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

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

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

"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."

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

"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."

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

"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."

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

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

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

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

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

"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."

"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."

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

"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"

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

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

"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."

"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."

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

"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."

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

"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."

"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."

"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."

"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"

"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."

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

"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."

"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."

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

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

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

"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."

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

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

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

"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."

"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."

"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."

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

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

"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."

"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."

"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."

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

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

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

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

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

"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."

"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."

"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."

"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."

"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."

"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."

"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."

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

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

"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"

"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)."

"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."

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

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

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

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

"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."

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

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

"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."

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

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

"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."

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

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

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

"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."

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

"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."

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

"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."

"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."

"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."

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

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

"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."

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

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

"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."

"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."

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

"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."

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

"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."

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

"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."

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

"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."

"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)."

"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."

"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."

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

"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."

"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."

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

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

"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."

"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."

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

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

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

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

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

"GRB2 binds to phosphorylated tyrosine residues Y1068 and Y1086"

"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."

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

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

"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)."

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

"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."

"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."

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

"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."

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

"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."

"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."

"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."

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

"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."

"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."

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

"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)."

"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)."

"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)."

"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)."

"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."

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

"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."

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

"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."

"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."

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

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

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

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

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

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

"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."

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

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

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

"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."

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

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

"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."

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

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

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

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

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

"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."

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

"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."

"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."

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

"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."

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

"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."

"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."

"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."

"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)."

"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."

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

"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)."

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

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

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

"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)."

"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)."

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

"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)."

"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)."

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

"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."

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

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

"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."

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

"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)."

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

"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)."

"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)."

"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)."

"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."

"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."

"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."

"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)."

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

"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)."

"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)."

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

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

"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)."

"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)."

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

"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)."

"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)."

"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."

"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."

"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)."

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

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

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

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

"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)."

"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)."

"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)."

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

"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)."

"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)."

"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)."

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

"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)."

"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)."

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

"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)."

"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)."

"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)."

"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)."

"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)."

"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."

"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)."

"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."

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

"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)."

"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."

"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."

"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."

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

"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)."

"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)."

"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."

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

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

"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:"

"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:"

"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:"

"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:"

"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:"

"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:"

"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:"

"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:"

"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:"

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

"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."

"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."

"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."

"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."

"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."

"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."

"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."

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

"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."

"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."

"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."

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

"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."

"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:"

"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."

"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."

"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."

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

"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."

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

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

"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."

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

"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)."

"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)."

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

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

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