clathrin-coated pits by 
            two distinct modes of Eps15 recruitment.
  - term:
      id: GO:0018108
      label: peptidyl-tyrosine phosphorylation
    evidence_type: IEA
    review:
      summary: Core catalytic function of EGFR as a receptor tyrosine kinase 
        that phosphorylates substrate proteins on tyrosine residues
      action: NEW
      reason: EGFR is a receptor tyrosine kinase that catalyzes the 
        phosphorylation of tyrosine residues on target substrate proteins. Upon 
        ligand binding and receptor dimerization, EGFR undergoes 
        autophosphorylation of its C-terminal tyrosine residues, which then 
        serve as docking sites for adaptor proteins. EGFR also phosphorylates 
        numerous downstream substrate proteins on tyrosine residues to propagate
        growth factor signaling. This peptidyl-tyrosine phosphorylation activity
        is fundamental to EGFR's mechanism of signal transduction.
      supported_by:
        - reference_id: file:human/EGFR/EGFR-uniprot.txt
          supporting_text: Receptor tyrosine-protein kinase that binds ligands 
            of the EGF family and activates several signaling cascades
  - term:
      id: GO:0046777
      label: protein autophosphorylation
    evidence_type: IEA
    review:
      summary: Essential mechanism of EGFR activation through 
        trans-autophosphorylation of C-terminal tyrosine residues upon 
        ligand-induced dimerization
      action: NEW
      reason: Protein autophosphorylation is the fundamental mechanism by which 
        EGFR activates its signaling cascade. Upon EGF or other ligand binding, 
        EGFR undergoes dimerization, which brings two kinase domains into 
        proximity for trans-autophosphorylation. EGFR phosphorylates multiple 
        tyrosine residues in its own C-terminal tail (including Y1068, Y1086, 
        Y1148, Y1173), creating docking sites for SH2 and PTB domain-containing 
        signaling proteins. This autophosphorylation is essential for EGFR 
        signal transduction and downstream pathway activation.
      supported_by:
        - reference_id: file:human/EGFR/EGFR-uniprot.txt
          supporting_text: Receptor tyrosine-protein kinase that binds ligands 
            of the EGF family and activates several signaling cascades
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms.
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity.
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt.
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara.
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on on
      inter-ontology links.
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:10026169
    title: Identification of Grb4/Nckbeta, a src homology 2 and 3 
      domain-containing adapter protein having similar binding and biological 
      properties to Nck.
    findings:
      - statement: Grb4 and Nck adaptor proteins associate with receptor 
          tyrosine kinases and SOS1.
        supporting_text: Both Nck and Grb4 proteins could associate with 
          receptor tyrosine kinases and the SH3-binding proteins PAK, Sos1, and 
          PRK2,
  - id: PMID:10229072
    title: Association of Nck with tyrosine-phosphorylated SLP-76 in activated T
      lymphocytes.
    findings:
      - statement: Nck SH2 domain binds tyrosine-phosphorylated SLP-76.
        supporting_text: In vitro experiments show that the interaction between 
          Nck and SLP-76 is mediated via the Nck SH2 domain.
  - id: PMID:10572067
    title: Dominance of ErbB-1 heterodimers in lung epithelial cells 
      overexpressing ErbB-2. Both ErbB-1 and ErbB-2 contribute significantly to 
      tumorigenicity.
    findings:
      - statement: EGFR (ErbB-1) forms heterodimers with ErbB-2 that drive 
          tumorigenic signaling in HBECs.
        supporting_text: These data demonstrate the importance of 
          TGF-alpha-mediated signaling through the ErbB-1/-2 heterodimer in 
          development of the tumorigenic phenotype.
  - id: PMID:10805725
    title: Class II phosphoinositide 3-kinases are downstream targets of 
      activated polypeptide growth factor receptors.
    findings:
      - statement: PI3K-C2alpha and PI3K-C2beta are recruited to activated EGFR 
          signaling complexes.
        supporting_text: We demonstrate that PI3K-C2alpha and PI3K-C2beta 
          represent two downstream targets of the activated epidermal growth 
          factor (EGF) receptor in human carcinoma-derived A431 cells. 
          Stimulation of quiescent cultures with EGF resulted in the rapid 
          recruitment of both enzymes to a phosphotyrosine signaling complex 
          that contained the EGF receptor and Erb-B2.
  - id: PMID:11279102
    title: Sorting nexin 6, a novel SNX, interacts with the transforming growth 
      factor-beta family of receptor serine-threonine kinases.
    findings:
      - statement: SNX1-4 interact with receptor tyrosine kinases including 
          EGFR, and SNX6 shows similar behavior.
        supporting_text: have been shown to bind to several receptor tyrosine 
          kinases, including receptors for epidermal growth factor
  - id: PMID:11331309
    title: Real time fluorescence imaging of PLC gamma translocation and its 
      interaction with the epidermal growth factor receptor.
    findings:
      - statement: PLC gamma translocates to the plasma membrane and colocalizes
          with EGFR after EGF stimulation.
        supporting_text: Colocalization with the receptor was observed in the 
          plasma membrane and in membrane ruffles where PI 4,5-P(2) substrate 
          could also be visualized.
  - id: PMID:11336639
    title: Heterodimerization of the epidermal-growth-factor (EGF) receptor and 
      ErbB2 and the affinity of EGF binding are regulated by different 
      mechanisms.
    findings:
      - statement: EGFR-ErbB2 heterodimer formation is ligand-independent and 
          regulated separately from high-affinity EGF binding.
        supporting_text: ErbB2-EGFR heterodimer formation was found to be 
          ligand-independent, and the number of heterodimers was not altered by 
          overexpression of [K44A]dynamin.
  - id: PMID:11896612
    title: Use of signal specific receptor tyrosine kinase oncoproteins reveals 
      that pathways downstream from Grb2 or Shc are sufficient for cell 
      transformation and metastasis.
    findings:
      - statement: Recruitment of Grb2 or Shc downstream of a RTK is sufficient 
          to drive transformation and metastasis.
        supporting_text: Variants that recruit the Shc or Grb2 adaptor proteins 
          generated foci of morphologically transformed fibroblast cells and 
          induced anchorage-independent growth, scattering of epithelial cells 
          and experimental metastasis.
  - id: PMID:12009895
    title: Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts 
      and interacts with the epidermal growth factor receptor.
    findings:
      - statement: EGFR physically associates with PLSCR1 in lipid rafts and EGF
          stimulates PLSCR1 tyrosine phosphorylation.
        supporting_text: physical and functional interactions between the 
          epidermal growth factor (EGF) receptor and phospholipid scramblase 1 
          (PLSCR1)
  - id: PMID:12070153
    title: Identification of both positive and negative domains within the 
      epidermal growth factor receptor COOH-terminal region for signal 
      transducer and activator of transcription (STAT) activation.
    findings:
      - statement: EGFR C-terminal tail regions regulate STAT activation, with 
          truncations causing constitutive STAT signaling.
        supporting_text: Transient transfection of 293 cells with EGFR lacking 
          the C-tail, i.e. Y974DeltaEGFR or Y992DeltaEGFR, led to 
          EGF-independent or constitutive STAT activation
  - id: PMID:12297049
    title: Crystal structure of a truncated epidermal growth factor receptor 
      extracellular domain bound to transforming growth factor alpha.
    findings:
      - statement: The EGFR ectodomain binds TGFalpha via L1 and L2 domains in 
          the ligand-receptor crystal structure.
        supporting_text: We report the crystal structure, at 2.5 A resolution, 
          of a truncated human EGFR ectodomain bound to TGFalpha.
  - id: PMID:12297050
    title: Crystal structure of the complex of human epidermal growth factor and
      receptor extracellular domains.
    findings:
      - statement: EGF binds between EGFR domains I and III and promotes 
          receptor-mediated dimerization.
        supporting_text: EGFR domains I-III are arranged in a C shape, and EGF 
          is docked between domains I and III.
  - id: PMID:12435727
    title: Epidermal growth factor receptor mediates increased cell 
      proliferation, migration, and aggregation in esophageal keratinocytes in 
      vitro and in vivo.
    findings:
      - statement: EGFR overexpression activates Akt and STAT pathways and 
          promotes migration and aggregation in esophageal keratinocytes.
        supporting_text: EGFR overexpression in primary esophageal keratinocytes
          resulted in the biochemical activation of Akt and STAT pathways and 
          induced enhanced cell migration and cell aggregation.
  - id: PMID:12577067
    title: A proteomics strategy to elucidate functional protein-protein 
      interactions applied to EGF signaling.
    findings:
      - statement: The Grb2 SH2 domain binds phosphorylated EGFR and Shc in 
          EGF-stimulated cells.
        supporting_text: Combined cell lysates were affinity-purified over the 
          SH2 domain of the adapter protein Grb2 (GST-SH2 fusion protein) that 
          specifically binds phosphorylated EGFR and Src homologous and collagen
          (Shc) protein.
  - id: PMID:12620237
    title: EGF activates its receptor by removing interactions that autoinhibit 
      ectodomain dimerization.
    findings:
      - statement: EGF binding relieves autoinhibition of the EGFR ectodomain to
          expose the dimerization interface.
        supporting_text: The structure reveals an autoinhibited configuration, 
          where the dimerization interface recently identified in activated 
          sEGFR structures is completely occluded by intramolecular 
          interactions. To activate the receptor, EGF binding must promote a 
          large domain rearrangement that exposes this dimerization interface.
  - id: PMID:12646923
    title: Segregation of receptor and ligand regulates activation of epithelial
      growth factor receptor.
    findings:
      - statement: Heregulin-alpha activates erbB2 when epithelial polarity is 
          disrupted, indicating ligand-receptor segregation controls activation.
        supporting_text: Here we show that in differentiated human airway 
          epithelia, heregulin-alpha is present exclusively in the apical 
          membrane
  - id: PMID:12828935
    title: Activation of epidermal growth factor receptor signals induction of 
      nitric oxide synthase-2 in human optic nerve head astrocytes in 
      glaucomatous optic neuropathy.
    findings:
      - statement: EGFR activation induces NOS-2 in human optic nerve head 
          astrocytes.
        supporting_text: We have now found that activation of the epidermal 
          growth factor receptor (EGFR) induces NOS-2 in astrocytes of the human
          optic nerve head (ONH) in vitro
  - id: PMID:12925580
    title: Mice humanised for the EGF receptor display hypomorphic phenotypes in
      skin, bone and heart.
    findings:
      - statement: Humanized EGFR mice show tissue-specific hypomorphic 
          phenotypes and reveal an EGFR role in bone development.
        supporting_text: These results demonstrate that mice humanised for EGFR 
          display tissue-specific hypomorphic phenotypes and describe a novel 
          function for EGFR in bone development.
  - id: PMID:14568990
    title: Role of the pleckstrin homology domain of PLCgamma1 in its 
      interaction with the insulin receptor.
    findings:
      - statement: PLCgamma1 associates with the insulin receptor via its 
          PH-EF-hand domain.
        supporting_text: This association was found to be independent of 
          PLCgamma1 Src homology 2 domains, and instead required the pleckstrin 
          homology (PH)-EF-hand domain.
  - id: PMID:14679214
    title: A novel proteomic screen for peptide-protein interactions.
    findings:
      - statement: A tyrosine-phosphorylated EGFR peptide specifically binds the
          adaptor protein Grb2.
        supporting_text: A tyrosine-phosphorylated peptide of the epidermal 
          growth factor receptor specifically retrieved the Src homology domain 
          (SH) 2- and SH3 domain-containing adapter protein Grb2.
  - id: PMID:14702346
    title: Sorting of ligand-activated epidermal growth factor receptor to 
      lysosomes requires its actin-binding domain.
    findings:
      - statement: EGFR residues 985-996 are required for lysosomal sorting and 
          degradation after ligand activation.
        supporting_text: Here we demonstrate that the second transport step 
          requires a domain of the EGFR that encompasses residues 985-996 and 
          was previously found to interact with actin. Deletion of domain 
          989-994 (Delta989-994 EGFR) did not interfere with EGFR uptake but 
          completely abrogated its degradation.
  - id: PMID:14966128
    title: Structural requirements for signal transducer and activator of 
      transcription 3 binding to phosphotyrosine ligands containing the YXXQ 
      motif.
    findings:
      - statement: STAT3 SH2 binds phosphotyrosine peptides containing a YXXQ 
          motif.
        supporting_text: Only phosphotyrosine (Tyr(P)) peptides containing +3 
          Gln (not Leu, Met, Glu, or Arg) bound to wild type Stat3.
  - id: PMID:15082764
    title: Epidermal growth factor receptor stimulation activates the RNA 
      binding protein CUG-BP1 and increases expression of C/EBPbeta-LIP in 
      mammary epithelial cells.
    findings:
      - statement: EGFR signaling phosphorylates CUG-BP1 and increases 
          C/EBPbeta-LIP expression.
        supporting_text: Our data demonstrate that EGFR signaling results in the
          phosphorylation of CUG-BP1 and this leads to an increase in the 
          binding of CUG-BP1 to C/EBP beta mRNA and elevated expression of the 
          LIP isoform.
  - id: PMID:15225635
    title: Identification of 14-3-3zeta as an EGF receptor interacting protein.
    findings:
      - statement: EGF rapidly induces association of 14-3-3zeta with EGFR.
        supporting_text: Here, we describe an association of 14-3-3zeta with the
          epidermal growth factor receptor (EGFR) that is rapidly induced by 
          EGF.
  - id: PMID:15282549
    title: LRIG1 restricts growth factor signaling by enhancing receptor 
      ubiquitylation and degradation.
    findings:
      - statement: LRIG1 upregulation enhances EGFR ubiquitylation and 
          degradation via c-Cbl recruitment.
        supporting_text: Upregulation of LRIG1 is followed by enhanced 
          ubiquitylation and degradation of EGFR. The underlying mechanism 
          involves recruitment of c-Cbl, an E3 ubiquitin ligase that 
          simultaneously ubiquitylates EGFR and LRIG1 and sorts them for 
          degradation.
  - id: PMID:15345710
    title: The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB
      family receptor tyrosine kinases.
    findings:
      - statement: LRIG1 associates with ErbB receptors and promotes EGFR 
          ubiquitination and degradation.
        supporting_text: We observed that in co-transfected 293T cells, LRIG1 
          forms a complex with each of the ErbB receptors independent of growth 
          factor binding. We further observed that co-expression of LRIG1 with 
          EGF receptor suppresses cellular receptor levels, shortens receptor 
          half-life, and enhances ligand-stimulated receptor ubiquitination.
  - id: PMID:15465819
    title: Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor
      receptor into clathrin-coated pits by two distinct modes of Eps15 
      recruitment.
    findings:
      - statement: c-Cbl ubiquitin ligase activity and the Eps15 UIM are 
          required for EGFR entry into clathrin-coated pits.
        supporting_text: Both the ubiquitin ligase activity of c-Cbl and the UIM
          of Eps15 were necessary for plasma membrane recruitment of Eps15 and 
          entry of ligand-bound EGFR into coated pits and vesicles containing 
          Eps15.
  - id: PMID:15467833
    title: CEACAM1 modulates epidermal growth factor receptor--mediated cell 
      proliferation.
    findings:
      - statement: CEACAM1 is phosphorylated by EGFR and suppresses 
          EGFR-mediated proliferation by sequestering Shc.
        supporting_text: CEACAM1 is a substrate of the EGFR and that upon being 
          phosphorylated, CEACAM1 reduces EGFR-mediated growth of transfected 
          Cos-7 and MCF-7 cells
  - id: PMID:15542601
    title: Activation of the epidermal growth factor receptor by respiratory 
      syncytial virus results in increased inflammation and delayed apoptosis.
    findings:
      - statement: RSV activates EGFR in lung epithelial cells, increasing ERK 
          activity and IL-8 release while prolonging cell survival.
        supporting_text: We demonstrate for the first time that RSV activates 
          EGFR in lung epithelial cells. Activation of EGFR results in increased
          ERK activity, contributing to both the inflammatory response (IL-8 
          release) and prolonging the survival of RSV-infected cells.
  - id: PMID:15590694
    title: Suppressors of cytokine signaling 4 and 5 regulate epidermal growth 
      factor receptor signaling.
    findings:
      - statement: SOCS5 expression promotes EGFR degradation and reduces EGFR 
          signaling.
        supporting_text: The expression of SOCS5 led to a marked reduction in 
          EGFR expression levels by promoting EGFR degradation.
  - id: PMID:15611079
    title: Epigen, the last ligand of ErbB receptors, reveals intricate 
      relationships between affinity and mitogenicity.
    findings:
      - statement: Epigen (EPG) is more mitogenic than EGF despite lower 
          affinity, likely due to inefficient receptor ubiquitylation and 
          down-regulation.
        supporting_text: Interestingly, soluble EPG is more mitogenic than EGF, 
          although its binding affinity is 100-fold lower. Our results attribute
          the anomalous mitogenic power of EPG to evasion of receptor-mediated 
          depletion of ligand molecules, as well as to inefficient receptor 
          ubiquitylation and down-regulation.
  - id: PMID:15657067
    title: Phosphotyrosine signaling networks in epidermal growth factor 
      receptor overexpressing squamous carcinoma cells.
    findings:
      - statement: Erlotinib inhibition of EGFR reduces phosphorylation of 
          downstream targets including PLCgamma, PI-3 kinase, and STAT3/5.
        supporting_text: Pharmacological inhibition of EGF receptor kinase 
          activity by erlotinib resulted in reduced phosphorylation of 
          downstream signaling, for example through Cbl/Cbl-B, phospholipase 
          Cgamma (PLCgamma), Erk1/2, PI-3 kinase, and STAT3/5.
  - id: PMID:15899872
    title: Transforming growth factor {beta} (TGF-{beta})-Smad target gene 
      protein tyrosine phosphatase receptor type kappa is required for 
      TGF-{beta} function.
    findings:
      - statement: RPTPkappa associates with EGFR and HER2, suppressing basal 
          and ligand-induced receptor phosphorylation and proliferation.
        supporting_text: Endogenous RPTPkappa associated with EGF receptor and 
          HER2, resulting in suppression of basal and ErbB ligand-induced 
          proliferation and receptor phosphorylation.
  - id: PMID:15962011
    title: Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth 
      factor receptor downregulation.
    findings:
      - statement: Sprouty2 inhibits EGFR downregulation by acting at the 
          Cbl/CIN85 interface.
        supporting_text: Here, we show that Sprouty2 associates with CIN85 and 
          acts at the interface between Cbl and CIN85 to inhibit EGFR 
          downregulation.
  - id: PMID:16076471
    title: 'The epidermal growth factor receptors and their family of ligands: their
      putative role in atherogenesis.'
    findings:
      - statement: EGFR is a tyrosine kinase receptor activated by multiple 
          ligands and is detected on intimal smooth muscle cells in 
          atherosclerotic plaques.
        supporting_text: The epidermal growth factor receptor is a member of 
          type-I growth factor receptor family with tyrosine kinase activity
  - id: PMID:16253990
    title: Increased proliferation and altered growth factor dependence of human
      mammary epithelial cells overexpressing the Gab2 docking protein.
    findings:
      - statement: Gab2 overexpression enhances EGF-induced signaling and cell 
          cycle progression.
        supporting_text: expression of Gab2 at levels comparable with those 
          detected in human breast cancer cells accelerated epidermal growth 
          factor (EGF)-induced cell cycle progression and was associated with 
          increased basal Stat5 tyrosine phosphorylation and enhanced and/or 
          more sustained EGF-induced Erk and Akt activation.
  - id: PMID:16273093
    title: A quantitative protein interaction network for the ErbB receptors 
      using protein microarrays.
    findings:
      - statement: EGFR phosphotyrosine sites recruit many SH2/PTB domains, with
          increased promiscuity at lower affinity thresholds.
        supporting_text: Most notably, EGFR and ErbB2 become markedly more 
          promiscuous as the threshold is lowered, whereas ErbB3 does not.
  - id: PMID:16499958
    title: Crystal structure of the ubiquitin binding domains of rabex-5 reveals
      two modes of interaction with ubiquitin.
    findings:
      - statement: Rabex-5 ubiquitin-binding domains enable interaction with 
          ubiquitinated EGFR in vivo.
        supporting_text: These UBDs determine a number of properties of Rabex-5,
          including its coupled monoubiquitination and interaction in vivo with 
          ubiquitinated EGFRs.
  - id: PMID:16516204
    title: 'Activation of ErbB2 by 2-methyl-1,4-naphthoquinone (menadione) in human
      keratinocytes: role of EGFR and protein tyrosine phosphatases.'
    findings:
      - statement: Menadione activates ErbB2 via EGFR in keratinocytes.
        supporting_text: ErbB2 is activated via the epidermal growth factor 
          receptor (EGFR) upon exposure of cultured human keratinocytes to 
          2-methyl-1,4-naphthoquinone (menadione).
  - id: PMID:16554368
