Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007219 Notch signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: NOTCH1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), NOTCH1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex. Reason: This is the core function of NOTCH1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x). Supporting Evidence: PMID:10713164 Notch proteins are transmembrane receptors that mediate intercell communication and direct individual cell fate decisions. The activated intracellular form of Notch, NotchIC, translocates to the nucleus, where it targets the DNA binding protein CBF1. file:human/NOTCH1/NOTCH1-deep-research-cyberian.md model: deep-research
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: NOTCH1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells. Reason: Plasma membrane localization is essential for NOTCH1 receptor function. The mature NOTCH1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization. Supporting Evidence: PMID:10713164 Notch proteins are transmembrane receptors that mediate intercell communication
GO:0007411 axon guidance	IBA GO_REF:0000033	REMOVE	Summary: The IBA annotation derives from PTHR45836 family which includes both NOTCH receptors and SLIT proteins. Axon guidance is a primary function of SLIT proteins, not NOTCH1. Reason: This annotation likely results from family-level inference that inappropriately transfers SLIT protein functions to NOTCH1. While NOTCH signaling has roles in neurogenesis, axon guidance is not a characterized function of NOTCH1. SLIT1-3 proteins (also in PTHR45836) are the canonical axon guidance molecules.
GO:0009986 cell surface	IBA GO_REF:0000033	ACCEPT	Summary: NOTCH1 is expressed at the cell surface where it functions as a receptor for trans-acting ligands on neighboring cells. Reason: Cell surface localization is essential for NOTCH1 receptor function. The extracellular domain (N(EC)) binds ligands at the cell surface, triggering the proteolytic cascade. Supporting Evidence: PMID:10713164 Notch proteins are transmembrane receptors that mediate intercell communication
GO:0043235 receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: NOTCH1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface. Reason: NOTCH1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies.
GO:0000139 Golgi membrane	IEA GO_REF:0000117	ACCEPT	Summary: NOTCH1 undergoes S1 cleavage by furin in the trans-Golgi network during maturation, converting the precursor into the functional heterodimer. Reason: Golgi membrane localization is part of the NOTCH1 biosynthetic pathway. UniProt states the precursor is proteolytically cleaved by furin-like convertase in the trans-Golgi network before reaching the plasma membrane.
GO:0001525 angiogenesis	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: NOTCH1 plays a key role in angiogenesis by negatively regulating endothelial cell proliferation and migration. DLL4-NOTCH1 signaling controls tip/stalk cell selection during vascular development. Reason: While angiogenesis is a well-documented biological context for NOTCH1 function, it represents a tissue-specific outcome rather than the core molecular function. UniProt confirms NOTCH1 is involved in angiogenesis, negatively regulating endothelial cell proliferation.
GO:0005509 calcium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: NOTCH1 contains multiple EGF-like domains that bind calcium ions, which are essential for proper domain folding and ligand binding. Reason: Calcium binding is a core molecular function of NOTCH1. The EGF-like calcium-binding domains (IPR001881) are essential for NOTCH1 structure and function. UniProt lists calcium ion binding in the domain annotations.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: The NOTCH1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription. Reason: Nuclear localization of NICD is essential for NOTCH1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000117	ACCEPT	Summary: NOTCH1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi. Reason: ER membrane localization is part of the NOTCH1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Mature NOTCH1 heterodimer resides at the plasma membrane where it functions as a receptor. Reason: Plasma membrane is the primary site of NOTCH1 receptor function. Duplicate of IBA annotation - both are correct.
GO:0006355 regulation of DNA-templated transcription	IEA GO_REF:0000002	ACCEPT	Summary: NICD forms a transcriptional activation complex with RBPJ and MAML to regulate target gene expression. Reason: Transcriptional regulation is a core downstream function of NOTCH1 signaling. The NICD-RBPJ-MAML complex directly activates transcription of target genes like HES and HEY family members.
GO:0007219 Notch signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: NOTCH1 is the founding member and primary receptor of the Notch signaling pathway. Reason: Duplicate of IBA annotation - this is the core function of NOTCH1. Both evidence codes correctly annotate this term.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: NOTCH1 is a type I transmembrane protein that localizes to various cellular membranes during its lifecycle. Reason: Generic membrane annotation is correct but less informative than more specific terms (plasma membrane, Golgi membrane, ER membrane) which are also annotated.