    title: The ESCRT-III subunit hVps24 is required for degradation but not 
      silencing of the epidermal growth factor receptor.
    findings:
      - statement: hVps24 is required for EGFR degradation and transport to 
          lysosomes.
        supporting_text: Depletion of hVps24 by siRNA showed that this ESCRT 
          subunit, like Tsg101, is important for degradation of the epidermal 
          growth factor (EGF) receptor (EGFR) and for transport of the receptor 
          from early endosomes to lysosomes.
  - id: PMID:16777603
    title: An allosteric mechanism for activation of the kinase domain of 
      epidermal growth factor receptor.
    findings:
      - statement: EGFR activation is driven by asymmetric kinase domain 
          dimerization rather than activation loop phosphorylation.
        supporting_text: EGFR activation results from the formation of an 
          asymmetric dimer in which the C-terminal lobe of one kinase domain 
          plays a role analogous to that of cyclin in activated CDK/cyclin 
          complexes.
  - id: PMID:16799092
    title: Dynamic profiling of the post-translational modifications and 
      interaction partners of epidermal growth factor receptor signaling after 
      stimulation by epidermal growth factor using Extended Range Proteomic 
      Analysis (ERPA).
    findings:
      - statement: ERPA profiling of EGFR identified 13 phosphorylation sites 
          and quantified their dynamics after EGF stimulation.
        supporting_text: A total of 13 phosphorylation sites were identified, 
          and the estimated stoichiometry was determined over the stimulation 
          time points, including Thr(P) and Ser(P) sites in addition to Tyr(P) 
          sites.
  - id: PMID:16843263
    title: HER2 kinase domain mutation results in constitutive phosphorylation 
      and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase 
      inhibitors.
    findings:
      - statement: HER2(YVMA) transphosphorylates EGFR even in the presence of 
          EGFR TKIs.
        supporting_text: HER2(YVMA) transphosphorylated kinase-dead EGFR(K721R) 
          and EGFR(WT) in the presence of EGFR tyrosine kinase inhibitors 
          (TKIs).
  - id: PMID:16914641
    title: Intersectin regulates epidermal growth factor receptor endocytosis, 
      ubiquitylation, and signaling.
    findings:
      - statement: Intersectin scaffolds Cbl to promote EGFR ubiquitylation and 
          degradation, supporting EGFR internalization and ERK activation.
        supporting_text: This interaction stimulates the ubiquitylation and 
          degradation of the activated EGFR.
  - id: PMID:16954185
    title: Advanced glycation end product (AGE) receptor 1 suppresses cell 
      oxidant stress and activation signaling via EGF receptor.
    findings:
      - statement: AGER1 suppresses AGE-induced EGFR phosphorylation and 
          downstream signaling.
        supporting_text: AGE responses also included EGF receptor (EGFR) 
          phosphorylation in MCs or HEK293 cells, but this link was blocked in 
          both MC-R1 and HEK293-R1 cells.
  - id: PMID:17115032
    title: Tyrosine phosphorylation controls PCNA function through protein 
      stability.
    findings:
      - statement: Nuclear EGFR phosphorylates PCNA Tyr211 to stabilize 
          chromatin-bound PCNA.
        supporting_text: the chromatin-bound PCNA protein is phosphorylated on 
          Tyr 211, which is required for maintaining its function on chromatin 
          and is dependent on the tyrosine kinase activity of EGF receptor 
          (EGFR) in the nucleus.
  - id: PMID:17126326
    title: Extracellular heat shock protein 70 mediates heat stress-induced 
      epidermal growth factor receptor transactivation in A431 carcinoma cells.
    findings:
      - statement: Secreted Hsp70 mediates ligand-independent EGFR 
          transactivation during heat stress.
        supporting_text: the depletion of Hsp70 from the conditioned medium of 
          heated cells abolishes EGFR transactivation indicating that secreted 
          Hsp70 is essential for EGFR transactivation during heat shock.
  - id: PMID:17148612
    title: A system for quantifying dynamic protein interactions defines a role 
      for Herceptin in modulating ErbB2 interactions.
    findings:
      - statement: ErbB2 interacts stably with EGFR, and Herceptin inhibits this
          interaction, promoting EGFR internalization.
        supporting_text: The widely used anti-cancer antibody Herceptin was 
          found to effectively inhibit the interaction of the EGFR and ErbB2
  - id: PMID:17182860
    title: Activated Cdc42-associated kinase 1 is a component of EGF receptor 
      signaling complex and regulates EGF receptor degradation.
    findings:
      - statement: ACK1 associates with EGFR upon EGF stimulation and promotes 
          ligand-induced EGFR degradation.
        supporting_text: ACK1 interacted with epidermal growth factor receptor 
          (EGFR) upon EGF stimulation
  - id: PMID:17284441
    title: Epidermal growth factor directs sex-specific steroid signaling 
      through Src activation.
    findings:
      - statement: EGFR forms a complex with estrogen receptor and Src during E2
          signaling in breast cancer cells.
        supporting_text: EGFR, estrogen receptor, and Src were found to form a 
          complex upon E2 stimulation.
  - id: PMID:17334392
    title: A crucial role of plasma membrane-associated sialidase in the 
      survival of human cancer cells.
    findings:
      - statement: NEU3 enhances EGF-stimulated EGFR tyrosine phosphorylation.
        supporting_text: NEU3 actually enhanced EGF-stimulated 
          tyrosine-phosphorylation of EGFR
  - id: PMID:17403676
    title: Rin1 interacts with signal-transducing adaptor molecule (STAM) and 
      mediates epidermal growth factor receptor trafficking and degradation.
    findings:
      - statement: Rin1 promotes EGFR degradation after EGF stimulation.
        supporting_text: overexpression of Rin1 accelerates EGFR degradation in 
          EGF-stimulated cells.
  - id: PMID:17599051
    title: The evolutionarily conserved EBR module of RALT/MIG6 mediates 
      suppression of the EGFR catalytic activity.
    findings:
      - statement: RALT/MIG6 suppresses EGFR catalytic activity via its 
          ErbB-binding region.
        supporting_text: We report that RALT suppresses EGFR function by 
          inhibiting its catalytic activity. The evolutionarily conserved 
          ErbB-binding region (EBR) is necessary and sufficient to carry out 
          RALT-dependent suppression of EGFR kinase activity in vitro and in 
          intact cells.
  - id: PMID:17655843
    title: 'EGF receptor transactivation and PI3-kinase mediate stimulation of ERK
      by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role in wound
      healing.'
    findings:
      - statement: alpha2A-adrenoreceptor activates ERK/Akt via EGFR 
          transactivation in intestinal epithelial cells.
        supporting_text: Both effects are strongly attenuated by inhibition or 
          desensitization of epidermal growth factor (EGF) receptor, matrix 
          metalloproteinase (MMP) blockade, heparin-binding-EGF neutralization 
          or phosphatidylinositol 3-kinase (PI3-kinase) inhibitors.
  - id: PMID:17697999
    title: Ligand-induced structural transitions in ErbB receptor extracellular 
      domains.
    findings:
      - statement: Ligand binding shifts EGFR extracellular domain from a 
          tethered autoinhibited state to an extended dimerization-competent 
          conformation.
        supporting_text: Without bound ligand, the extracellular region of the 
          receptor (sEGFR) adopts a "tethered" configuration with its 
          dimerization site occluded by apparently autoinhibitory intramolecular
          interactions. Ligand binding causes the receptor to become "extended,"
          breaking the tether and exposing the dimerization site.
  - id: PMID:17714434
    title: Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor 
      and chemokine receptors destined for lysosomal degradation.
    findings:
      - statement: Vps22 is required for ligand-induced EGFR degradation and 
          proper endosomal sorting.
        supporting_text: Depletion of Vps22 by small interfering RNA, which was 
          accompanied by decreased levels of other ESCRT-II subunits, greatly 
          reduced degradation of EGFR and its ligand EGF as well as the 
          chemokine receptor CXCR4.
  - id: PMID:17726113
    title: Inhibition of the leucine-rich repeat protein LINGO-1 enhances 
      survival, structure, and function of dopaminergic neurons in Parkinson's 
      disease models.
    findings:
      - statement: LINGO-1 antagonists improve dopaminergic neuron survival via 
          EGFR/Akt activation by blocking LINGO-1 binding to EGFR.
        supporting_text: LINGO-1 antagonists (LINGO-1-Fc, dominant negative 
          LINGO-1, and anti-LINGO-1 antibody) improved DA neuron survival in 
          response to MPP+ in part by mechanisms that involve activation of the 
          EGFR/Akt signaling pathway through a direct inhibition of LINGO-1's 
          binding to EGFR.
  - id: PMID:17909029
    title: The phosphoinositide kinase PIKfyve mediates epidermal growth factor 
      receptor trafficking to the nucleus.
    findings:
      - statement: PIKfyve mediates HB-EGF-stimulated EGFR nuclear trafficking 
          and EGFR binding to the cyclin D1 promoter.
        supporting_text: RNA silencing indicated that PIKfyve is a mediator of 
          HB-EGF-stimulated EGFR nuclear trafficking, EGFR binding to the cyclin
          D1 promoter, and cell cycle progression.
  - id: PMID:18042729
    title: Epidermal growth factor receptor juxtamembrane region regulates 
      allosteric tyrosine kinase activation.
    findings:
      - statement: The EGFR juxtamembrane region is required for allosteric 
          kinase activation.
        supporting_text: Deletion of the JM region (DeltaJM) results in a severe
          loss of ICD tyrosine phosphorylation, indicating that this region is 
          required for maximal activity of the tyrosine kinase domain.
  - id: PMID:18046415
    title: Inhibition of the EGF receptor by binding of MIG6 to an activating 
      kinase domain interface.
    findings:
      - statement: MIG6 inhibits EGFR by blocking formation of the activating 
          asymmetric dimer interface.
        supporting_text: Biochemical and cell-based analyses confirm that this 
          interaction contributes to EGFR inhibition by blocking the formation 
          of the activating dimer interface.
  - id: PMID:18070883
    title: A novel role of Sprouty 2 in regulating cellular apoptosis.
    findings:
      - statement: Spry2 supports EGFR signaling and survival pathways; its 
          silencing reduces EGFR levels and EGF-elicited AKT/ERK activation.
        supporting_text: Silencing of hSPRY2 decreased serum- or epidermal 
          growth factor (EGF)-elicited activation of AKT and ERK1/2 and reduced 
          the levels of EGF receptor.
  - id: PMID:18273061
    title: Structural basis for a novel intrapeptidyl H-bond and reverse binding
      of c-Cbl-TKB domain substrates.
    findings:
      - statement: The c-Cbl TKB domain binds phosphorylated EGFR peptides as 
          substrates for ubiquitination.
        supporting_text: To address how this domain can bind to disparate 
          recognition mofits and to determine whether this results in variations
          in substrate-binding affinity, we compared crystal structures of the 
          Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, 
          Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors 
          and validated the binding with point-mutational analyses using 
          full-length proteins
  - id: PMID:18455122
    title: Survival of cancer cells is maintained by EGFR independent of its 
      kinase activity.
    findings:
      - statement: Kinase-independent EGFR maintains survival by stabilizing 
          SGLT1 and preventing autophagic death.
        supporting_text: the function of kinase-independent EGFR is to prevent 
          autophagic cell death by maintaining intracellular glucose level 
          through interaction and stabilization of the sodium/glucose 
          cotransporter 1 (SGLT1).
  - id: PMID:18483258
    title: UVA-induced cell cycle progression is mediated by a disintegrin and 
      metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in
      keratinocytes.
    findings:
      - statement: UVA activates EGFR upstream of AKT/cyclin D1 to drive cell 
          cycle progression in keratinocytes.
        supporting_text: Activation of epidermal growth factor receptor (EGFR) 
          was observed after UVA exposure. EGFR kinase inhibitor AG attenuated 
          the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, 
          indicating that EGFR is upstream of AKT/cyclin D1 pathway activation.
  - id: PMID:18542056
    title: LRIG1 negatively regulates the oncogenic EGF receptor mutant 
      EGFRvIII.
    findings:
      - statement: LRIG1 binds EGFRvIII and suppresses its oncogenic signaling.
        supporting_text: We find that EGFRvIII retains interaction with LRIG1 
          and is in fact more sensitive to LRIG1 action than wild-type receptor.
  - id: PMID:18602463
    title: Ataxin-2 associates with the endocytosis complex and affects EGF 
      receptor trafficking.
    findings:
      - statement: Ataxin-2 influences EGFR endocytic trafficking.
        supporting_text: Functional studies demonstrated that ataxin-2 affects 
          endocytic trafficking of the epidermal growth factor receptor (EGFR).
  - id: PMID:18722344
    title: BCAR3 regulates EGF-induced DNA synthesis in normal human breast 
      MCF-12A cells.
    findings:
      - statement: BCAR3 associates with activated EGFR and is required for 
          EGF-induced DNA synthesis.
        supporting_text: Direct association of BCAR3 with activated EGF receptor
          and Cas was observed.
  - id: PMID:18776048
    title: Comparisons of tyrosine phosphorylated proteins in cells expressing 
      lung cancer-specific alleles of EGFR and KRAS.
    findings:
      - statement: Mutant EGFR increases tyrosine phosphorylation of signaling 
          proteins relative to WT EGFR.
        supporting_text: Tyrosine phosphorylation of signaling molecules was 
          greater in HBECs expressing the mutant EGFRs than in cells expressing 
          WT EGFR or mutant KRAS.
  - id: PMID:18824549
    title: Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth
      factor receptor-dependent pathway and stimulates chemokine production by 
      pulmonary epithelial cells.
    findings:
      - statement: AMCase secretion is EGFR-dependent and involves EGFR 
          interaction.
        supporting_text: In vitro cotransfection experiments in A549 cells 
          demonstrated that AMCase and EGFR physically interact with each other.
          Cotransfection of AMCase and EGFR also increased, whereas EGFR 
          inhibition decreased AMCase secretion.
  - id: PMID:19167335
    title: Large-scale structural analysis of the classical human protein 
      tyrosine phosphatome.
    findings:
      - statement: Protein tyrosine phosphatases regulate signaling by 
          selectively dephosphorylating substrates.
        supporting_text: Protein tyrosine phosphatases (PTPs) play a critical 
          role in regulating cellular functions by selectively dephosphorylating
          their substrates.
  - id: PMID:19172738
    title: Phosphorylation-dependent binding of 14-3-3 terminates signalling by 
      the Gab2 docking protein.
    findings:
      - statement: 14-3-3 binding to phosphorylated Gab2 terminates 
          receptor-associated signaling by uncoupling Gab2 from Grb2.
        supporting_text: We now demonstrate that growth factor-induced 
          phosphorylation of Gab2 on two residues, S210 and T391, leads to 
          recruitment of 14-3-3 proteins.
  - id: PMID:19509291
    title: GAREM, a novel adaptor protein for growth factor receptor-bound 
      protein 2, contributes to cellular transformation through the activation 
      of extracellular signal-regulated kinase signaling.
    findings:
      - statement: GAREM is phosphorylated after EGF stimulation and binds Grb2 
          to regulate ERK signaling downstream of EGFR.
        supporting_text: GAREM is phosphorylated at tyrosine 105 and 453 after 
          EGF stimulation. Grb2 was identified as its binding partner, and the 
          proline-rich motifs of GAREM are recognized by the N- and C-terminal 
          SH3 domains of Grb2.
  - id: PMID:19563760
    title: Mechanism for activation of the EGF receptor catalytic domain by the 
      juxtamembrane segment.
    findings:
      - statement: The EGFR juxtamembrane segment promotes kinase activation by 
          dimerizing kinase domains.
        supporting_text: We show that the intracellular juxtamembrane segment of
          the receptor, known to potentiate kinase activity, is able to dimerize
          the kinase domains.
  - id: PMID:19602593
    title: Cetuximab/C225-induced intracellular trafficking of epidermal growth 
      factor receptor.
    findings:
      - statement: Cetuximab induces EGFR endocytosis and trafficking to the ER 
          and nucleus.
        supporting_text: The data herein show that C225-dependent EGFR 
          trafficking relocalizes the receptor to the endoplasmic reticulum (ER)
          and nucleus.
  - id: PMID:19650109
    title: Flow cytometric in situ proximity ligation analyses of protein 
      interactions and post-translational modification of the epidermal growth 
      factor receptor family.
    findings:
      - statement: In situ PLA quantifies EGFR-HER2 interactions and EGFR 
          activation in cells.
        supporting_text: The in situ proximity ligation assay (in situ PLA) was 
          used to quantify homo- and heteromeric interactions between EGFR and 
          HER2 in cultured cells, using flow cytometry as the readout method.
  - id: PMID:19798056
    title: Participation of Tom1L1 in EGF-stimulated endocytosis of EGF 
      receptor.
    findings:
      - statement: Tom1L1 is required for EGFR endocytosis following EGF 
          stimulation.
        supporting_text: RNAi-mediated knockdown of Tom1L1 inhibits endocytosis 
          of EGFR.
  - id: PMID:20007378
    title: Structural analysis of the catalytically inactive kinase domain of 
      the human EGF receptor 3.
    findings:
      - statement: HER3 is catalytically inactive but can activate the EGFR 
          kinase domain.
        supporting_text: we confirm that it is catalytically inactive but can 
          serve as an activator of the EGFR kinase domain.
  - id: PMID:20029029
    title: Regulation of epidermal growth factor receptor trafficking by lysine 
      deacetylase HDAC6.
    findings:
      - statement: HDAC6 negatively regulates EGFR endocytosis and degradation 
          by controlling tubulin acetylation.
        supporting_text: histone deacetylase 6 (HDAC6), a cytoplasmic lysine 
          deacetylase, which we found negatively regulated EGFR endocytosis and 
          degradation
  - id: PMID:20153921
    title: EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial 
      translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR 
      kinase activity.
    findings:
      - statement: EGFR/EGFRvIII bind PUMA and sequester it in the cytoplasm, 
          inhibiting apoptosis independently of EGFR kinase activity.
        supporting_text: EGFR/EGFRvIII binds to PUMA constitutively and under 
          apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. 
          The EGFR-PUMA interaction is independent of EGFR activation and is 
          sustained under EGFR inhibition.
  - id: PMID:20302655
    title: Epidermal growth factor receptor regulates beta-catenin location, 
      stability, and transcriptional activity in oral cancer.
    findings:
      - statement: EGFR activation increases nuclear beta-catenin and regulates 
          its transcriptional activity in oral cancer.
        supporting_text: Activation of EGFR signaling increased the amount of 
          beta-catenin in the nucleus and decreased the amount in the membranes.
  - id: PMID:20308550
    title: The phosphatase and tensin homolog regulates epidermal growth factor 
      receptor (EGFR) inhibitor response by targeting EGFR for degradation.
    findings:
      - statement: PTEN inactivation elevates EGFR activity by impairing 
          Cbl-mediated ubiquitylation and degradation.
        supporting_text: PTEN inactivation specifically raises EGFR activity by 
          impairing the ligand-induced ubiquitylation and degradation of the 
          activated receptor through destabilization of newly formed ubiquitin 
          ligase Cbl complexes.
  - id: PMID:20359299
    title: 'A proximity ligation assay using transiently transfected, epitope-tagged
      proteins: application for in situ detection of dimerized receptor tyrosine kinases.'
    findings:
      - statement: PLA enables in situ detection and quantification of 
          ligand-dependent EGFR dimerization.
        supporting_text: utility of a proximity ligation assay (PLA)-based 
          methodology for in situ visualization and quantification of 
          ligand-dependent EGFR receptor dimerization in intact cells.
  - id: PMID:20403327
    title: TRP channel regulates EGFR signaling in hair morphogenesis and skin 
      barrier formation.
    findings:
      - statement: TRPV3 forms a signaling complex with TGF-alpha/EGFR and 
          amplifies EGFR signaling via TGF-alpha release.
        supporting_text: keratinocyte TRPV3, a member of the transient receptor 
          potential (TRP) family of Ca(2+)-permeant channels, forms a signaling 
          complex with TGF-alpha/EGFR. Activation of EGFR leads to increased 
          TRPV3 channel activity, which in turn stimulates TGF-alpha release.
  - id: PMID:20462955
    title: A G{alpha}i-GIV molecular complex binds epidermal growth factor 
      receptor and determines whether cells migrate or proliferate.
    findings:
      - statement: GIV directly interacts with EGFR and enhances EGFR 
          autophosphorylation while prolonging membrane association.
        supporting_text: GIV directly interacts with EGFR, and when its GEF 
          function is intact, a Galpha(i)-GIV-EGFR signaling complex assembles, 
          EGFR autophosphorylation is enhanced, and the receptor's association 
          with the plasma membrane (PM) is prolonged.
  - id: PMID:20473329
    title: SIRPalpha1 receptors interfere with the EGFRvIII signalosome to 
      inhibit glioblastoma cell transformation and migration.
    findings:
      - statement: SIRPalpha1 reduces EGFRvIII signalosome interactions and 
          inhibits EGFRvIII-driven migration and transformation.