GO:0030154 cell differentiation	IEA GO_REF:0000120	ACCEPT	Summary: NOTCH1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts. Reason: Cell differentiation regulation is a core biological role of NOTCH1 signaling. UniProt states NOTCH1 affects implementation of differentiation, proliferation and apoptotic programs.
GO:0031902 late endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: Non-activated NOTCH1 receptor is targeted for lysosomal degradation via the endosomal pathway. Reason: UniProt explicitly states late endosome membrane localization and notes that non-activated receptor is targeted for lysosomal degradation via the endosomal pathway.
GO:0038023 signaling receptor activity	IEA GO_REF:0000002	ACCEPT	Summary: NOTCH1 functions as a signaling receptor that transduces cell-cell contact signals into transcriptional responses. Reason: Signaling receptor activity is a core molecular function of NOTCH1. This is the primary role of the protein.
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000117	ACCEPT	Summary: NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors. Reason: NOTCH1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription.
GO:0046579 positive regulation of Ras protein signal transduction	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: NOTCH1 has been reported to crosstalk with Ras/MAPK signaling in certain cellular contexts. Reason: This represents crosstalk with other signaling pathways rather than the core NOTCH1 function. The canonical Notch pathway does not involve direct Ras activation, though downstream effects can influence Ras signaling.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: NOTCH1 binds calcium ions through its EGF-like domains. Reason: Metal ion binding (specifically calcium) is correct but less specific than GO:0005509 calcium ion binding which is also annotated.
GO:0050793 regulation of developmental process	IEA GO_REF:0000002	ACCEPT	Summary: NOTCH1 is a key regulator of developmental processes including cell fate determination. Reason: Developmental regulation is a well-established function of NOTCH1. UniProt notes roles in postimplantation development, mesoderm development, somite formation, and neurogenesis.
GO:0051152 positive regulation of smooth muscle cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: NOTCH1 promotes vascular smooth muscle cell differentiation and is required for arterial smooth muscle development. Reason: Smooth muscle differentiation is a tissue-specific developmental outcome of NOTCH1 signaling rather than a core function. It represents one of many differentiation contexts where NOTCH1 plays a role.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: NOTCH1 can promote ERK1/2 signaling in certain cellular contexts, representing pathway crosstalk. Reason: ERK cascade regulation is not part of canonical Notch signaling but may occur through indirect mechanisms or crosstalk in specific contexts.
GO:0071228 cellular response to tumor cell	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: NOTCH1 has been implicated in tumor microenvironment responses. Reason: This is a specialized context-dependent role of NOTCH1 in cancer biology rather than a core function of the protein.
GO:0005515 protein binding	IPI PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin ...	REMOVE	Summary: NOTCH1 NICD interacts with SNW1/SKIP, which facilitates NOTCH1 transcriptional function by competing with SMRT corepressor. Reason: Generic protein binding is uninformative. The specific interaction with SNW1/SKIP should be captured by more specific MF terms or documented via protein-protein interaction databases. NOTCH1 has many specific binding partners including RBPJ, MAML1/2/3, ligands, etc. Supporting Evidence: PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
GO:0005515 protein binding	IPI PMID:12370315 Identification of a family of mastermind-like transcriptiona...	REMOVE	Summary: Identifies NOTCH1 interaction with MAML2 and MAML3 transcriptional coactivators. Reason: Generic protein binding is uninformative. The specific MAML interactions are critical for transcriptional activation but should not be annotated with this overly broad term. Supporting Evidence: PMID:12370315 Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors.
GO:0005515 protein binding	IPI PMID:16319921 Notch1 augments NF-kappaB activity by facilitating its nucle...	REMOVE	Summary: NOTCH1 interaction with NF-kappaB to facilitate its nuclear retention. Reason: Generic protein binding is uninformative. This represents crosstalk with NF-kappaB signaling. Supporting Evidence: PMID:16319921 Notch1 augments NF-kappaB activity by facilitating its nuclear retention.