        supporting_text: We observed reduced EGFRvIII/SHP-2/Gab1/Grb2/Sos-1 
          interaction and enhanced SIRP/SHP-2 association in 
          U87MG.EGFRvIII/SIRPalpha1 cells when compared with empty vector 
          control cells.
  - id: PMID:20551055
    title: Nuclear alternate estrogen receptor GPR30 mediates 
      17beta-estradiol-induced gene expression and migration in breast 
      cancer-associated fibroblasts.
    findings:
      - statement: E2 promotes a physical interaction between GPR30 and 
          phosphorylated EGFR at the cyclin D1 promoter.
        supporting_text: E2 stimulates a physical interaction between GPR30 and 
          phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter.
  - id: PMID:20562913
    title: Differential roles of ERK and Akt pathways in regulation of 
      EGFR-mediated signaling and motility in prostate cancer cells.
    findings:
      - statement: ERK inhibition enhances EGF-induced EGFR activation, 
          ubiquitination, and downregulation.
        supporting_text: pharmacological inhibition of ERK (but not Akt) 
          signaling enhances EGF-induced EGFR activation, ubiquitination and 
          downregulation
  - id: PMID:20624308
    title: EGFR/Met association regulates EGFR TKI resistance in breast cancer.
    findings:
      - statement: EGFR and Met form a complex that supports ligand-independent 
          Met phosphorylation and EGFR TKI resistance.
        supporting_text: we identified an EGFR/Met complex via 
          co-immunoprecipitation. However, we only observed Met constitutive 
          phosphorylation when c-Src also was part of this complex.
  - id: PMID:20878056
    title: Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary 
      carcinogenesis.
    findings:
      - statement: RQCD1 knockdown reduces EGF-induced Akt phosphorylation 
          downstream of EGFR.
        supporting_text: Knockdown of RQCD1 reduced the Akt phosphorylation 
          level that was induced by epidermal growth factor (EGF) stimulation.
  - id: PMID:20935677
    title: A positive feedback loop of ER-α36/EGFR promotes malignant growth of 
      ER-negative breast cancer cells.
    findings:
      - statement: ER-alpha36 mediates estrogen-induced EGFR phosphorylation via
          interaction with EGFR/Src/Shc.
        supporting_text: ER-α36 physically interacted with the EGFR/Src/Shc 
          complex and mediated estrogen-induced phosphorylation of epidermal 
          growth factor receptor (EGFR) and Src.
  - id: PMID:21203579
    title: HER2 phosphorylation is maintained by a PKB negative feedback loop in
      response to anti-HER2 herceptin in breast cancer.
    findings:
      - statement: HER2 phosphorylation is maintained by ligand-mediated 
          EGFR/HER3/HER4 activation via ADAM17.
        supporting_text: HER2 phosphorylation is maintained by ligand-mediated 
          activation of EGFR, HER3, and HER4 receptors, resulting in their 
          dimerisation with HER2. The release of HER ligands was mediated by 
          ADAM17 through a PKB negative feedback loop.
  - id: PMID:21258405
    title: Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR 
      downstream pathways in pancreatic cancer cells.
    findings:
      - statement: Galectin-3 promotes endocytosis of EGFR; its depletion 
          increases EGFR phosphorylation and nuclear translocation.
        supporting_text: galectin-3, an endogenous lectin, is co-expressed with 
          MUC1 in human pancreatic ductal adenocarcinoma, and that it favours 
          the endocytosis of MUC1 and EGFR. Depletion of galectin-3 by RNA 
          interference increased the interaction between MUC1 and EGFR, EGFR and
          ERK-1,2 phosphorylation, and translocation of EGFR to the nucleus.
  - id: PMID:21266349
    title: EGFR nuclear translocation modulates DNA repair following cisplatin 
      and ionizing radiation treatment.
    findings:
      - statement: EGFR nuclear localization and DNA-PKcs binding enhance DNA 
          repair after cisplatin or IR.
        supporting_text: Immunoprecipitation showed wtEGFR and EGFRvIII binding 
          to DNA-PKcs, increasing 2-fold 18 hours after cisplatin therapy.
  - id: PMID:21278786
    title: PI3K inhibition results in enhanced HER signaling and acquired ERK 
      dependency in HER2-overexpressing breast cancer.
    findings:
      - statement: PI3K inhibition enhances HER receptor dimerization and 
          phosphorylation, including EGFR, leading to ERK activation.
        supporting_text: This enhanced ERK signaling occurred as a result of 
          activation of HER family receptors as evidenced by induction of HER 
          receptors dimerization and phosphorylation, increased expression of 
          HER3 and binding of adaptor molecules to HER2 and HER3.
  - id: PMID:21278788
    title: Translationally controlled tumor protein induces human breast 
      epithelial cell transformation through the activation of Src.
    findings:
      - statement: TCTP activates Src and induces phosphorylation of EGFR 
          tyrosines.
        supporting_text: We found that TCTP (a) induces Src release from 
          Na,K-ATPase α subunit and Src activation
  - id: PMID:21349850
    title: MAPK scaffold IQGAP1 binds the EGF receptor and modulates its 
      activation.
    findings:
      - statement: IQGAP1 binds EGFR and is required for robust EGFR 
          autophosphorylation.
        supporting_text: In IQGAP1-null cells, EGF-stimulated tyrosine 
          phosphorylation of EGFR is severely attenuated. Normal levels of 
          autophosphorylation are restored by reconstituting wild type IQGAP1 
          and enhanced by an IQGAP1 S1443D mutant.
  - id: PMID:21376233
    title: Activation of multiple proto-oncogenic tyrosine kinases in breast 
      cancer via loss of the PTPN12 phosphatase.
    findings:
      - statement: PTPN12 suppresses EGFR and HER2 signaling by inhibiting 
          multiple oncogenic tyrosine kinases.
        supporting_text: PTPN12 suppresses transformation by interacting with 
          and inhibiting multiple oncogenic tyrosine kinases, including HER2 and
          EGFR.
  - id: PMID:21423176
    title: Analysis of the myosin-II-responsive focal adhesion proteome reveals 
      a role for β-Pix in negative regulation of focal adhesion maturation.
    findings:
      - statement: β-Pix negatively regulates focal adhesion maturation and 
          promotes lamellipodial protrusion.
        supporting_text: We focused on the Rac guanine nucleotide exchange 
          factor β-Pix, documenting its role in the negative regulation of focal
          adhesion maturation and the promotion of lamellipodial protrusion and 
          focal adhesion turnover to drive cell migration.
  - id: PMID:21439278
    title: Engineered epidermal growth factor mutants with faster binding 
      on-rates correlate with enhanced receptor activation.
    findings:
      - statement: EGF mutants with faster binding on-rates increase EGFR 
          activation compared to wild-type EGF.
        supporting_text: We found that EGF mutants with faster kinetic on-rates 
          stimulate increased EGFR activation compared to wild-type EGF.
  - id: PMID:21480528
    title: Comparative analysis of fluorescence resonance energy transfer (FRET)
      and proximity ligation assay (PLA).
    findings:
      - statement: PLA is semiquantitative due to signal saturation, whereas 
          FRET signals scale linearly with expression.
        supporting_text: Our data imply that PLA is a semiquantitative measure 
          of protein colocalizations due to non-linear effects in the reaction 
          and that caution should be exercised when interpreting PLA data in a 
          quantitative way.
  - id: PMID:21482778
    title: Quantification of receptor tyrosine kinase transactivation through 
      direct dimerization and surface density measurements in single cells.
    findings:
      - statement: SpIDA quantifies EGFR dimerization and surface trafficking 
          during GPCR-driven transactivation.
        supporting_text: Here, we show the use of SpIDA to quantify 
          dimerization/activation and surface transport of receptor protein 
          kinases--EGF receptor and TrkB--at early stages of their 
          transactivation by several G protein-coupled receptors (GPCRs).
  - id: PMID:21673316
    title: TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal
      transition in breast cancer.
    findings:
      - statement: miR-221/222 abundance decreases with EGFR or MEK inhibition, 
          placing these miRNAs downstream of EGFR-RAS signaling.
        supporting_text: the abundance of these miRNAs decreased with inhibition
          of the epidermal growth factor receptor (EGFR) or MEK 
          (mitogen-activated or extracellular signal-regulated protein kinase 
          kinase), placing miR-221/222 downstream of the RAS pathway.
  - id: PMID:21706016
    title: Selected reaction monitoring mass spectrometry reveals the dynamics 
      of signaling through the GRB2 adaptor.
    findings:
      - statement: AP-SRM profiling defines time-dependent GRB2 interaction 
          networks after stimulation.
        supporting_text: Our data reliably define context-specific and 
          time-dependent networks that form around GRB2 after stimulation, and 
          reveal core and growth factor-selective complexes comprising 90 
          proteins identified as interacting with GRB2 in HEK293T cells.
  - id: PMID:2176151
    title: The tyrosine phosphorylated carboxyterminus of the EGF receptor is a 
      binding site for GAP and PLC-gamma.
    findings:
      - statement: EGFR C-terminal autophosphorylation sites mediate binding of 
          GAP SH2 and PLC-gamma.
        supporting_text: This fragment bound both TRP E GAP SH2 and PLC-gamma 
          but only when tyrosine phosphorylated.
  - id: PMID:21822280
    title: Simultaneous visualization of the extracellular and cytoplasmic 
      domains of the epidermal growth factor receptor.
    findings:
      - statement: Liganded EGFR ectodomain can couple to both active asymmetric
          kinase dimers and inactive symmetric dimers.
        supporting_text: The liganded, dimeric EGFR ectodomain can couple both 
          to putatively active, asymmetrically associated kinase dimers and to 
          putatively inactive, symmetrically associated kinase dimers and 
          monomers.
  - id: PMID:21951318
    title: Ligand-dependent differences in estrogen receptor beta-interacting 
      proteins identified in lung adenocarcinoma cells corresponds to estrogenic
      responses.
    findings:
      - statement: ERbeta and EGFR interact in lung adenocarcinoma cells in 
          response to E2 or EGF.
        supporting_text: Coimmunoprecipitation experiments in these and other 
          lung adenocarcinoma cells confirmed that ERβ and EGFR interact in a 
          gender-dependent manner and in response to E2 or EGF.
  - id: PMID:22232519
    title: In situ analysis of mutant EGFRs prevalent in glioblastoma multiforme
      reveals aberrant dimerization, activation, and differential response to 
      anti-EGFR targeted therapy.
    findings: []
  - id: PMID:22298428
    title: The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor 
      endocytosis from the plasma membrane.
    findings: []
  - id: PMID:22411794
    title: Hypoxia promotes ligand-independent EGF receptor signaling via 
      hypoxia-inducible factor-mediated upregulation of caveolin-1.
    findings: []
  - id: PMID:22439932
    title: NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival 
      signaling in lung adenocarcinoma.
    findings: []
  - id: PMID:22579287
    title: Oncogenic mutations counteract intrinsic disorder in the EGFR kinase 
      and promote receptor dimerization.
    findings: []
  - id: PMID:22719997
    title: SNX12 role in endosome membrane transport.
    findings: []
  - id: PMID:22732145
    title: Diacylglycerol kinase θ counteracts protein kinase C-mediated 
      inactivation of the EGF receptor.
    findings: []
  - id: PMID:22939624
    title: Quantitative analysis of HSP90-client interactions reveals principles
      of substrate recognition.
    findings: []
  - id: PMID:23069713
    title: The promotion of cardiogenic differentiation of hMSCs by targeting 
      epidermal growth factor receptor using microRNA-133a.
    findings: []
  - id: PMID:23178489
    title: The role of insulin-like growth factor binding protein-3 in the 
      breast cancer cell response to DNA-damaging agents.
    findings: []
  - id: PMID:23178716
    title: SnoN/SkiL expression is modulated via arsenic trioxide-induced 
      activation of the PI3K/AKT pathway in ovarian cancer cells.
    findings: []
  - id: PMID:23273428
    title: Insights into the aberrant activity of mutant EGFR kinase domain and 
      drug recognition.
    findings: []
  - id: PMID:23374349
    title: Conformational coupling across the plasma membrane in activation of 
      the EGF receptor.
    findings: []
  - id: PMID:23382219
    title: Structural basis for endosomal trafficking of diverse transmembrane 
      cargos by PX-FERM proteins.
    findings: []
  - id: PMID:23397142
    title: Analysis of protein-protein interactions in cross-talk pathways 
      reveals CRKL protein as a novel prognostic marker in hepatocellular 
      carcinoma.
    findings: []
  - id: PMID:23418353
    title: The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal 
      sorting of the epidermal growth factor receptor.
    findings: []
  - id: PMID:23436906
    title: Parallel visualization of multiple protein complexes in individual 
      cells in tumor tissue.
    findings: []
  - id: PMID:23520446
    title: 'Protein phosphorylation profiling using an in situ proximity ligation
      assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung
      cancer cells.'
    findings: []
  - id: PMID:23597562
    title: Inhibition of tumor angiogenesis and growth by a small-molecule 
      multi-FGF receptor blocker with allosteric properties.
    findings: []
  - id: PMID:23636329
    title: EGFR modulates microRNA maturation in response to hypoxia through 
      phosphorylation of AGO2.
    findings: []
  - id: PMID:23764002
    title: Epidermal growth factor receptor potentiates MCM7-mediated DNA 
      replication through tyrosine phosphorylation of Lyn kinase in human 
      cancers.
    findings: []
  - id: PMID:23799367
    title: Threshold-controlled ubiquitination of the EGFR directs receptor 
      fate.
    findings: []
  - id: PMID:23866081
    title: Lyn, a Src family kinase, regulates activation of epidermal growth 
      factor receptors in lung adenocarcinoma cells.
    findings: []
  - id: PMID:23912460
    title: Hyperactivation of EGFR and downstream effector phospholipase D1 by 
      oncogenic FAM83B.
    findings: []
  - id: PMID:24034250
    title: EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, 
      tumor progression, and tumor chemoresistance.
    findings: []
  - id: PMID:24076656
    title: Endophilin, Lamellipodin, and Mena cooperate to regulate 
      F-actin-dependent EGF-receptor endocytosis.
    findings: []
  - id: PMID:24135280
    title: EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and 
      progression in glioblastoma.
    findings: []
  - id: PMID:24189400
    title: Perturbation of the mutated EGFR interactome identifies 
      vulnerabilities and resistance mechanisms.
    findings: []
  - id: PMID:24557338
    title: Characterisation of HER heterodimers in breast cancer using in situ 
      proximity ligation assay.
    findings: []
  - id: PMID:24658140
    title: The mammalian-membrane two-hybrid assay (MaMTH) for probing 
      membrane-protein interactions in human cells.
    findings: []
  - id: PMID:2472218
    title: 'EGF induces tyrosine phosphorylation of phospholipase C-II: a potential
      mechanism for EGF receptor signaling.'
    findings: []
  - id: PMID:24780295
    title: Importance of EGFR/ERCC1 interaction following radiation-induced DNA 
      damage.
    findings: []
  - id: PMID:24854121
    title: Endophilin-1 regulates blood-brain barrier permeability by 
      controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway.
    findings: []
  - id: PMID:24947832
    title: Differential protein-protein interactions of LRRK1 and LRRK2 indicate
      roles in distinct cellular signaling pathways.
    findings: []
  - id: PMID:25036637
    title: A quantitative chaperone interaction network reveals the architecture
      of cellular protein homeostasis pathways.
    findings: []
  - id: PMID:25136068
    title: Mycoplasma hyorhinis infection promotes NF-κB-dependent migration of 
      gastric cancer cells.
    findings: []
  - id: PMID:25187647
    title: Structural basis for activation of trimeric Gi proteins by multiple 
      growth factor receptors via GIV/Girdin.
    findings: []
  - id: PMID:25241761
    title: Using an in situ proximity ligation assay to systematically profile 
      endogenous protein-protein interactions in a pathway network.
    findings: []
  - id: PMID:25311788
    title: EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung
      cancer.
    findings: []
  - id: PMID:25353163
    title: Soluble LRIG2 ectodomain is released from glioblastoma cells and 
      promotes the proliferation and inhibits the apoptosis of glioblastoma 
      cells in vitro and in vivo in a similar manner to the full-length LRIG2.
    findings: []
  - id: PMID:25468996
    title: E-cadherin interactome complexity and robustness resolved by 
      quantitative proteomics.
    findings: []
  - id: PMID:25594178
    title: A kinase-independent role for EGF receptor in autophagy initiation.
    findings: []
  - id: PMID:25666625
    title: Epidermal growth factor receptor (EGFR) signaling requires a specific
      endoplasmic reticulum thioredoxin for the post-translational control of 
      receptor presentation to the cell surface.
    findings: []
  - id: PMID:25678558
    title: Navigator-3, a modulator of cell migration, may act as a suppressor 
      of breast cancer progression.
    findings: []
  - id: PMID:25796184
    title: PEA-15 facilitates EGFR dephosphorylation via ERK sequestration at 
      increased ER-PM contacts in TNBC cells.
    findings: []
  - id: PMID:25873175
    title: AXL mediates resistance to PI3Kα inhibition by activating the 
      EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell 
      carcinomas.
    findings: []
  - id: PMID:25970784
    title: PTPRG suppresses tumor growth and invasion via inhibition of Akt 
      signaling in nasopharyngeal carcinoma.
    findings: []
  - id: PMID:26005835
    title: RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts 
      intestinal epithelial cell growth.
    findings: []
  - id: PMID:26280537
    title: Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and 
      inhibits its activation.
    findings: []
  - id: PMID:26551075
    title: EGF-receptor specificity for phosphotyrosine-primed substrates 
      provides signal integration with Src.
    findings: []
  - id: PMID:26751287
    title: The LINK-A lncRNA activates normoxic HIF1α signalling in 
      triple-negative breast cancer.
    findings: []
  - id: PMID:26988023
    title: Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates 
      cancer proliferation and chemoresistance.
    findings: []
  - id: PMID:27057632
    title: Tumor-suppressive miR-218-5p inhibits cancer cell proliferation and 
      migration via EGFR in non-small cell lung cancer.
    findings: []
  - id: PMID:27059931
    title: Weak binding to E3 ubiquitin ligase c-Cbl increases EGFRvA protein 
      stability.
    findings: []
  - id: PMID:27569582
    title: GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive 
      Hepatocellular Carcinoma Metastasis.
    findings: []
  - id: PMID:27872189
    title: Biophysical Evidence for Intrinsic Disorder in the C-terminal Tails 
      of the Epidermal Growth Factor Receptor (EGFR) and HER3 Receptor Tyrosine 
      Kinases.
    findings: []
  - id: PMID:2790960
    title: Functional independence of the epidermal growth factor receptor from 
      a domain required for ligand-induced internalization and calcium 
      regulation.
    findings: []
  - id: PMID:27956147
    title: Systematic Identification of Oncogenic EGFR Interaction Partners.
    findings: []
  - id: PMID:28065597
    title: A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase
      Interactome.
    findings: []
  - id: PMID:28479384
    title: Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in gastric 
      cancer cells.
    findings: []
  - id: PMID:28759036
    title: Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, 
      reveals its role in regulating cell adhesion and migration.
    findings: []
  - id: PMID:28988771
    title: EGFR Ligands Differentially Stabilize Receptor Dimers to Specify 
      Signaling Kinetics.
    findings: []
  - id: PMID:29455656
    title: The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of 
      EGFR in lung cancer cells.
    findings: []
  - id: PMID:29844572
    title: RANK-c attenuates aggressive properties of ER-negative breast cancer 
      by inhibiting NF-κB activation and EGFR signaling.
    findings: []
  - id: PMID:30083275
    title: The S100A4 Protein Signals through the ErbB4 Receptor to Promote 
      Neuronal Survival.
    findings: []
  - id: PMID:30662352
    title: COPI-Mediated Nuclear Translocation of EGFRvIII Promotes STAT3 
      Phosphorylation and PKM2 Nuclear Localization.
    findings: []
  - id: PMID:31585087
    title: Oncogenic Mutations Rewire Signaling Pathways by Switching Protein 
      Recruitment to Phosphotyrosine Sites.
    findings: []
  - id: PMID:31862538
    title: Neuropeptide bombesin receptor activation stimulates growth of lung 
      cancer cells through HER3 with a MAPK-dependent mechanism.
    findings: []
  - id: PMID:31980649
    title: Extensive rewiring of the EGFR network in colorectal cancer cells 
      expressing transforming levels of KRAS(G13D).
    findings: []
  - id: PMID:33420426
    title: AXL is a candidate receptor for SARS-CoV-2 that promotes infection of
      pulmonary and bronchial epithelial cells.
    findings: []
  - id: PMID:34591612
    title: A protein interaction landscape of breast cancer.
    findings: []
  - id: PMID:34591642
    title: A protein network map of head and neck cancer reveals PIK3CA mutant 
      drug sensitivity.
    findings: []
  - id: PMID:35384245
    title: Physical and functional interactome atlas of human receptor tyrosine 
      kinases.
    findings: []
  - id: PMID:35512704
    title: Systematic discovery of mutation-directed neo-protein-protein 
      interactions in cancer.
    findings: []
  - id: PMID:37100772
    title: Large-scale phage-based screening reveals extensive pan-viral mimicry
      of host short linear motifs.
    findings: []
  - id: PMID:38572507