GO:0005515 protein binding	IPI PMID:16530044 Structural basis for cooperativity in recruitment of MAML co...	REMOVE	Summary: Structural basis for MAML coactivator recruitment to NOTCH transcription complexes - crystal structure of NICD-RBPJ-MAML1 complex. Reason: Generic protein binding is uninformative. The structural study documents the ternary transcription complex, which is better captured by specific complex annotations. Supporting Evidence: PMID:16530044 Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.
GO:0005515 protein binding	IPI PMID:17284587 Cooperative assembly of higher-order Notch complexes functio...	REMOVE	Summary: Studies cooperative assembly of higher-order Notch transcription complexes. Reason: Generic protein binding is uninformative. Documents transcription complex assembly dynamics. Supporting Evidence: PMID:17284587 Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription.
GO:0005515 protein binding	IPI PMID:17318174 Notch inhibits apoptosis by direct interference with XIAP ub...	REMOVE	Summary: NOTCH1 interaction with XIAP to inhibit apoptosis. Reason: Generic protein binding is uninformative. The XIAP interaction represents a non-canonical NOTCH1 function. Supporting Evidence: PMID:17318174 Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.
GO:0005515 protein binding	IPI PMID:17909182 Kaposi's sarcoma herpesvirus-encoded latency-associated nucl...	REMOVE	Summary: KSHV LANA stabilizes activated NOTCH by targeting FBXW7. Reason: Generic protein binding is uninformative. This is about viral protein interaction and NOTCH1 regulation. Supporting Evidence: PMID:17909182 Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.
GO:0005515 protein binding	IPI PMID:18427106 Notch signaling mediates hypoxia-induced tumor cell migratio...	REMOVE	Summary: NOTCH1 signaling in hypoxia-induced tumor cell migration. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:18427106 Notch signaling mediates hypoxia-induced tumor cell migration and invasion.
GO:0005515 protein binding	IPI PMID:18660822 A conserved face of the Jagged/Serrate DSL domain is involve...	REMOVE	Summary: Jagged/Serrate DSL domain interaction with NOTCH for trans-activation and cis-inhibition. Reason: Generic protein binding is uninformative. Ligand-receptor interaction is critical for NOTCH1 function but should be captured by receptor activity terms. Supporting Evidence: PMID:18660822 Jul 27. A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.
GO:0005515 protein binding	IPI PMID:19151708 The prolyl-isomerase Pin1 is a Notch1 target that enhances N...	REMOVE	Summary: Pin1 prolyl isomerase interaction enhances NOTCH1 activation. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:19151708 The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.
GO:0005515 protein binding	IPI PMID:19907488 Direct inhibition of the NOTCH transcription factor complex.	REMOVE	Summary: Direct inhibition of NOTCH transcription factor complex - stapled peptide SAHM1. Reason: Generic protein binding is uninformative. This is about therapeutic targeting. Supporting Evidence: PMID:19907488 Direct inhibition of the NOTCH transcription factor complex.
GO:0005515 protein binding	IPI PMID:20823234 Notch signaling contributes to proliferation and tumor forma...	REMOVE	Summary: NOTCH1 signaling in HTLV-1-associated adult T-cell leukemia. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:20823234 Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia.
GO:0005515 protein binding	IPI PMID:20972443 Structural and mechanistic insights into cooperative assembl...	REMOVE	Summary: Cooperative assembly of dimeric NOTCH transcription complexes. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:20972443 Oct 24. Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes.
GO:0005515 protein binding	IPI PMID:21475249 Ataxin-1 and Brother of ataxin-1 are components of the Notch...	REMOVE	Summary: Ataxin-1 and BOAT are components of NOTCH signaling pathway. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:21475249 Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway.
GO:0005515 protein binding	IPI PMID:22325781 Conformational locking upon cooperative assembly of notch tr...	REMOVE	Summary: Conformational locking upon cooperative assembly of NOTCH transcription complexes. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:22325781 Conformational locking upon cooperative assembly of notch transcription complexes.
GO:0005515 protein binding	IPI PMID:23022380 NOTCH1 nuclear interactome reveals key regulators of its tra...	REMOVE	Summary: NOTCH1 nuclear interactome studies. Reason: Generic protein binding is uninformative. High-throughput interactome data. Supporting Evidence: PMID:23022380 2012 Sep 27. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.