    title: DRD1 suppresses cell proliferation and reduces EGFR activation and 
      PD-L1 expression in NSCLC.
    findings: []
  - id: PMID:39073202
    title: SNX32 Regulates Sorting and Trafficking of Activated EGFR to the 
      Lysosomal Degradation Pathway.
    findings: []
  - id: PMID:6325948
    title: ATP-stimulated interaction between epidermal growth factor receptor 
      and supercoiled DNA.
    findings: []
  - id: PMID:7518560
    title: Hierarchy of binding sites for Grb2 and Shc on the epidermal growth 
      factor receptor.
    findings: []
  - id: PMID:7542744
    title: The phosphotyrosine interaction domain of Shc binds an LXNPXY motif 
      on the epidermal growth factor receptor.
    findings: []
  - id: PMID:7588596
    title: WT1 suppresses synthesis of the epidermal growth factor receptor and 
      induces apoptosis.
    findings: []
  - id: PMID:7657591
    title: Tyrosine phosphorylation of the c-cbl proto-oncogene protein product 
      and association with epidermal growth factor (EGF) receptor upon EGF 
      stimulation.
    findings: []
  - id: PMID:7685104
    title: Substrate specificity of the protein tyrosine phosphatases.
    findings: []
  - id: PMID:7693694
    title: Sequence specificity in recognition of the epidermal growth factor 
      receptor by protein tyrosine phosphatase 1B.
    findings: []
  - id: PMID:7736574
    title: Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and 
      lck cooperate in hematopoietic cell proliferation.
    findings: []
  - id: PMID:7797556
    title: Src phosphorylation of the epidermal growth factor receptor at novel 
      sites mediates receptor interaction with Src and P85 alpha.
    findings: []
  - id: PMID:7993895
    title: Identification of amino acids in the N-terminal SH2 domain of 
      phospholipase C gamma 1 important in the interaction with epidermal growth
      factor receptor.
    findings: []
  - id: PMID:8034616
    title: Tyrosines 1148 and 1173 of activated human epidermal growth factor 
      receptors are binding sites of Shc in intact cells.
    findings: []
  - id: PMID:8305738
    title: The human GRB2 and Drosophila Drk genes can functionally replace the 
      Caenorhabditis elegans cell signaling gene sem-5.
    findings: []
  - id: PMID:8621392
    title: Determinants of substrate recognition in the protein-tyrosine 
      phosphatase, PTP1.
    findings: []
  - id: PMID:8887653
    title: The phosphotyrosine interaction domains of X11 and FE65 bind to 
      distinct sites on the YENPTY motif of amyloid precursor protein.
    findings: []
  - id: PMID:8940013
    title: The Grb2-mSos1 complex binds phosphopeptides with higher affinity 
      than Grb2.
    findings: []
  - id: PMID:9020117
    title: Subsets of epidermal growth factor receptors during activation and 
      endocytosis.
    findings: []
  - id: PMID:9050838
    title: Development of "substrate-trapping" mutants to identify physiological
      substrates of protein tyrosine phosphatases.
    findings: []
  - id: PMID:9103388
    title: Expression of a truncated epidermal growth factor receptor-like 
      protein (TEGFR) in ovarian cancer.
    findings: []
  - id: PMID:9135143
    title: Activation of HER4 by heparin-binding EGF-like growth factor 
      stimulates chemotaxis but not proliferation.
    findings: []
  - id: PMID:9355745
    title: Protein tyrosine phosphatase 1B interacts with and is tyrosine 
      phosphorylated by the epidermal growth factor receptor.
    findings: []
  - id: PMID:9419975
    title: Epiregulin binds to epidermal growth factor receptor and ErbB-4 and 
      induces tyrosine phosphorylation of epidermal growth factor receptor, 
      ErbB-2, ErbB-3 and ErbB-4.
    findings: []
  - id: PMID:9506989
    title: Grb10 interacts differentially with the insulin receptor, 
      insulin-like growth factor I receptor, and epidermal growth factor 
      receptor via the Grb10 Src homology 2 (SH2) domain and a second novel 
      domain located between the pleckstrin homology and SH2 domains.
    findings: []
  - id: PMID:9544989
    title: Shc phosphotyrosine-binding domain dominantly interacts with 
      epidermal growth factor receptors and mediates Ras activation in intact 
      cells.
    findings: []
  - id: PMID:9852145
    title: Interaction of ZPR1 with translation elongation factor-1alpha in 
      proliferating cells.
    findings: []
  - id: PMID:9890893
    title: Identification of tyrosine phosphorylation sites in human Gab-1 
      protein by EGF receptor kinase in vitro.
    findings: []
  - id: Reactome:R-HSA-1169421
    title: Trans-autophosphorylation of activated ligand-responsive EGFR mutant 
      dimers
    findings:
      - statement: Ligand-responsive EGFR mutant dimers trans-autophosphorylate 
          multiple tyrosine residues after activation.
        supporting_text: Activation of ligand-responsive EGFR mutants through 
          spontaneous or EGF-induced dimerization results in 
          trans-autophosphorylation of 5 tyrosine residues
  - id: Reactome:R-HSA-1218833
    title: Binding of ligand-responsive EGFR mutants to chaperoning proteins 
      HSP90 and CDC37
    findings:
      - statement: EGFR kinase domain mutants require continuous association 
          with HSP90 for proper functioning.
        supporting_text: EGFR kinase domain mutants need continuous association 
          with HSP90 chaperone protein for proper functioning.
  - id: Reactome:R-HSA-1220610
    title: Non-covalent tyrosine kinase inhibitors bind and inactivate sensitive
      ligand-responsive EGFR cancer mutants
    findings:
      - statement: Reversible TKIs inhibit mutant EGFR autophosphorylation by 
          competitively blocking ATP binding.
        supporting_text: Non-covalent (reversible) tyrosine kinase inhibitors 
          (TKIs), erlotinib, gefitinib, lapatinib and vandetanib, selectively 
          inhibit EGFR-stimulated tumor cell growth by blocking EGFR mutant 
          autophosphorylation through competitive inhibition of ATP binding to 
          the kinase domain.
  - id: Reactome:R-HSA-1220611
    title: Covalent tyrosine kinase inhibitors bind and inactivate EGFR kinase 
      domain mutant dimers resistant to non-covalent tyrosine kinase inhibitors
    findings:
      - statement: Covalent TKIs bind EGFR C397 and inhibit 
          trans-autophosphorylation of mutants resistant to non-covalent TKIs.
        supporting_text: Covalent (irreversible) tyrosine kinase inhibitors 
          (TKIs), pelitinib, WZ4002, HKI-272, canertinib and afatinib, form a 
          covalent bond with the EGFR cysteine residue C397 and inhibit 
          trans-autophosphorylation of mutants resistant to non-covalent TKIs.
  - id: Reactome:R-HSA-1220612
    title: Binding of EGF to ligand-responsive EGFR mutants
    findings:
      - statement: Ligand-responsive EGFR mutants bind EGF and show increased 
          activity in its presence.
        supporting_text: Ligand-responsive EGFR mutants are able to bind EGF and
          exhibit increased activity in the presence of EGF.
  - id: Reactome:R-HSA-1220613
    title: EGF-induced dimerization of ligand-responsive EGFR mutants
    findings:
      - statement: EGF increases dimerization of ligand-responsive EGFR mutants.
        supporting_text: Although ligand-responsive EGFR mutants dimerize 
          spontaneously, dimerization is increased in the presence of EGF.
  - id: Reactome:R-HSA-1220614
    title: Spontaneous dimerization of ligand-responsive EGFR mutants
    findings:
      - statement: Ligand-responsive EGFR mutants spontaneously dimerize without
          ligand binding.
        supporting_text: EGFR ligand-responsive mutants dimerize spontaneously, 
          without ligand binding, although ligand binding ability is preserved.
  - id: Reactome:R-HSA-1225947
    title: Binding of SHC1 to p-6Y-EGFR mutants
    findings:
      - statement: SHC1 binds phosphorylated EGFR docking sites Y1148 and Y1173 
          in EGFR mutants.
        supporting_text: "SHC1 (Src homology 2 domain-containing transforming protein)
          is known to bind two phosphorylated tyrosine docking sites of EGFR: Y1148
          and Y1173"
  - id: Reactome:R-HSA-1225949
    title: Binding of CBL to ligand-responsive p-6Y-EGFR mutants
    findings:
      - statement: CBL binds phosphorylated Y1069 (Y1045) on EGFR cancer 
          mutants.
        supporting_text: CBL binds to phosphorylated tyrosine Y1069 (i.e. Y1045 
          in the mature protein) residue of EGFR cancer mutants.
  - id: Reactome:R-HSA-1225950
    title: Binding of GRB2:SOS1 complex to phosphorylated ligand-responsive EGFR
      mutants
    findings:
      - statement: GRB2 binds phosphorylated EGFR mutant tyrosines Y1068 and 
          Y1086.
        supporting_text: GRB2 binds to phosphorylated tyrosine residues Y1068 
          and Y1086
  - id: Reactome:R-HSA-1225951
    title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in 
      complex with ligand-responsive p-6Y-EGFR mutants)
    findings:
      - statement: SOS1 recruited via GRB2 to phosphorylated EGFR mutants 
          activates RAS.
        supporting_text: Based on the wild-type EGFR signaling, it is assumed 
          that the guanine nucleotide exchange factor SOS1 interacts with 
          phosphorylated EGFR mutants through the adaptor protein, GRB2. Upon 
          formation of this complex, SOS1 activates RAS by promoting GDP release
          and GTP binding.
  - id: Reactome:R-HSA-1225952
    title: Phosphorylation of SHC1 by ligand-responsive p-6Y-EGFR mutants
    findings:
      - statement: EGFR L858R mutant constitutively phosphorylates SHC1.
        supporting_text: Constitutive phosphorylation of SHC1 was directly 
          demonstrated in cells expressing EGFR L858R mutant (Greulich et al. 
          2005).
  - id: Reactome:R-HSA-1225956
    title: Inefficient ubiquitination of ligand-responsive p-6Y-EGFR mutants by 
      p-Y371-CBL
    findings:
      - statement: Phosphorylated CBL does not efficiently ubiquitinate EGFR 
          kinase domain mutants.
        supporting_text: Phosphorylated CBL does not ubiquitinate EGFR kinase 
          domain mutants efficiently, which enables mutant proteins to escape 
          degradation.
  - id: Reactome:R-HSA-1225957
    title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in 
      complex with phosphorylated SHC1 and ligand-responsive p-6Y-EGFR mutants)
    findings:
      - statement: GRB2-bound SOS1 is assumed to activate RAS downstream of 
          p-SHC1:p-EGFR mutants.
        supporting_text: SOS1, recruited by GRB2 bound to p-SHC1:p-EGFR mutants,
          is assumed to activate RAS nucleotide exchange from the inactive form 
          (bound to GDP) to an active form (bound to GTP).
  - id: Reactome:R-HSA-1225960
    title: Phosphorylation of CBL by ligand-responsive p-6Y-EGFR mutants
    findings:
      - statement: EGFR L858R mutant directly phosphorylates CBL on Y371.
        supporting_text: EGFR L858R mutant was shown to directly phosphorylate 
          CBL on tyrosine residue Y371.
  - id: Reactome:R-HSA-1225961
    title: Phosphorylated SHC1 in complex with ligand-responsive p-6Y-EGFR 
      mutants recruits GRB2:SOS1 complex
    findings:
      - statement: SHC1 bound to phosphorylated EGFR mutant dimers is assumed to
          recruit GRB2:SOS1.
        supporting_text: Recruitment of GRB2:SOS1 complex by SHC1 bound to 
          phosphorylated dimers of EGFR cancer mutants has not been directly 
          tested, but is assumed to happen in the same way it happens with the 
          SHC1 bound to the phosphorylated homodimer of wild-type EGFR.
  - id: Reactome:R-HSA-1225978
    title: Covalent tyrosine kinase inhibitors bind and inhibit wild-type 
      EGF:EGFR dimers
    findings:
      - statement: Covalent TKIs inhibit wild-type EGFR by covalently binding 
          Cys397.
        supporting_text: Covalent (irreversible) TKIs, pelitinib, WZ4002, 
          HKI-272, canertinib and afatinib, inhibit the wild-type EGFR through 
          formation of the covalent bond with the cysteine residue C397.
  - id: Reactome:R-HSA-1226012
    title: Binding of PI3K to complex of GRB2:GAB1 and ligand-responsive 
      p-6Y-EGFR mutants
    findings:
      - statement: EGFR cancer mutants are assumed to recruit PI3K in a manner 
          similar to wild-type EGFR.
        supporting_text: EGFR cancer mutants are assumed to recruit the PI3K 
          complex PIK3CA:PIK3R1 in a manner similar to wild-type EGFR.
  - id: Reactome:R-HSA-1226014
    title: Conversion of PIP2 to PIP3 by PI3K bound to ligand-responsive 
      p-6Y-EGFR mutants
    findings:
      - statement: EGFR cancer mutants are assumed to induce PI3K/AKT signaling 
          via PI3K-mediated conversion of PIP2 to PIP3.
        supporting_text: The kinase activity of PI3K mediates the 
          phosphorylation of PIP2 to form PIP3. It is assumed that EGFR cancer 
          mutants induce PI3K/AKT signaling in a manner similar to wild-type 
          EGFR.
  - id: Reactome:R-HSA-1226016
    title: Binding of GRB2:GAB1 complex to ligand-responsive p-6Y-EGFR mutants
    findings:
      - statement: Recruitment of GRB2:GAB1 to phosphorylated EGFR cancer 
          mutants is assumed and not directly tested.
        supporting_text: Direct binding of GRB2:GAB1 complex to phosphorylated 
          homodimers of EGFR cancer mutants has not been tested.
  - id: Reactome:R-HSA-1247841
    title: PLCG1 binds to ligand-responsive p-6Y-EGFR mutants
    findings:
      - statement: EGFR cancer mutants phosphorylate Y992 and are expected to 
          recruit PLCG1 similarly to wild-type EGFR.
        supporting_text: Tyrosine residue Y992 (corresponding to Y1016 when 
          counting from the first amino acid of the EGFR precursor, prior to 
          cleavage of the 24-amino acid signal peptide at the N-terminus), a 
          docking site for PLC-gamma 1 (PLCG1), is phosphorylated in EGFR cancer
          mutants and expected to recruit PLC-gamma 1 in the same way as the 
          wild-type EGFR receptor.
  - id: Reactome:R-HSA-1247842
    title: Dissociation of phosphorylated PLCG1 from ligand-responsive p-6Y-EGFR
      mutants
    findings:
      - statement: After EGFR mutant-driven phosphorylation, PLCG1 is expected 
          to dissociate, a release event following activation rather than an 
          active EGFR role at this step.
        supporting_text: Once phosphorylated, PLC-gamma 1 is expected to 
          dissociate from phosphorylated EGFR cancer mutants and induce 
          downstream signaling in the same way it does when activated by the 
          wild-type EGFR.
  - id: Reactome:R-HSA-1247844
    title: Phosphorylation of PLCG1 by ligand-responsive p-6Y-EGFR mutants
    findings:
      - statement: EGFR cancer mutants are assumed to phosphorylate PLCG1 after 
          recruitment.
        supporting_text: Once recruited, PLC-gamma 1 is assumed to be 
          phosphorylated by EGFR cancer mutants in the same way it is 
          phosphorylated by the wild-type EGFR.
  - id: Reactome:R-HSA-1247999
    title: EGFRvIII mutant binds chaperone proteins HSP90 and CDC37
    findings:
      - statement: EGFRvIII requires HSP90 and CDC37 chaperones for proper 
          function.
        supporting_text: Association of EGFRvIII mutant with HSP90 chaperone 
          protein and its co-chaperone CDC37 is necessary for the proper 
          functioning of mutant EGFR.
  - id: Reactome:R-HSA-1248002
    title: Ligand-independent dimerization of EGFRvIII mutant
    findings:
      - statement: EGFRvIII cannot bind ligand but dimerizes spontaneously, 
          potentially influenced by N-linked glycosylation.
        supporting_text: EGFRvIII mutant lacks the ligand binding domain and is 
          therefore unable to bind EGFR ligands, but is able to dimerize 
          spontaneously. Self-dimerization may be dependent on N-linked 
          glycosylation.
  - id: Reactome:R-HSA-1248655
    title: Trans-autophosphorylation of EGFRvIII mutant dimers
    findings:
      - statement: EGFRvIII dimers trans-autophosphorylate multiple tyrosines 
          while Y1045 remains hypo/unphosphorylated, enabling signaling and 
          reduced downregulation.
        supporting_text: Upon dimerization, EGFRvIII mutants 
          trans-autophosphorylate on tyrosine residues Y1016 i.e. Y992 in the 
          mature protein, Y1092 i.e. Y1068 in the mature protein, Y1110 i.e. 
          Y0186 in the mature protein, Y1172 i.e. Y1148 in the mature protein 
          and Y1197 i.e. Y1173 in the mature protein, while the tyrosine residue
          Y1069 i.e. Y1045 in the mature protein, a docking site for CBL, 
          remains either unphosphorylated or hypophosphorylated, allowing 
          EGFRvIII to activate downstream signaling cascades while escaping 
          downregulation.
  - id: Reactome:R-HSA-1248677
    title: Inactivation of over-expressed wild type EGFR by Cetuximab 
      recombinant antibody
    findings:
      - statement: Cetuximab inhibits EGFR by blocking ligand binding and 
          promoting receptor inactivation and degradation.
        supporting_text: Cetuximab binds to the extracellular domain of EGFR and
          blocks ligand binding, leading to receptor inactivation, 
          internalization and degradation.
  - id: Reactome:R-HSA-1250195
    title: SHC1 phosphorylation by ERBB2 heterodimers
    findings:
      - statement: In ERBB2 heterodimers, EGFR can phosphorylate SHC1 on 
          tyrosine residues.
        supporting_text: Once bound to ERBB2 heterodimers, SHC1 is 
          phosphorylated on tyrosine residues by the tyrosine kinase activity of
          either ERBB2 or its heterodimerization partners EGFR and ERBB4 
          (Segatto et al. 1993, Soler et al. 1994).
  - id: Reactome:R-HSA-1306957
    title: PIP2 to PIP3 conversion by PI3K bound to GRB2:GAB1 in complex with 
      phosphorylated heterodimer of ERBB2 and EGFR
    findings:
      - statement: PI3K associated with phosphorylated ERBB2:EGFR converts PIP2 
          to PIP3 to activate AKT signaling.
        supporting_text: Active PI3K in complex with p-EGFR:p-ERBB2:GRB2:GAB1 
          phosphorylates PIP2 into PIP3, leading to activation of AKT signaling 
          (Jackson et al. 2004).
  - id: Reactome:R-HSA-1306963
    title: Binding of GRB2:GAB1 to p-ERBB2:p-EGFR
    findings:
      - statement: GRB2:GAB1 is recruited to activated ERBB2:EGFR via 
          phosphorylated docking tyrosines.
        supporting_text: GAB1 in complex with GRB2 is recruited to activated 
          ERBB2:EGFR heterodimer through phosphorylated tyrosine residues that 
          serve as docking sites for GRB2 (Jackson et al. 2004).
  - id: Reactome:R-HSA-1306965
    title: Binding of PI3K to GRB2:GAB1 in complex with phosphorylated 
      heterodimer of ERBB2 and EGFR
    findings:
      - statement: PI3K activation follows PIK3R1 binding to GRB2:GAB1 in 
          complex with phosphorylated ERBB2:EGFR.
        supporting_text: Binding of PIK3R1 to GRB2:GAB1 in complex with 
          phosphorylated heterodimer of ERBB2 and EGFR triggers a conformational
          change in the PI3K complex, resulting in PI3K activation (Jackson et 
          al. 2004).
  - id: Reactome:R-HSA-177922
    title: EGFR dimerization
    findings:
      - statement: EGF binding stabilizes the active dimeric form of EGFR.
        supporting_text: EGF and other growth factors induce oligomerization of 
          their specific receptors. Inactive EGFR monomers are in equilibrium 
          with active EGFR dimers and binding of the EGF ligand stabilizes the 
          active dimeric form.
  - id: Reactome:R-HSA-177923
    title: Sustained activation of SRC kinase by SHP2
    findings:
      - statement: SHP2-mediated dephosphorylation of paxillin promotes SRC 
          activation in EGF-stimulated signaling.
        supporting_text: SHP2 can dephosphorylate paxillin, which leads to CSK 
          dissociation from the paxillin-SRC complex and SRC activation.
  - id: Reactome:R-HSA-177924
    title: Dephosphorylation of Gab1 by SHP2
    findings:
      - statement: SHP2 dephosphorylation of GAB1 blocks PI3K binding and 
          activation.
        supporting_text: SHP2 dephosphorylation of the tyrosine residues 447, 
          472 and 589 on GAB1 means PI3 kinase can no longer bind to the complex
          in the plasma membrane and cannot be activated.
  - id: Reactome:R-HSA-177925
    title: SHC1 binds to the phosphorylated EGF receptor:ligand complex
    findings:
      - statement: SHC1 binds phosphorylated EGFR at Y1148 or Y1173 sites.
        supporting_text: SHC1 (Src homology 2 domain-containing) transforming 
          protein can bind to either phosphorylated tyrosine sites Y1172 
          (p-Y1172) i.e. Y1148 (p-Y1148) in the mature protein and/or tyrosine 
          Y1197 (p-Y1197) i.e. Y1173 (p-Y1173) in the mature protein on the EGF 
          receptor.
  - id: Reactome:R-HSA-177926
    title: Dephosphorylation of PAG by SHP2
    findings:
      - statement: SHP2 dephosphorylation of CBP/PAG reduces recruitment of Csk 
          and limits Src inhibition.
        supporting_text: Dephosphorylation of CBP/PAG negatively regulates the 
          recruitment of the Src inhibiting kinase, Csk.
  - id: Reactome:R-HSA-177927
    title: PI3K binds to EGF:EGFR:GRB2:GAB1
    findings:
      - statement: PI3K regulatory subunit PIK3R1 binds GAB1 to recruit PI3K to 
          EGFR signaling complexes.
        supporting_text: The Src homology 2 (SH2) domain of the 
          phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. 
          PI3Kp85) binds to GAB1 in a phosphorylation-independent manner.
  - id: Reactome:R-HSA-177929
    title: Signaling by EGFR
    findings:
      - statement: EGFR ligand binding triggers dimerization and 
          trans-autophosphorylation to initiate downstream signaling.
        supporting_text: Binding of EGFR to its ligands induces conformational 
          change that unmasks the dimerization interface in the extracellular 
          domain of EGFR, leading to receptor homo- or heterodimerization at the
          cell surface. Dimerization of the extracellular regions of EGFR 
          triggers additional conformational change of the cytoplasmic EGFR 
          regions, enabling the kinase domains of two EGFR molecules to achieve 
          the catalytically active conformation. Ligand activated EGFR dimers 
          trans-autophosphorylate on tyrosine residues in the cytoplasmic tail 
          of the receptor.
  - id: Reactome:R-HSA-177930
    title: GAB1 phosphorylation by EGFR kinase
    findings:
      - statement: EGFR kinase phosphorylates GAB1 at Y627 and Y659.
        supporting_text: EGFR kinase phosphorylates the phosphorylation sites 
          tyrosine 627 and 659 on GAB1
  - id: Reactome:R-HSA-177933
    title: SHC1 phosphorylation by phosphorylated EGFR
    findings:
      - statement: EGFR-bound SHC1 is phosphorylated on Y349 and Y350.
        supporting_text: Once bound to EGFR, SHC1 is phosphorylated on two 
          tyrosines (Y349, Y350).
  - id: Reactome:R-HSA-177934
    title: EGFR autophosphorylation
    findings:
      - statement: EGFR dimerization activates kinase activity and leads to 
          autophosphorylation of six tyrosines in the cytoplasmic tail.
        supporting_text: Dimerization of EGFR activates its intrinsic protein 
          kinase activity and results in autophosphorylation of 6 tyrosine 
          residues in the cytoplasmic tail of EGFR.
  - id: Reactome:R-HSA-177935
    title: SHP2 dephosphorylates Tyr 992 on EGFR
    findings:
      - statement: SHP2 dephosphorylates a RasGAP binding site on EGFR to 
          prevent RasGAP recruitment.
        supporting_text: This inhibition is achieved by the dephosphorylation of
          a RasGAP binding site on the EGF receptor.
  - id: Reactome:R-HSA-177936
    title: GRB2:SOS1 binds to phosphorylated SHC1 in complex with EGFR
    findings:
      - statement: Phosphorylated SHC1 provides binding sites for the GRB2:SOS1 
          complex.
        supporting_text: The tyrosine sites on SHC1 become possible binding 
          sites for the GRB2:SOS1 complex.
  - id: Reactome:R-HSA-177937
    title: Phosphorylation of EGFR by SRC kinase
    findings:
      - statement: SRC can tyrosine-phosphorylate EGFR in addition to EGFR 
          autophosphorylation.
        supporting_text: Besides autophosphorylation, EGFR can become 
          tyrosine-phosphorylated by the action of  the proto-oncogene 
          tyrosine-protein kinase, c-src.
  - id: Reactome:R-HSA-177938
    title: SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:GRB2:SOS1)
    findings:
      - statement: SOS1 interacts with EGFR via GRB2 to activate RAS by GDP-GTP 
          exchange.
        supporting_text: The guanine nucleotide exchange factor SOS1 interacts 
          with EGFR through the adaptor protein, GRB2. Upon formation of this 
          complex, SOS activates RAS by promoting GDP release and GTP binding.
  - id: Reactome:R-HSA-177939
    title: PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to 
      phosphatidylinositol-3,4,5-trisphosphate (PIP3)
    findings:
      - statement: PI3K phosphorylates PIP2 to form PIP3.
        supporting_text: The kinase activity of PIK3 mediates the 
          phosphorylation of PIP2 to form PIP3
  - id: Reactome:R-HSA-177941
    title: GRB2:GAB1 binds to phosphorylated EGFR
    findings:
      - statement: PIK3 regulatory subunit mediates GAB1 association with EGFR, 
          enabling GAB1 phosphorylation.
        supporting_text: The regulatory subunit of PIK3 mediates the association
          of GAB1 and receptor protein-tyrosine kinases such as the  EGF 
          receptor, which can phosphorylate GAB1.
  - id: Reactome:R-HSA-177942
    title: EGFR binds EGF ligand
    findings:
      - statement: EGF binding to EGFR transmits the signal from the 
          extracellular to cytoplasmic domain.
        supporting_text: EGF binds to the extracellular domain from where the 
          signal is transmitted to the cytoplasmic domain.
  - id: Reactome:R-HSA-177943
    title: GRB2:SOS1 complex binds to EGF:EGFR complex
    findings:
      - statement: GRB2 binds activated EGFR while in complex with SOS1.
        supporting_text: One such protein, growth factor receptor-bound protein 
          2 (GRB2), can bind activated EGFR with its SH2 domain whilst in 
          complex with SOS through its SH3 domain.
  - id: Reactome:R-HSA-177944
    title: Activation of SHP2 through the binding to phospho-Gab1
    findings:
      - statement: SHP2 activation occurs when its SH2 domains bind 
          phosphotyrosine proteins to relieve autoinhibition.
        supporting_text: Binding of these domains to phosphotyrosine-containing 
          proteins relieves this autoinhibition, possibly by inducing a 
          conformational change in the enzyme.
  - id: Reactome:R-HSA-177945
    title: SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:SHC1:GRB2:SOS1)
    findings:
      - statement: SOS1 activates RAS by promoting nucleotide exchange from GDP 
          to GTP.
        supporting_text: SOS1 activates RAS nucleotide exchange from the 
          inactive form (bound to GDP) to an active form (bound to GTP).
  - id: Reactome:R-HSA-182969
    title: Phosphorylation of CBL (EGFR:CBL)
    findings:
      - statement: EGF stimulation leads to CBL phosphorylation on Tyr-371, 
          enabling its ubiquitin ligase activity.
        supporting_text: EGF (and indeed FGF, PDGF and NGF) stimulation results 
          in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for 
          CBL to exhibit ubiquitin ligase activity.
  - id: Reactome:R-HSA-182971
    title: EGFR downregulation
    findings:
      - statement: CBL proteins poly-ubiquitinate activated EGFR, promoting 
          degradation and downregulation.
        supporting_text: The Cbl family of RING-type ubiquitin ligases are able 
          to poly-ubiquitinate EGFR, an essential step in EGFR degradation.
  - id: Reactome:R-HSA-182986
    title: CBL-mediated ubiquitination of CIN85
    findings:
      - statement: CBL monoubiquitinates CIN85 after EGF stimulation, 
          influencing receptor internalization.
        supporting_text: The adaptor protein CIN85 is monoubiquitinated by CBL 
          after EGF stimulation.
  - id: Reactome:R-HSA-182990
    title: Sprouty sequesters CBL away from active EGFR
    findings:
      - statement: Sprouty can block CIN85-mediated CBL clustering and thereby 
          reduce EGFR ubiquitination and downregulation.
        supporting_text: This allows Sprouty to block CIN85-mediated clustering 
          of CBL molecules, stablization of CBL-EGFR interactions and efficient 
          ubiquitination and down-regulation of EGFR.
  - id: Reactome:R-HSA-182993
    title: Ubiquitination of stimulated EGFR (CBL)
    findings:
      - statement: CBL ubiquitinates activated EGFR to drive receptor 
          internalization and degradation.
        supporting_text: CBL down-regulates receptor tyrosine kinases by 
          conjugating ubiquitin to them. This leads to receptor internalization 
          and degradation.
  - id: Reactome:R-HSA-182994
    title: Assembly of EGFR complex in clathrin-coated vesicles
    findings:
      - statement: The CBL-CIN85-Endophilin complex mediates ligand-induced EGFR
          downregulation.
        supporting_text: CBL-CIN85-Endophilin complex mediates ligand-induced 
          down-regulation of the EGF receptor.
  - id: Reactome:R-HSA-183002
    title: Beta-Pix:CDC42:GTP binds CBL in EGF:p-6Y-EGFR:CBL:CIN85
    findings:
      - statement: Active CDC42 and Beta-Pix can promote Beta-Pix binding to 
          CBL, displacing CIN85 and potentially blocking CBL clustering.
        supporting_text: High concentrations of active CDC42 (bound to GTP) and 
          Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the 
          usually preferred binding partner CIN85 (SH3KBP1) from the CBL 
          complex.
  - id: Reactome:R-HSA-183036
    title: Ubiquitination of stimulated EGFR (CBL:GRB2)
    findings:
      - statement: CBL ubiquitinates activated EGFR, leading to receptor 
          internalization and degradation.
        supporting_text: CBL down-regulates receptor tyrosine kinases by 
          conjugating ubiquitin to them. This leads to receptor internalization 
          and degradation.
  - id: Reactome:R-HSA-183051
    title: CBL ubiquitinates Sprouty
    findings:
      - statement: EGF stimulation induces Sprouty phosphorylation and 
          CBL-mediated ubiquitination for proteasomal degradation.
        supporting_text: Sprouty is ubiquitinated by CBL in an EGF-dependent 
          manner. EGF stimulation induces the tyrosine phosphorylation of 
          Sprouty, which in turn enhances the interaction of Sprouty with CBL.
  - id: Reactome:R-HSA-183055
    title: Binding of CBL to EGFR
    findings:
      - statement: EGFR phosphorylation at Y1069 (Y1045) creates a docking site 
          for CBL required for lysosomal sorting.
        supporting_text: Phosphorylation at tyrosine Y1069 (i.e. Y1045 in the 
          mature protein) of EGFR creates a major docking site for E3 
          ubiquitin-protein ligase, CBL (Casitas B-lineage lymphoma proto- 
          oncogene) and  is required to sort the EGFR to lysosomes for 
          degradation.
  - id: Reactome:R-HSA-183058
    title: Phosphorylation of CBL (EGFR:GRB2:CBL)
    findings:
      - statement: EGF stimulation leads to CBL phosphorylation on Tyr-371, 
          enabling ubiquitin ligase activity.
        supporting_text: EGF (and indeed FGF, PDGF and NGF) stimulation results 
          in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for 
          CBL to exhibit ubiquitin ligase activity.
  - id: Reactome:R-HSA-183067
    title: Localization of CBL:GRB2 to the membrane
    findings:
      - statement: EGFR phosphorylation after EGF stimulation allows GRB2 
          binding to phosphorylated tyrosines.
        supporting_text: Upon EGF stimulation and consequent EGFR 
          phosphorylation, GRB2 binds phosphorylated tyrosines
  - id: Reactome:R-HSA-183072
    title: EGFR non-clathrin mediated endocytosis
    findings:
      - statement: At high ligand levels, EGFR undergoes clathrin-independent 
          endocytosis when Y1069 is phosphorylated and ubiquitinated.
        supporting_text: At higher concentrations of ligand, a substantial 
          fraction of the receptor (>50%) is endocytosed through a clathrin 
          independent, lipid-raft-dependent route as the receptor becomes Y1069 
          (i.e. Y1045 in the mature protein) phosphorylated and ubiquitnated.
  - id: Reactome:R-HSA-183084
    title: CBL escapes CDC42-mediated inhibition by down-regulating the adaptor 
      molecule Beta-Pix
    findings:
      - statement: Beta-Pix association with CBL is a critical step in 
          CDC42-mediated inhibition of EGFR ubiquitylation and downregulation.
        supporting_text: Beta-Pix (Cool-1) associates with CBL, which appears to
          be a critical step in CDC42-mediated inhibition of EGFR ubiquitylation
          and downregulation.
  - id: Reactome:R-HSA-183089
    title: CBL binds and ubiquitinates phosphorylated Sprouty
    findings:
      - statement: EGF stimulation promotes Sprouty phosphorylation and 
          CBL-mediated ubiquitination for degradation.
        supporting_text: Sprouty is ubiquitinated by CBL in an EGF-dependent 
          manner. EGF stimulation induces the tyrosine phosphorylation of 
          Sprouty, which in turn enhances the interaction of Sprouty with CBL.
  - id: Reactome:R-HSA-1963563
    title: MATK (CSK homologous kinase) binds phosphorylated ERBB2
    findings:
      - statement: MATK binds ERBB2 at phosphorylated Y1253 to inhibit 
          downstream signaling.
        supporting_text: MATK (also known as CHK or CSK homologous kinase) binds
          to ERBB2 through phosphorylated tyrosine residue Y1253 in the C-tail 
          of ERBB2 and, through an unknown mechanism, inhibits ERBB2 downstream 
          signaling.
  - id: Reactome:R-HSA-1963581
    title: Trans-autophosphorylation of p-Y877-ERBB2 heterodimers
    findings:
      - statement: ERBB2 Y877 phosphorylation by SRC kinases increases the 
          trans-autophosphorylation rate of ERBB2 heterodimers.
        supporting_text: Phosphorylation of ERBB2 on tyrosine residue Y877 by 
          SRC family kinases significantly increases trans-autophosphorylation 
          rate of ERBB2 heterodimers, presumably by enabling the kinase domain 
          of ERBB2 to achieve a conformation that positively affects ERBB2 
          kinase activity.
  - id: Reactome:R-HSA-1963582
    title: Trans-autophosphorylation of ERBB2 heterodimers
    findings:
      - statement: ERBB2 and EGF-bound EGFR heterodimers trans-autophosphorylate
          on multiple tyrosines to activate signaling.
        supporting_text: Dimers of ERBB2 and EGF-bound EGFR 
          trans-autophosphorylate on six EGFR tyrosine residues and six ERBB2 
          tyrosine residues to form phosphorylated heterodimers that activate 
          downstream signaling cascades (Ricci et al. 1995, Pinkas-Kramarski et 
          al. 1996, Walton et al. 1990, Margolis et al. 1989, Hazan et al. 1990,
          Helin et al. 1991).
  - id: Reactome:R-HSA-1963586
    title: SRC family kinases phosphorylate ERBB2
    findings:
      - statement: After ERBB2 heterodimerization, SRC family kinases 
          phosphorylate ERBB2 Y877, enhancing kinase activity.
        supporting_text: Dissociation of HSP90 from ERBB2 upon formation of 
          ERBB2 heterodimers (with either EGFR, ERBB3 or ERBB4) enables 
          phosphorylation of ERBB2 on the tyrosine residue Y877, mediated by one
          of SRC family kinases  - SRC, FYN or YES1.
  - id: Reactome:R-HSA-1963589
    title: 'ERBB2 forms heterodimers with ligand-activated ERBB receptors: EGFR, ERBB3
      and ERBB4'
    findings:
      - statement: ERBB2 is activated by heterodimerization with 
          ligand-activated EGFR, ERBB3, or ERBB4.
        supporting_text: ERBB2, which does not bind any known ligand, is 
          activated through formation of a heterodimer with another 
          ligand-activated ERBB family member.
  - id: Reactome:R-HSA-1977959
    title: ERBB4 forms heterodimers with EGFR
    findings:
      - statement: Ligand-stimulated ERBB4 forms heterodimers with 
          ligand-stimulated EGFR that undergo trans-autophosphorylation.
        supporting_text: Heterodimers of ERBB4 and EGFR undergo 
          trans-autophosphorylation, but the exact phosphorylation pattern, 
          downstream signaling and physiological significance of these 
          heterodimers have not been studied (Riese et al. 1995, Cohen et al. 
          1996).
  - id: Reactome:R-HSA-212706
    title: Phospholipase C-gamma1 binds to the activated EGF receptor
    findings:
      - statement: Inactive PLCG1 binds activated EGFR.
        supporting_text: Inactive phospholipase C-gamma1 (PLCG1) binds to 
          activated epidermal growth factor receptor (EGFR).
  - id: Reactome:R-HSA-212710
    title: EGFR activates PLC-gamma1 by phosphorylation
    findings:
      - statement: EGFR phosphorylates PLCG1 to activate it.
        supporting_text: EGFR phosphorylates PLC-gamma1, thus activating it.
  - id: Reactome:R-HSA-212713
    title: Active PLC-gamma1 dissociates from EGFR
    findings:
      - statement: Activated PLCG1 dissociates from EGFR as a release step 
          before hydrolyzing PIP2.
        supporting_text: Once activated PLC-gamma1 dissociates from EGFR, it can
          hydrolyze PIP2.
  - id: Reactome:R-HSA-212718
    title: EGFR interacts with phospholipase C-gamma
    findings:
      - statement: Activated EGFR activates PLCG1 to hydrolyze PIP2 into IP3 and
          DAG.
        supporting_text: Activated EGFR can activate phospholipase C-gamma1 
          (PLC-gamma1, i.e. PLCG1) which hydrolyses phosphatidylinositol 
          4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and 
          diacylglycerol (DAG).
  - id: Reactome:R-HSA-2179387
    title: Mature HBEGF binds to EGFR, triggering dimerisation and 
      autophosphorylation of the receptor
    findings:
      - statement: HBEGF binds and activates EGFR/ErbB1 and ErbB4.
        supporting_text: The heparin-binding EGF growth factor (HBEGF) is a 
          member of the EGF family of growth factors that binds to and activates
          the EGF receptor EGFR/ErbB1 and ErbB4 (not shown here) (Higashiyama et
          al. 1991, Elenius et al. 1997).
  - id: Reactome:R-HSA-2179407
    title: SOS1-mediated nucleotide exchange of RAS (HB-EFG-initiated)
    findings:
      - statement: SOS1 activates RAS by promoting GDP-GTP exchange.
        supporting_text: SOS1 activates RAS nucleotide exchange from the 
          inactive form (bound to GDP) to an active form (bound to GTP) (Chardin
          et al. 1993).
  - id: Reactome:R-HSA-2179415
    title: GRB2:SOS1 binds to HBEGF:p-Y-EGFR
    findings:
      - statement: GRB2 binds activated EGFR while in complex with SOS, at Y1068
          and/or Y1086.
        supporting_text: One such protein, growth factor receptor-bound protein 
          2 (GRB2), can bind activated EGFR with its SH2 domain whilst in 
          complex with SOS through its SH3 domain. GRB2 can bind at either Y1068
          and/or Y1086 autophosphorylation sites on the receptor (Batzer et al. 
          1994, Okutani et al. 1994).
  - id: Reactome:R-HSA-2316434
    title: PI3K phosphorylates PIP2 to PIP3
    findings:
      - statement: PI3K can be activated downstream of EGFR and other RTKs.
        supporting_text: PI3K can be activated downstream of receptor tyrosine 
          kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 
          2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), 
          PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), 
          insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and
          EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 
          2004, Kainulainen et al. 2000, Junttila et al. 2009).
  - id: Reactome:R-HSA-2400009
    title: PI3K inhibitors block PI3K catalytic activity
    findings:
      - statement: Multiple inhibitors have been developed that block the 
          phosphoinositide kinase activity of PI3K.
        supporting_text: A variety of inhibitors capable of blocking the 
          phosphoinositide kinase activity of PI3K have been developed.
  - id: Reactome:R-HSA-445069
    title: L1-EGFR trans-heterodimerization
    findings:
      - statement: L1CAM-EGFR trans interaction induces EGFR kinase activity, 
          but autophosphorylation requires additional cis interactions.
        supporting_text: L1CAM and EGFR engage in a weak heterophilic trans 
          interaction and this induces EGFR tyrosine kinase activity and its 
          activation. However, this trans interaction alone is not sufficient to
          induce EGFR autophosphorylation, which requires additional cis type 
          interactions between the two proteins.
  - id: Reactome:R-HSA-5637764
    title: Binding of GRB2:GAB1 complex to p-EGFRvIII mutant
    findings:
      - statement: GRB2:GAB1 binding to phosphorylated EGFRvIII is assumed and 
          not directly tested.
        supporting_text: Direct binding of the GRB2:GAB1 complex to 
          phosphorylated homodimers of EGFRvIII cancer mutant has not been 
          tested.
  - id: Reactome:R-HSA-5637765
    title: Binding of PI3K to complex of GRB2:GAB1 and p-EGFRvIII
    findings:
      - statement: EGFRvIII is assumed to recruit the PI3K complex similarly to 
          wild-type EGFR.
        supporting_text: EGFRvIII cancer mutant is assumed to recruit the PI3K 
          complex PIK3CA:PIK3R1 in a manner similar to wild-type EGFR (Rodrigues
          et al. 2000).
  - id: Reactome:R-HSA-5637766
    title: Binding of SHC1 to p-5Y-EGFRvIII
    findings:
      - statement: SHC1 binding to EGFRvIII is assumed based on its binding to 
          phosphorylated EGFR Y1148 and Y1173.
        supporting_text: Binding of SHC1 to EGFRvIII cancer mutant has not been 
          tested but SHC1 is assumed to bind EGFRvIII in the same way it binds 
          wild-type EGFR.
  - id: Reactome:R-HSA-5637770
    title: Binding of GRB2:SOS1 complex to phosphorylated EGFRvIII
    findings:
      - statement: Direct binding of GRB2:SOS1 to phosphorylated EGFRvIII has 
          not been tested, but GRB2 binds Y1068 and Y1086.
        supporting_text: Direct binding of GRB2:SOS1 complex to phosphorylated 
          homodimers of EGFRvIII cancer mutant has not been tested.
  - id: Reactome:R-HSA-5637792
    title: PLC-gamma 1 binds to p-EGFRvIII mutant
    findings:
      - statement: EGFRvIII phosphorylates Y992 and is expected to recruit PLCG1
          like wild-type EGFR.
        supporting_text: Tyrosine residue Y992 (corresponding to Y1016 when 
          counting from the first amino acid of the EGFR precursor, prior to 
          cleavage of the 24-amino acid signal peptide at the N-terminus), a 
          docking site for PLC-gamma 1 (PLCG1), is phosphorylated in EGFRvIII 
          cancer mutant and expected to recruit PLC-gamma 1 in the same way as 
          the wild-type EGFR receptor (Grandal et al. 2007).
  - id: Reactome:R-HSA-5637794
    title: EGFRvIII does not bind CBL
    findings:
      - statement: EGFRvIII lacks Y1069 phosphorylation and shows little or no 
          CBL binding.
        supporting_text: In EGFRvIII mutant, Y1069 (i.e. Y1045 in the mature 
          protein) is not phosphorylated (Han et al. 2006, Grandal et al. 2007).
  - id: Reactome:R-HSA-5637795
    title: Phosphorylation of PLC-gamma 1 by p-EGFRvIII mutant
    findings:
      - statement: EGFRvIII is assumed to phosphorylate PLCG1 after recruitment,
          as in wild-type EGFR.
        supporting_text: Once recruited, PLC-gamma 1 is assumed to be 
          phosphorylated by EGFRvIII cancer mutant in the same way it is 
          phosphorylated by the wild-type EGFR (Meisenhelder et al. 1989, Wahl 
          et al. 1990).
  - id: Reactome:R-HSA-5637796
    title: Phosphorylation of SHC1 by p-5Y-EGFRvIII
    findings:
      - statement: EGFRvIII phosphorylation of SHC1 is assumed based on 
          wild-type EGFR behavior.
        supporting_text: EGFRvIII cancer mutant was not directly tested for its 
          ability to phosphorylate SHC1, but is assumed to interact with SHC1 in
          the same way as the wild-type EGFR protein (Soler et al. 1994, 
          VanderKuur et al. 1995).
  - id: Reactome:R-HSA-5637798
    title: Phosphorylated SHC1 in complex with p-5Y-EGFRvIII recruits GRB2:SOS1 
      complex
    findings:
      - statement: GRB2:SOS1 recruitment by SHC1 bound to EGFRvIII is assumed 
          and not directly tested.
        supporting_text: Recruitment of GRB2:SOS1 complex by SHC1 bound to 
          phosphorylated dimers of EGFRvIII cancer mutant has not been directly 
          tested, but is assumed to happen in the same way it happens with the 
          SHC1 bound to the phosphorylated homodimer of wild-type EGFR (Chardin 
          et al. 1993).
  - id: Reactome:R-HSA-5637800
    title: Dissociation of phosphorylated PLC-gamma 1 from p-EGFRvIII mutant
    findings:
      - statement: Phosphorylated PLCG1 is expected to dissociate from EGFRvIII 
          as a release step before downstream signaling.
        supporting_text: Once phosphorylated, PLC-gamma 1 is expected to 
          dissociate from phosphorylated EGFRvIII cancer mutant and induce 
          downstream signaling in the same way it does when activated by the 
          wild-type EGFR.
  - id: Reactome:R-HSA-5637801
    title: Conversion of PIP2 to PIP3 by PI3K bound to phosphorylated EGFRvIII
    findings:
      - statement: EGFRvIII is assumed to induce PI3K/AKT signaling via 
          PI3K-mediated conversion of PIP2 to PIP3.
        supporting_text: The kinase activity of PI3K mediates the 
          phosphorylation of PIP2 to form PIP3. It is assumed that EGFRvIII 
          cancer mutant induces PI3K/AKT signaling in a manner similar to 
          wild-type EGFR.
  - id: Reactome:R-HSA-5637806
    title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in 
      complex with p-EGFRvIII)
    findings:
      - statement: SOS1 is assumed to activate RAS downstream of EGFRvIII via 
          GRB2, with RAS-MAPK activation observed in EGFRvIII cells.
        supporting_text: Based on the wild-type EGFR signaling, it is assumed 
          that the guanine nucleotide exchange factor SOS1 interacts with 
          phosphorylated EGFRvIII mutant through the adaptor protein, GRB2. Upon
          formation of this complex, SOS1 activates RAS by promoting GDP release
          and GTP binding.
  - id: Reactome:R-HSA-5637808
    title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in 
      complex with phosphorylated SHC1 and p-EGFRvIII)
    findings:
      - statement: SOS1 recruited by GRB2 bound to p-SHC1:p-EGFRvIII is assumed 
          to activate RAS.
        supporting_text: SOS1, recruited by GRB2 bound to p-SHC1:p-EGFRvIII 
          mutant, is assumed to activate RAS nucleotide exchange from the 
          inactive form (bound to GDP) to an active form (bound to GTP).
  - id: Reactome:R-HSA-5638137
    title: EGFRvIII cancer variant does not bind EGF ligand
    findings:
      - statement: EGFRvIII lacks the ligand-binding domain and cannot bind EGFR
          ligands.
        supporting_text: EGFRvIII mutant lacks the ligand binding domain and is 
          therefore unable to bind EGFR ligands (Fernandes et al. 2001).
  - id: Reactome:R-HSA-5672965
    title: RAS GEFs promote RAS nucleotide exchange
    findings:
      - statement: RAS GEFs promote GDP-GTP exchange on membrane-associated RAS 
          in response to signaling.
        supporting_text: The human genome is predicted to encode 27 RAS guanine 
          nucleotide exchange factors (GEFs) that promote the exchange of GDP 
          for GTP on membrane-associated RAS in response to RAS-MAPK pathway 
          activation by growth factors, hormones, cytokines and other stimuli 
          (reviewed in Cherfils and Zeghouf, 2013; Cargnello and Roux, 2011).
  - id: Reactome:R-HSA-6785636
    title: Phosphorylated ERBB2 heterodimers bind MEMO1
    findings:
      - statement: ERBB2 phosphorylated at Y1222 binds MEMO1.
        supporting_text: ERBB2 phosphorylated on tyrosine residue Y1222 binds 
          MEMO1 (mediator of ERBB2-driven cell motility) (Marone et al. 2004, 
          Qiu et al. 2008, Zaoui et al. 2010, Feracci et al. 2011).
  - id: Reactome:R-HSA-6785648
    title: MEMO1 binds RHOA:GTP:DIAPH1
    findings:
      - statement: MEMO1 associated with phosphorylated ERBB2 heterodimers binds
          the RHOA:GTP:DIAPH1 complex.
        supporting_text: MEMO1, in complex with phosphorylated ERBB2 
          heterodimers, associates with the complex of activated RHOA and formin
          family member DIAPH1.
  - id: Reactome:R-HSA-8847995
    title: Activated ERBB2 binds PTK6 (BRK)
    findings:
      - statement: PTK6 (BRK) binds activated ERBB2.
        supporting_text: PTK6 (BRK) is a nonreceptor tyrosine kinase that can 
          bind activated ERBB2 receptor (Xiang et al. 2008).
  - id: Reactome:R-HSA-8848005
    title: ERBB2 promotes PTK6 autophosphorylation
    findings:
      - statement: PTK6 binding to activated ERBB2 stimulates PTK6 Y342 
          autophosphorylation, increasing catalytic activity.
        supporting_text: Binding of PTK6 (BRK) to activated ERBB2 receptor 
          stimulates autophosphorylation of PTK6 on tyrosine residue Y342 (Xiang
          et al. 2008, Peng et al. 2015). Autophosphorylation at Y342 
          significantly increases catalytic activity of PTK6 (Qiu and Miller 
          2002).
  - id: Reactome:R-HSA-8857549
    title: HBEGF-bound EGFR forms a heterodimer with GPNMB
    findings:
      - statement: HBEGF-bound EGFR forms heterodimers with GPNMB via 
          interaction of the GPNMB intracellular domain with the EGFR kinase 
          domain.
        supporting_text: EGFR bound to HBEGF (HB-EGF) can form heterodimers with
          the transmembrane glycoprotein GPNBM. The intracellular domain of 
          GPNMB interacts with the kinase domain of EGFR (Lin et al. 2016).
  - id: Reactome:R-HSA-8857555
    title: EGFR phosphorylates GPNMB
    findings:
      - statement: HBEGF-bound EGFR phosphorylates GPNMB at Y525.
        supporting_text: HBEGF-bound EGFR phosphorylates its heterodimerization 
          partner GPNMB at tyrosine residue Y525 (Lin et al. 2016).
  - id: Reactome:R-HSA-8857565
    title: Phosphorylated GPNMB recruits PTK6 and LRRK2 in the presence of 
      LINC01139
    findings:
      - statement: GPNMB phosphorylation at Y525 recruits PTK6 and LRRK2 in the 
          presence of LINC01139.
        supporting_text: Phosphorylation of GPNBM at tyrosine residue Y525 upon 
          heterodimerization with HBEGF-bound EGFR promotes, in the presence of 
          long non-coding RNA LINC011139 (LINK-A), the recruitment of PTK6 
          (BRK). In addition to PTK6, LINC01139 simultaneously recruits 
          serine/threonine kinase LRRK2 to phosphorylated GPNBM (Lin et al. 
          2016).
  - id: Reactome:R-HSA-8857577
    title: LINC01139 facilitates PTK6 autophosphorylation
    findings:
      - statement: LINC01139 induces a PTK6 conformational change that 
          facilitates PTK6 autophosphorylation on Y351.
        supporting_text: The long non-coding RNA LINC01139 (LINK-A) induces 
          conformational change of PTK6 (BRK), which facilitates PTK6 
          autophosphorylation on tyrosine residue Y351 and possibly other sites 
          (Lin et al. 2016).
  - id: Reactome:R-HSA-8857583
    title: LINC01139 promotes phosphorylation of HIF1A by PTK6
    findings:
      - statement: PTK6 activated via LINC01139-mediated recruitment 
          phosphorylates HIF1A at Y565.
        supporting_text: PTK6 (BRK) tyrosine kinase, activated via long 
          non-coding RNA LINC01139 (LINK-A) mediated recruitment to 
          phosphorylated GPNMB (bound to HBEGF-activated EGFR), phosphorylates 
          hypoxia inducible factor 1 alpha (HIF1A) at tyrosine residue Y565.
  - id: Reactome:R-HSA-8863804
    title: PTPN12 dephosphorylates ERBB2 on tyrosine Y1248
    findings:
      - statement: PTPN12 dephosphorylates ERBB2 Y1248, attenuating downstream 
          RAS activation.
        supporting_text: PTPN12 protein tyrosine phosphatase dephosphorylates 
          activated ERBB2 at tyrosine residue Y1248 and activated EGFR at 
          tyrosine residue Y1148 (Y1148 corresponds to Y1172 of the nascent 
          EGFR, with 24 amino acid signal peptide at the N-terminus). 
          PTPN12-mediated dephosphorylation of ERBB2 attenuates downstream RAS 
          activation, as Y1248 is involved in SHC1 recruitment.
  - id: Reactome:R-HSA-8864029
    title: PTPN12 dephosphorylates EGFR at Y1172 (Y1148)
    findings:
      - statement: PTPN12 dephosphorylates EGFR Y1148 (Y1172), inhibiting SHC1 
          recruitment and downstream RAS activation.
        supporting_text: PTPN12-mediated dephosphorylation of activated EGFR 
          inhibits SHC1 recruitment to the p-Y1148 (i.e. p-Y1172) docking site, 
          thus attenuating downstream RAS activation (Sun et al. 2011).
  - id: Reactome:R-HSA-8864105
    title: PTPN18 binds ERBB2:EGFR heterodimers
    findings:
      - statement: PTPN18 binds ERBB2 activated in response to EGF stimulation.
        supporting_text: PTPN18 protein tyrosine phosphatase (BDP1) binds ERBB2,
          activated in response to EGF stimulation, via PEST and catalytic 
          domains of PTPN18 (Wang et al. 2014).
  - id: Reactome:R-HSA-8864125
    title: PTPN18 dephosphorylates ERBB2 at Y1196, Y1112 and Y1248
    findings:
      - statement: PTPN18 dephosphorylates ERBB2 Y1196, Y1112, and Y1248, 
          attenuating PI3K/AKT and RAS signaling.
        supporting_text: Dephosphorylation of ERBB2 tyrosines Y1196 and Y1248 
          attenuates downstream activation of PI3K/AKT and RAS signaling.
  - id: Reactome:R-HSA-8866279
    title: Epsin family proteins bind ubiquitinated cargo
    findings:
      - statement: EGFR undergoes ubiquitination at the plasma membrane, 
          triggering endocytosis.
        supporting_text: A number of receptor tyrosine kinases, including EGFR, 
          VEGFR, FGFR and others undergo ubiquitination at the plasma membrane, 
          triggering endocytosis.
  - id: Reactome:R-HSA-8867041
    title: EGFR phosphorylates EPS15
    findings:
      - statement: Activated EGFR phosphorylates EPS15 at Y849, influencing 
          endocytic routing.
        supporting_text: EPS15 is phosphorylated at Y849 by activated EGFR 
          (Confalonieri et al, 2000).
  - id: Reactome:R-HSA-8867044
    title: EGFR binds EPS15, EPN1, EPS15L1
    findings:
      - statement: EPS15, EPN1, and EPS15L1 are required for endocytosis of 
          ligand-activated EGFR.
        supporting_text: EH-containing proteins such as EPS15, EPN1 and EPS15L1 
          are required for the endocytosis of ligand-activated EGFR 
          (Confalonieri et al, 2000; Huang et al, 2004; reviewed in van Bergen 
          en Henegouwen, 2009).
  - id: Reactome:R-HSA-8867047
    title: PTPN3 dephosphorylates EPS15
    findings:
      - statement: PTPN3 dephosphorylates EPS15, promoting EGFR internalization 
          into caveolin-enriched structures.
        supporting_text: Overexpression of the phosphatase PTPN3, which 
          dephosphorylates EPS15 in vitro and in vivo, promotes the 
          internalization of EGFR into caveolin-enriched structures and targets 
          it for lysosomal degradation (Li et al, 2015).
  - id: Reactome:R-HSA-8867754
    title: F- and N- BAR domain proteins bind the clathrin-coated pit
    findings:
      - statement: F-BAR domain proteins such as FCHo1 and FCHo2 are recruited 
          early to clathrin-coated pit formation by recognizing shallow membrane
          curvature.
        supporting_text: F-BAR domain proteins such as FCHo 1 and 2 recognize 
          shallow membrane curvature and are generally recruited early in the 
          formation of clathrin-coated pit (Itoh et al, 2005; Kamioka et al, 
          2004; Henne et al, 2007; Shimada et al, 2007; Henne et al, 2010).
  - id: Reactome:R-HSA-8867756
    title: CLASP proteins and cargo are recruited to the nascent clathrin-coated
      pit
    findings:
      - statement: CLASP proteins are recruited to nascent clathrin-coated pits 
          via interactions with AP-2 and clathrin, bringing cargo into the pit.
        supporting_text: CLASP proteins are recruited to nascent clathrin-coated
          pits (CCPs) through interactions with AP-2 and clathrin.
  - id: Reactome:R-HSA-8868071
    title: Clathrin recruits PIK3C2A
    findings:
      - statement: PIK3C2A binds clathrin and localizes to late-stage 
          clathrin-coated pits, where clathrin binding stimulates its kinase 
          activity.
        supporting_text: PIK3C2A interacts with clathrin through a 
          clathrin-binding domain in its unique N-terminal tail and localizes to
          late-stage clathrin-coated pits (Domin et al, 2000; Gaidarov et al, 
          2001; Gaidarov et al, 2005).  Binding to clathrin stimulates the 
          kinase activity of PIK3C2A and promotes the production of PI(3,4)P2 at
          the plasma membrane (Gaidarov et al, 2001).
  - id: Reactome:R-HSA-8868072
    title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
    findings:
      - statement: Clathrin-associated PIK3C2A converts PI(4)P to PI(3,4)P2, 
          promoting recruitment of BAR domain proteins such as SNX9.
        supporting_text: Clathrin-associated PIK3C2A catalyzes the conversion of
          PI(4)P to PI(3,4)P2, which contributes to the recruitment of BAR 
          domain proteins such as SNX9 to the clathrin-coated pit (Domin et al, 
          2000; Gaidarov et al, 2001; Gaidarov et al, 2005; Posor et al, 2013; 
          reviewed in Daumke et al, 2014).
  - id: Reactome:R-HSA-8868230
    title: SNX9 recruits components of the actin polymerizing machinery
    findings:
      - statement: Actin is recruited late to clathrin-coated pits via ARP2/3 
          and N-BAR proteins such as SNX9 when required for vesicle formation.
        supporting_text: In cases where actin is required, it appears to be 
          recruited late to the emerging clathrin-coated pit, just prior to or 
          coincident with the recruitment of dynamin and vesicle scission 
          (Taylor et al, 2011; Taylor et al, 2012; reviewed in McMahon and 
          Boucrot, 2011).
  - id: Reactome:R-HSA-8868236
    title: BAR domain proteins recruit dynamin
    findings:
      - statement: Dynamin self-assembly stimulates its GTPase activity to drive
          vesicle scission from the plasma membrane.
        supporting_text: dynamin self assembles into helical oligomers, 
          stimulating its GTPase activity
  - id: Reactome:R-HSA-8868648
    title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
    findings:
      - statement: SYNJ/OCRL hydrolyze PI(4,5)P2 to PI(4)P, aiding scission and 
          clathrin uncoating during endocytosis.
        supporting_text: Inositol-5-phosphatases like SYNJs and OCRL hydrolyze 
          PI(4,5)P2 to PI(4)P.  In the context of CME, this promotes the 
          abortive turnover (disassembly) of some CCPs, contributes to the 
          dynamin-mediated scission of the clathrin-coated vesicle neck, and 
          promotes clathrin uncoating following scission (Guan et al, 2010; 
          Cremona et al, 1999; Mani et al, 2007; Chang-Ileto et al, 2011; 
          Antonescu et al, 2011; reviewed in McMahon and Boucrot, 2011; Daumke 
          et al, 2014).
  - id: Reactome:R-HSA-8868651
    title: Endophilins recruit synaptojanins to the clathrin-coated pit
    findings:
      - statement: Synaptojanins are recruited to clathrin-coated pits through 
          interactions with endophilins and other endocytic proteins.
        supporting_text: SYNJ proteins are recruited to the clathrin-coated pit 
          through interactions with a number of endocytic proteins including 
          ITSNs, EPS15, PACSIN proteins and endophilins, as well as with 
          clathrin and AP-2 (Haffner et al, 1997; Cestra et al, 1999; Maire et 
          al, 2004; Schuske et al, 2003; Verstreken et al, 2003; Modregger et 
          al, 2000; Perera et al 2006; Milosevic et al, 2011; reviewed in 
          Dittman and Ryan, 2009).
  - id: Reactome:R-HSA-8868658
    title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
    findings:
      - statement: HSPA8 ATP hydrolysis promotes dissociation of the clathrin 
          coat from vesicles.
        supporting_text: HSPA8 hydrolyzes ATP to promote dissociation of the 
          clathrin coat from the vesicle (reviewed in Sousa and Lafer, 2015).
  - id: Reactome:R-HSA-8868659
    title: Clathrin recruits auxilins to the clathrin-coated vesicle
    findings:
      - statement: Auxilin proteins DNAJC6 and GAK are recruited to 
          clathrin-coated vesicles via clathrin and PI4P.
        supporting_text: After fission from the plasma membrane, auxilin 
          proteins DNAJC6 and GAK are recruited to the vesicle through 
          interaction with clathrin and phosphoinositides, in particular PI4P 
          (Greener et al, 2000; Lee et al, 2006; Massol et al, 2006; Taylor et 
          al, 2011; Scheele et al, 2001; Fotin et al, 2004a; Fotin et al, 2004b;
          Guan et al, 2010; reviewed in McMahon and Boucrot, 2011; Sousa and 
          Lafer, 2015).
  - id: Reactome:R-HSA-8868660
    title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
    findings:
      - statement: Auxilin recruits HSPA8 (HSC70) to clathrin-coated vesicles 
          for uncoating.
        supporting_text: HSPA8 (also known as HSC70) is recruited to the 
          clathrin-coated vesicle through interaction with DNA J proteins GAK 
          and DNAJC6 (Rapoport et al, 2008; Xing et al, 2010; reviewed in Sousa 
          and Lafer, 2015).
  - id: Reactome:R-HSA-8868661
    title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
    findings:
      - statement: Dynamin GTP hydrolysis promotes membrane fission of 
          clathrin-coated vesicles.
        supporting_text: Self-assembly of dynamin around the neck of the 
          emerging clathrin-coated vesicle stimulates its GTPase activity. This 
          in turn promotes a conformational change in dynamin organization that 
          is required for membrane fission (Hinshaw and Schmid, 1995; Sweitzer 
          and Hinshaw, 1998; Takei et al, 1999; Yoshida et al, 2004; Chappie et 
          al, 2010;  Chappie et al, 2011; Ford et al, 2011; Faelber et al, 2011;
          reviewed in Daumke et al, 2014).
  - id: Reactome:R-HSA-8869438
    title: Dissociation of clathrin-associated proteins
    findings:
      - statement: After clathrin coat removal, associated proteins dissociate 
          in a poorly understood step.
        supporting_text: After the removal of the clathrin coat, it is likely 
          that many of the proteins that contributed to vesicle formation are 
          lost, although the timing and mechanism of this step are poorly 
          understood (reviewed in McMahon and Boucrot, 2011; Lemmon, 2001).
  - id: Reactome:R-HSA-8871193
    title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
    findings:
      - statement: GAPVD1 binding to AP-2 mu2 displaces AAK1 and promotes 
          dephosphorylation of AP-2 mu2, destabilizing AP-2 membrane 
          interactions.
        supporting_text: GAPVD1 binds the alpha adaptin ear domain of AP-2 mu2, 
          activating its RAB5-directed GEF activity and displacing AAK1.  AAK1 
          displacement results in a net dephosphorylation of the AP-2 mu2 
          subunit, destabilizing the interaction of AP-2 with the vesicle 
          membrane (Sato et al, 2005; Smerdjieva et al, 2008).
  - id: Reactome:R-HSA-8871194
    title: RAB5 and GAPVD1 bind AP-2
    findings:
      - statement: RAB5 and GAPVD1 may promote AP-2 uncoating by displacing AAK1
          and dephosphorylating AP-2 mu2.
        supporting_text: RAB5 and its associated GEF GAPVD1 may contribute to 
          AP-2 uncoating by displacing AAK1 and promoting the net 
          dephosphorylation of the AP-2 mu2 subunit.
  - id: Reactome:R-HSA-8874797
    title: EGFR gene expression is stimulated by TFAP2C
    findings:
      - statement: TFAP2C homodimers bind the EGFR promoter and stimulate EGFR 
          transcription.
        supporting_text: Binding of TFAP2C homodimers to the EGFR gene promoter 
          region stimulates EGFR transcription and may play an important role in
          the etiology of luminal breast cancer (Park et al. 2015, de Andrade et
          al. 2016).
  - id: Reactome:R-HSA-8951490
    title: CIN85 dissociates from EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP:CIN85
    findings:
      - statement: Active CDC42 and Beta-Pix promote displacement of CIN85 from 
          the CBL complex, a release step that can block CBL clustering.
        supporting_text: High concentrations of active CDC42 (bound to GTP) and 
          Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the 
          usually preferred binding partner CIN85 (SH3KBP1) from the CBL 
          complex.
  - id: Reactome:R-HSA-9018572
    title: EGFR phosphorylates NOTCH3
    findings:
      - statement: EGFR phosphorylates the NOTCH3 intracellular domain and 
          inhibits NOTCH3-mediated transcription.
        supporting_text: EGFR phosphorylates intracellular domain of NOTCH3 
          (NICD3) on an unknown tyrosine residue. EGFR signaling inhibits 
          NICD3-mediated transcription.
  - id: Reactome:R-HSA-9018573
    title: NOTCH3 binds activated EGFR
    findings:
      - statement: NOTCH3 intracellular domain binds activated EGFR, and this 
          binding is inhibited by erlotinib.
        supporting_text: The intracellular domain of NOTCH3 (NICD3) 
          co-immunoprecipitates with ligand activated, autophosphorylated EGFR. 
          Binding of NOTCH3 to EGFR is inhibited by erlotinib treatment, which 
          prevents EGFR activation (Arasada et al. 2014).
  - id: Reactome:R-HSA-9609689
    title: HCMV Binds to the Host Cell via heparan sulfate proteoglycans (HSPG)
    findings:
      - statement: HCMV entry occurs by fusion or endocytosis, with a pentameric
          complex facilitating entry into endothelial and epithelial cells.
        supporting_text: Viral attachment and penetration of Human 
          Cytomegalovirus (HCMV) occurs either via direct HCMV fusion with the 
          cell membrane or via endocytosis. The endocytic mechanism occurs with  
          cell types including endothelial and epithelial cells, where the 
          pentameric viral protein complex, gH:gL:p128:p130:p131A, facilitates 
          entry.
  - id: Reactome:R-HSA-9610867
    title: HCMV Binds Host Cell Receptor - Endocytic Pathway
    findings:
      - statement: HCMV can enter via endocytosis in endothelial and epithelial 
          cells using the pentameric gH:gL:p128:p130:p131A complex.
        supporting_text: Viral attachment and penetration of Human 
          Cytomegalovirus (HCMV) occurs either via direct HCMV fusion with the 
          cell membrane or via endocytosis. The endocytic mechanism occurs with  
          cell types including endothelial and epithelial cells, where the 
          pentameric viral protein complex, gH:gL:p128:p130:p131A, facilitates 
          entry.
  - id: Reactome:R-HSA-9611147
    title: Endocytic Uptake of HCMV Virion
    findings:
      - statement: HCMV enters epithelial and endothelial cells via endocytic 
          uptake and is released by low-pH-dependent fusion with endosomal 
          membranes.
        supporting_text: Once the  pentameric viral protein complex, 
          gH:gL:p128:p130:p131A, facilitates attchment of the Human 
          Cytomegalovirus (HCMV) endocytic uptake allows the virion to enter 
          epithelial and endothelial cells. The virion is released from the 
          endocytic vesicle by low-pH-dependent fusion of the virion coat with 
          endosomes membrane.
  - id: Reactome:R-HSA-9611158
    title: Fusion of HCMV Envelope with Plasma Membrane
    findings:
      - statement: HCMV fuses with the cell membrane after initial attachment to
          heparan sulfate proteoglycans.
        supporting_text: Once Human cytomegalovirus (HCMV) initial attachs to 
          cell surface heparan sulfate proteoglycans (HSPGs), the virus fuses 
          with thecell membrane.
  - id: Reactome:R-HSA-9625482
    title: PTK2 binds activated EGFR
    findings:
      - statement: PTK2 (FAK) binds activated EGFR.
        supporting_text: PTK2 (also known as FAK, focal adhesion kinase) binds 
          to the activated EGFR receptor as assessed by affinity chromatography 
          and co-immunoprecipitation (Sieg et al, 2000; Thelemann et al, 2005; 
          Liu et al, 2010).
  - id: Reactome:R-HSA-9625487
    title: PTK2 autophosphorylates downstream of EGFR
    findings:
      - statement: EGFR-dependent signaling enhances FAK autophosphorylation at 
          Y397.
        supporting_text: Stimulation of cells with either E2 (beta-estradiol), 
          tamoxifen or G1 (a GPER1 agonist) enhances EGFR-dependent FAK 
          autophosphorylation at Y397 (Sieg et al, 2000; Liu et al, 2010; Tsai 
          et al, 2013).
  - id: Reactome:R-HSA-9634702
    title: LINC01139 promotes phosphorylation of HIF1A by LRRK2
    findings:
      - statement: LRRK2 recruited via LINC01139 to phosphorylated GPNMB 
          phosphorylates HIF1A at S797.
        supporting_text: LRRK2 serine/threonine kinase, activated via long 
          non-coding RNA LINC01139 (LINK-A) mediated recruitment to 
          phosphorylated GPNMB (bound to HBEGF-activated EGFR), phosphorylates 
          hypoxia inducible factor 1 alpha (HIF1A) at serine residue S797.
  - id: Reactome:R-HSA-9664567
    title: ERBB2 KD mutants heterodimerize
    findings:
      - statement: Multiple ERBB2 kinase domain mutants are reported to form 
          heterodimers with EGFR.
        supporting_text: "The following ERBB2 KD mutants were directly or indirectly
          shown to form heterodimers with EGFR:"
  - id: Reactome:R-HSA-9664588
    title: ERBB2 KD mutants trans-autophosphorylate
    findings:
      - statement: ERBB2 kinase domain mutants undergo trans-autophosphorylation
          in the presence of EGFR.
        supporting_text: "The following ERBB2 KD mutants were shown to undergo trans-autophosphorylation
          in the presence of EGFR:"
  - id: Reactome:R-HSA-9664918
    title: Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind 
      GRB2:GAB1
    findings:
      - statement: Phosphorylated ERBB2 KD mutant:EGFR heterodimers are assumed 
          to bind GRB2:GAB1, like wild-type ERBB2:EGFR.
        supporting_text: "Phosphorylated heterodimers of the following ERBB2 KD mutants
          with EGFR are assumed to, like the wild type ERBB2:EGFR heterodimer, bind
          to the GRB2:GAB1 complex:"
  - id: Reactome:R-HSA-9664933
    title: Phosphorylated heterodimers of ERBB2 KD mutants and EGFR, in complex 
      with GRB2:GAB1, bind PI3K
    findings:
      - statement: For EGFR-binding ERBB2 KD mutants, GRB2:GAB1 binding is 
          assumed to recruit PI3K.
        supporting_text: "For the following EGFR-binding ERBB2 KD mutants that activate
          PI3K/AKT signaling, it is assumed that, like the wild type ERBB2:EGFR heterodimer,
          binding to the GRB2:GAB1 adaptor complex leads to recruitment of the PI3K
          complex:"
  - id: Reactome:R-HSA-9664940
    title: PI3K bound to phosphorylated heterodimers of ERBB2 KD mutants and 
      EGFR converts PIP2 to PIP3
    findings:
      - statement: EGFR-binding ERBB2 KD mutant heterodimers are assumed to 
          drive PI3K-mediated conversion of PIP2 to PIP3.
        supporting_text: "For the following EGFR-binding ERBB2 KD mutants that were
          shown to activate PI3K/AKT signaling, it is assumed that heterodimers of
          these mutants with EGFR, like the wild type ERBB2:EGFR heterodimer, bind
          to the PI3K complex through GRB2:GAB1, leading to conversion of PIP2 to
          PIP3:"
  - id: Reactome:R-HSA-9664950
    title: Phosphorylated heterodimers of ERBB2 KD mutants bind SHC1
    findings:
      - statement: Based on RAS/RAF/MAPK activation, phosphorylated ERBB2 KD 
          mutant heterodimers are assumed to bind SHC1.
        supporting_text: "Based on downstream activation of RAS/RAF/MAPK cascade,
          it is assumed that phosphorylated heterodimers of the following ERBB2 KD
          mutants, like phosphorylated heterodimers of the wild type ERBB2, bind to
          SHC1:"
  - id: Reactome:R-HSA-9664976
    title: Phosphorylated heterodimers of ERBB2 KD mutants phosphorylate SHC1
    findings:
      - statement: ERBB2 KD mutant heterodimers that activate RAS/RAF/MAPK are 
          assumed to bind and phosphorylate SHC1.
        supporting_text: "For the following ERBB2 KD mutants that were shown to activate
          RAS/RAF/MAPK signaling, it is assumed that they, like phosphorylated heterodimers
          of the wild type ERBB2, bind to SHC1 and phosphorylate it:"
  - id: Reactome:R-HSA-9664983
    title: Phosphorylated heterodimers of ERBB2 KD mutants recruit GRB2:SOS1 
      through SHC1
    findings:
      - statement: ERBB2 KD mutant heterodimers are assumed to recruit GRB2:SOS1
          via SHC1 after SHC1 phosphorylation.
        supporting_text: "For the following ERBB2 KD mutants that were shown to activate
          RAS/RAF/MAPK signaling, it is assumed that they, like phosphorylated heterodimers
          of the wild type ERBB2, bind to and phosphorylate SHC1, leading to recruitment
          of the GRB2:SOS1 complex:"
  - id: Reactome:R-HSA-9664991
    title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 
      KD mutants
    findings:
      - statement: ERBB2 KD mutant heterodimers are assumed to recruit GRB2:SOS1
          and activate RAS via nucleotide exchange.
        supporting_text: "For the following ERBB2 KD mutants that were shown to activate
          RAS/RAF/MAPK signaling, it is assumed that they, like phosphorylated heterodimers
          of the wild type ERBB2, bind to and phosphorylate SHC1, leading to recruitment
          of the GRB2:SOS1 complex and activating guanyl-nucleotide exchange on RAS:"
  - id: Reactome:R-HSA-9665000
    title: Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind 
      GRB2:SOS1
    findings:
      - statement: EGFR-binding ERBB2 KD mutant heterodimers are assumed to 
          directly bind GRB2:SOS1.
        supporting_text: "The following EGFR-binding ERBB2 KD mutants that were shown
          to activate RAS/RAF/MAPK signaling, evidenced by activating phosphorylation
          of ERKs (MAPK1 and MAPK3), are assumed to, like the wild type ERBB2:EGFR
          heterodimer, directly bind to the GRB2:SOS1 complex:"
  - id: Reactome:R-HSA-9665009
    title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 
      KD mutants and EGFR
    findings:
      - statement: EGFR-binding ERBB2 KD mutant heterodimers are assumed to 
          recruit GRB2:SOS1 and activate RAS via nucleotide exchange.
        supporting_text: "The following EGFR-binding ERBB2 KD mutants that were shown
          to activate RAS/RAF/MAPK signaling, evidenced by activating phosphorylation
          of ERKs (MAPK1 and MAPK3), are assumed to, like the wild type ERBB2:EGFR
          heterodimer, directly bind to the GRB2:SOS1 complex, leading to activating
          guanyl nucleotide exchange on RAS:"
  - id: Reactome:R-HSA-9665032
    title: Phosphorylated heterodimers of ERBB2 KD mutants and EGFR 
      phosphorylate PLCG1
    findings:
      - statement: EGFR-binding ERBB2 KD mutants that activate PLCG1 are assumed
          to recruit and phosphorylate PLCG1.
        supporting_text: "It is assumed that the following EGFR-binding ERBB2 mutants
          that were shown to activate PLCG1 (PLCgamma-1) signaling, evidenced by activating
          phosphorylation of PLCG1, recruit and phosphorylate PLCG1:"
  - id: Reactome:R-HSA-9665034
    title: Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind PLCG1
    findings:
      - statement: Phosphorylated ERBB2 KD mutant:EGFR heterodimers are assumed 
          to bind PLCG1, similar to wild-type ERBB2:EGFR.
        supporting_text: It is assumed that, like the wild type ERBB2:EGFR 
          heterodimer, phosphorylated heterodimers of these ERBB2 KD mutants and
          EGFR recruit PLCG1.
  - id: Reactome:R-HSA-9665388
    title: ERBB2 ECD mutants heterodimerize with EGFR
    findings:
      - statement: ERBB2 ECD mutants G309A, G309E, and S310F preferentially 
          heterodimerize with EGFR.
        supporting_text: The functionally studied ERBB2 ECD mutants, ERBB2 G309A
          (Bose et al. 2013), ERBB2 G309E (Greulich et al. 2012) and ERBB2 S310F
          (Greulich et al. 2012) seem to preferntially heterodimerize with EGFR.
  - id: Reactome:R-HSA-9665389
    title: Heterodimers of ERBB2 ECD mutants and EGFR trans-autophosphorylate
    findings:
      - statement: ERBB2 ECD mutant heterodimers trans-autophosphorylate, with 
          S310F showing stronger C-tail phosphorylation than G309A or G309E.
        supporting_text: ERBB2 S310F shows stronger activation of downstream 
          signaling than ERBB2 G309A and ERBB2 G309E, and is hyperphosphorylated
          on tyrosine residues in the C-tail (Greulich et al. 2012), while the 
          C-tail phosphorylation of ERBB2 G309A (Bose et al. 2013) and ERBB2 
          G309E (Greulich et al. 2012) is comparable to the wild type ERBB2.
  - id: Reactome:R-HSA-9665404
    title: RAS guanyl nucleotide exchange mediated by the p-6Y- ERBB2 ECD 
      mutants:EGF:p-6Y-EGFR:p-SHC1:GRB2:SOS1
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to recruit 
          GRB2:SOS1 via SHC1, activating RAS signaling.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like phosphorylated heterodimers of the wild 
          type ERBB2, can recruit the GRB2:SOS1 complex through phosphorylated 
          SHC1, leading to  guanyl nucleotide exchange on RAS and activation of 
          RAS signaling.
  - id: Reactome:R-HSA-9665406
    title: Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR 
      phosphorylate SHC1
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to bind and 
          phosphorylate SHC1.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like phosphorylated heterodimers of the wild 
          type ERBB2, can bind to and phosphorylate SHC1.
  - id: Reactome:R-HSA-9665407
    title: PI3K bound to phosphorylated heterodimers of ERBB2 ECD mutants and 
      EGFR converts PIP2 to PIP3
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to recruit PI3K via
          GRB2:GAB1, leading to PIP2 to PIP3 conversion.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and 
          EGFR, can bind to the GRB2:GAB1 complex, leading to recruitment of the
          PI3K complex, which results in conversion of PIP2 to PIP3 and 
          activation of the AKT signaling.
  - id: Reactome:R-HSA-9665408
    title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 
      ECD mutants and EGFR through GRB2
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to recruit 
          GRB2:SOS1 directly to activate RAS.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like phosphorylated heterodimers of the wild 
          type ERBB2, can directly recruit the GRB2:SOS1 complex, leading to  
          guanyl nucleotide exchange on RAS and activation of RAS signaling.
  - id: Reactome:R-HSA-9665409
    title: GRB2:SOS1 binds to phosphorylated heterodimers of ERBB2 ECD mutants 
      and EGFR
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to recruit 
          GRB2:SOS1.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like phosphorylated heterodimers of the wild 
          type ERBB2, can directly recruit the GRB2:SOS1 complex.
  - id: Reactome:R-HSA-9665410
    title: Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR bind PLCG1
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to bind PLCG1.
        supporting_text: It is assumed that heterodimers of ERBB2 ECD mutants 
          and EGFR, like the wild type heterodimers of ERBB2 and EGFR, bind to 
          PLCG1.
  - id: Reactome:R-HSA-9665411
    title: Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR 
      phosphorylate PLCG1
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to bind and 
          phosphorylate PLCG1, activating PLCG1 signaling.
        supporting_text: It is assumed that heterodimers of ERBB2 ECD mutants 
          and EGFR, like the wild type heterodimers of ERBB2 and EGFR, bind to 
          and phosphorylated PLCG1, leading to activation of PLCG1 signaling.
  - id: Reactome:R-HSA-9665413
    title: 'Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR recruit GRB2:SOS1
      through SHC1 '
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to recruit 
          GRB2:SOS1 via SHC1.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like phosphorylated heterodimers of the wild 
          type ERBB2, can recruit the GRB2:SOS1 complex through phosphorylated 
          SHC1.
  - id: Reactome:R-HSA-9665415
    title: Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR, in complex
      with GRB2:GAB1, bind PI3K
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to bind GRB2:GAB1 
          and recruit PI3K.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and 
          EGFR, can bind to the GRB2:GAB1 complex, leading to the recruitment of
          the PI3K complex.
  - id: Reactome:R-HSA-9665416
    title: Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR bind SHC1
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to bind SHC1.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like phosphorylated heterodimers of the wild 
          type ERBB2, bind to SHC1.
  - id: Reactome:R-HSA-9665417
    title: Phosphorylated heterodimers of ERBB2 ECD mutants and EGFR bind 
      GRB2:GAB1
    findings:
      - statement: ERBB2 ECD mutant heterodimers are assumed to bind GRB2:GAB1.
        supporting_text: It is assumed that phosphorylated heterodimers of ERBB2
          ECD mutants and EGFR, like the wild type heterodimers of ERBB2 and 
          EGFR, can bind to the GRB2:GAB1 complex.
  - id: Reactome:R-HSA-9665697
    title: ERBB2 TMD/JMD mutants hetrodimerize
    findings:
      - statement: ERBB2 TMD/JMD mutants such as S653C and R678Q are assumed to 
          form heterodimers with EGFR and ERBB3.
        supporting_text: "Based on trans-autophosphorylation of ERBB2 and its dimerization
          partners EGFR and ERBB3, the following ERBB2 TMD/JMD mutants are assumed
          to form heterodimers with EGFR and ERBB3:"
  - id: Reactome:R-HSA-9665698
    title: Phosphorylated heterodimers of ERBB2 TMD/JMD mutants and EGFR bind 
      GRB2:SOS1
    findings:
      - statement: ERBB2 TMD/JMD mutant heterodimers with EGFR are assumed to 
          directly bind GRB2:SOS1.
        supporting_text: It is assumed that heterodimers of ERBB2 TMD/JMD 
          mutants and EGFR, like the wild type ERBB2:EGFR heterodimers, directly
          bind to GRB:SOS1 complex.
  - id: Reactome:R-HSA-9665699
    title: Phosphorylated heterodimers of ERBB2 TMD/JMD mutants recruit 
      GRB2:SOS1 through SHC1
    findings:
      - statement: ERBB2 TMD/JMD mutant heterodimers are assumed to bind and 
          phosphorylate SHC1, recruiting GRB2:SOS1.
        supporting_text: It is assumed that heterodimers of ERBB2 TMD/JMD 
          mutants, like the wild type ERBB2 heterodimers, bind to and 
          phosphorylate SHC1, leading to the recruitment of the GRB2:SOS1 
          complex.
  - id: Reactome:R-HSA-9665700
    title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 
      TMD/JMD mutants
    findings:
      - statement: ERBB2 TMD/JMD mutant heterodimers are assumed to recruit 
          GRB2:SOS1 and activate RAS via nucleotide exchange.
        supporting_text: It is assumed that heterodimers of ERBB2 TMD/JMD 
          mutants, like the wild type ERBB2 heterodimers, bind to and 
          phosphorylate SHC1, leading to the recruitment of the GRB2:SOS1 
          complex and activation of RAS through guanyl nucleotide exchange.
  - id: Reactome:R-HSA-9665701
    title: Phosphorylated ERBB2 TMD/JMD heterodimers bind SHC1
    findings:
      - statement: ERBB2 TMD/JMD mutant heterodimers are assumed to bind SHC1.
        supporting_text: It is assumed that heterodimers of ERBB2 TMD/JMD 
          mutants, like the wild type ERBB2 heterodimers, bind SHC1.
  - id: Reactome:R-HSA-9665704
    title: Phosphorylated heterodimers of ERBB2 TMD/JMD mutants and EGFR 
      phosphorylate PLCG1
    findings:
      - statement: ERBB2 R678Q:EGFR heterodimers are assumed to bind and 
          phosphorylate PLCG1, activating PLCG1 signaling.
        supporting_text: It is assumed that the heterodimer of ERBB2 R678Q and 
          EGFR, like the wild type ERBB2:EGFR heterodimer, binds to and 
          phosphorylates PLCG1, leading to activation of PLCgamma1 signaling.
  - id: Reactome:R-HSA-9665705
    title: Phosphorylated heterodimers of ERBB2 TMD/JMD mutants phosphorylate 
      SHC1
    findings:
      - statement: ERBB2 TMD/JMD mutant heterodimers are assumed to bind and 
          phosphorylate SHC1.
        supporting_text: It is assumed that heterodimers of ERBB2 TMD/JMD 
          mutants, like the wild type ERBB2 heterodimers, bind to and 
          phosphorylate SHC1.
  - id: Reactome:R-HSA-9665706
    title: Phosphorylated heterodimers of ERBB2 TMD/JMD mutants and EGFR bind 
      PLCG1
    findings:
      - statement: ERBB2 R678Q:EGFR heterodimers are assumed to bind PLCG1.
        supporting_text: It is assumed that the heterodimer of ERBB2 R678Q and 
          EGFR, like the wild type ERBB2:EGFR heterodimer, binds PLCG1.
  - id: Reactome:R-HSA-9665707
    title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 
      TMD/JMD mutants and EGFR
    findings:
      - statement: ERBB2 TMD/JMD mutant heterodimers with EGFR are assumed to 
          directly bind GRB2:SOS1 and activate RAS.
        supporting_text: It is assumed that heterodimers of ERBB2 TMD/JMD 
          mutants and EGFR, like the wild type ERBB2:EGFR heterodimers, directly
          bind to GRB:SOS1 complex, resulting in activation of RAS signaling to 
          guanyl nucleotide exchange on RAS.
  - id: Reactome:R-HSA-9665709
    title: ERBB2 TMD/JMD heterodimers trans-autophosphorylate
    findings:
      - statement: ERBB2 TMD/JMD mutants show C-tail tyrosine phosphorylation 
          and can phosphorylate EGFR/ERBB3 C-tail residues in heterodimers.
        supporting_text: "Phosphorylation of tyrosine residues in the C-tail of ERBB2
          was shown for the following ERBB2 TMD/JMD mutants:"
  - id: Reactome:R-HSA-9674531
    title: AAMP binds EGFR
    findings:
      - statement: AAMP binds the intracellular domain of EGFR and promotes EGFR
          dimerization, trans-autophosphorylation, and downstream ERK 
          activation.
        supporting_text: AAMP (Angio-associated migratory cell protein) binds to
          EGFR. The interaction involves the intracellular domain of EGFR. AAMP 
          binding, through an unknown mechanism, promotes EGFR dimerization, 
          trans-autophosphorylation and downstream signaling, leading to 
          activation of ERKs (MAPK1 and MAPK3) and expression of cyclin D1 
          (CCND1).
  - id: Reactome:R-HSA-9851407
    title: FAM83B, (FAM83A, FAM83D) bind EGFR
    findings:
      - statement: FAM83B binds EGFR via K230 and stimulates basal and 
          EGF-induced EGFR trans-autophosphorylation before dissociating.
        supporting_text: Both recombinant and endogenous EGFR and FAM83B form a 
          complex. The lysine residue K230 of FAM83B, conserved in other FAM83 
          family members, including FAM83A and FAM83D, is needed for binding to 
          EGFR and stimulation of EGFR signaling. Through a mechanism that has 
          not been elucidated, FAM83B stimulates basal and EGF-induced EGFR 
          trans-autophosphorylation but dissociates from autophosphorylated EGFR
          (Cipriano et al. 2014).
  - id: Reactome:R-NUL-1248744
    title: Shc1 binds phosphorylated ERBB2:EGFR heterodimers
    findings:
      - statement: Shc1 binds phosphorylated ERBB2:EGFR heterodimers.
        supporting_text: Shc1 binds phosphorylated ERBB2:EGFR heterodimers in 
          engineered mouse 32D cells (Pinkas-Kramarski et al. 1996).
  - id: Reactome:R-NUL-1251923
    title: Plcg1 binds P-ERBB2:P-EGFR
    findings:
      - statement: Mouse PLCgamma1 is phosphorylated by human recombinant ERBB2 
          expressed in mouse fibroblasts.
        supporting_text: Mouse phospholipase C gamma 1 is phosphorylated by 
          human recombinant ERBB2 exogenously expressed in mouse fibroblasts.
  - id: Reactome:R-NUL-1251929
    title: Plcg1 phosphorylation by P-ERBB2:P-EGFR
    findings:
      - statement: Mouse PLCgamma1 is phosphorylated by human recombinant ERBB2 
          expressed in mouse fibroblasts.
        supporting_text: Mouse phospholipase C gamma 1 is phosphorylated by 
          human recombinant ERBB2 exogenously expressed in mouse fibroblasts.
  - id: file:human/EGFR/EGFR-deep-research-falcon.md
    title: Deep research report on EGFR
    findings: []
core_functions:
  - description: epidermal growth factor binding and signal transduction through
      transmembrane receptor protein tyrosine kinase activity
    supported_by:
      - reference_id: PMID:12297050
        supporting_text: Crystal structure of the complex of human epidermal 
          growth factor and receptor extracellular domains
      - reference_id: PMID:12297049
        supporting_text: Crystal structure of a truncated epidermal growth 
          factor receptor extracellular domain bound to transforming growth 
          factor alpha
      - reference_id: PMID:18042729
        supporting_text: Epidermal growth factor receptor juxtamembrane region 
          regulates allosteric tyrosine kinase activation
      - reference_id: PMID:19563760
        supporting_text: Mechanism for activation of the EGF receptor catalytic 
          domain by the juxtamembrane segment
    molecular_function:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    directly_involved_in:
      - id: GO:0007173
        label: epidermal growth factor receptor signaling pathway
      - id: GO:0043410
        label: positive regulation of MAPK cascade
      - id: GO:0000165
        label: MAPK cascade
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0016020
        label: membrane
    substrates:
      - id: GO:0048408
        label: epidermal growth factor binding
  - description: autophosphorylation activity mediating receptor dimerization 
      and downstream signaling activation
    supported_by:
      - reference_id: PMID:18042729
        supporting_text: Epidermal growth factor receptor juxtamembrane region 
          regulates allosteric tyrosine kinase activation
      - reference_id: PMID:19563760
        supporting_text: Mechanism for activation of the EGF receptor catalytic 
          domain by the juxtamembrane segment
    molecular_function:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    directly_involved_in:
      - id: GO:0018108
        label: peptidyl-tyrosine phosphorylation
      - id: GO:0046777
        label: protein autophosphorylation
    locations:
      - id: GO:0005886
        label: plasma membrane
status: COMPLETE

EGFR

Gene Description

Existing Annotations Review

Core Functions

epidermal growth factor binding and signal transduction through transmembrane receptor protein tyrosine kinase activity

autophosphorylation activity mediating receptor dimerization and downstream signaling activation

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

Deep Research Perplexity

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

The Epidermal Growth Factor Receptor: Structure, Function, and Signal Transduction Mechanisms

Molecular Architecture and Structural Organization

Overall Receptor Structure

The Extracellular Ligand-Binding Domain

The Transmembrane Domain and Juxtamembrane Region

Mechanism of Ligand-Induced Dimerization and Kinase Activation

The Two-Step Allosteric Model

The Asymmetric Kinase Domain Dimer

Substrate Specificity and Autophosphorylation Mechanisms

Identification of Autophosphorylation Sites

The Kinase Domain Active Site and Catalytic Mechanism

Substrate Specificity for Downstream Signaling Proteins

Subcellular Localization and Signal Compartmentalization

Plasma Membrane Signaling

Endosomal Trafficking and Signal Attenuation

Nuclear Translocation of EGFR

Signal Transduction Pathways Downstream of EGFR Activation

The MAPK/ERK Cascade

The PI3K/AKT/mTOR Pathway

The PLCγ Pathway and Calcium Signaling

STAT Pathway Activation

Regulation of EGFR Signaling

Negative Feedback Regulation by ERK

The Role of Protein Tyrosine Phosphatase SHP2

Cbl-Mediated Ubiquitination and Receptor Degradation

Biological Functions of EGFR

Cell Proliferation and Cell Cycle Progression

Cell Migration and Wound Healing

Embryonic Development and Placentation

Immune Function and Antimicrobial Defense

Fibrosis and Tissue Remodeling

EGFR Mutations and Oncogenic Activation

Oncogenic EGFR Mutations in Cancer