GO:0005515 protein binding	IPI PMID:23086448 The CD46-Jagged1 interaction is critical for human TH1 immun...	REMOVE	Summary: CD46-Jagged1 interaction in TH1 immunity. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:23086448 The CD46-Jagged1 interaction is critical for human TH1 immunity.
GO:0005515 protein binding	IPI PMID:25344755 Cyclin C is a haploinsufficient tumour suppressor.	REMOVE	Summary: Cyclin C as tumor suppressor - interactions with NOTCH1. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:25344755 Cyclin C is a haploinsufficient tumour suppressor.
GO:0005515 protein binding	IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ...	REMOVE	Summary: Proteomic study of transcription factor complexes. Reason: Generic protein binding is uninformative. High-throughput data. Supporting Evidence: PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
GO:0005515 protein binding	IPI PMID:25714926 Angiopoietin-like proteins stimulate HSPC development throug...	REMOVE	Summary: Angiopoietin-like proteins stimulate HSPC development through NOTCH receptor signaling. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:25714926 Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling.
GO:0005515 protein binding	IPI PMID:25895060 Notch is a direct negative regulator of the DNA-damage respo...	REMOVE	Summary: NOTCH as negative regulator of DNA-damage response. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:25895060 Apr 20. Notch is a direct negative regulator of the DNA-damage response.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	REMOVE	Summary: Human interactome in three quantitative dimensions - large-scale study. Reason: Generic protein binding is uninformative. High-throughput data. Supporting Evidence: PMID:26496610 Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
GO:0005515 protein binding	IPI PMID:27229929 Systematic interactome mapping of acute lymphoblastic leukem...	REMOVE	Summary: Systematic interactome mapping of ALL cancer gene products. Reason: Generic protein binding is uninformative. High-throughput data. Supporting Evidence: PMID:27229929 Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
GO:0005515 protein binding	IPI PMID:33189893 A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Inte...	REMOVE	Summary: PAK1-NOTCH1 axis in crypt homeostasis during intestinal inflammation. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:33189893 A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Dual proteome-scale networks showing cell-specific remodeling of interactome. Reason: Generic protein binding is uninformative. High-throughput data. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:38891776 Pin1 Downregulation Is Involved in Excess Retinoic Acid-Indu...	REMOVE	Summary: Pin1 downregulation in retinoic acid-induced neural tube closure failure. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:38891776 Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.
GO:0042802 identical protein binding	IPI PMID:16738328 Leukemia-associated mutations within the NOTCH1 heterodimeri...	ACCEPT	Summary: NOTCH1 can form homodimers through its heterodimerization domain. Mutations in this domain cause T-ALL. Reason: NOTCH1 homodimerization is documented and has functional significance. The study shows leukemia-associated mutations fall into distinct mechanistic classes affecting the HD domain. Supporting Evidence: PMID:16738328 Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes.
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms. Reason: While NOTCH1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
GO:0001554 luteolysis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH signaling has been implicated in ovarian function including corpus luteum regression. Reason: Luteolysis is a highly specialized reproductive process. NOTCH1 may play a role but this is tissue-specific rather than a core function.
GO:0001669 acrosomal vesicle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 may be present in acrosomal vesicles during spermatogenesis. Reason: This is a specialized spermatogenesis-related localization. NOTCH1 has roles in germ cell development but this is not a core localization.
GO:0001947 heart looping	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is required for proper cardiac morphogenesis including heart looping during development. Reason: Heart looping is a specific developmental process. NOTCH1 mutations cause congenital heart defects (AOVD1), confirming cardiac development roles, but this is tissue-specific.
GO:0002052 positive regulation of neuroblast proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 promotes neural progenitor/stem cell proliferation and maintains the undifferentiated state. Reason: NOTCH1 maintains neural stem cells and regulates neurogenesis, but this is a tissue-specific developmental function.
GO:0003157 endocardium development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is essential for endocardium development and endocardial cell differentiation. Reason: Cardiac development is a well-established NOTCH1 function based on human disease genetics (AOVD1, AOS5), but represents tissue-specific developmental role.
GO:0003160 endocardium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates endocardium morphogenesis during heart development. Reason: Related to cardiac development - tissue-specific developmental function.
GO:0003162 atrioventricular node development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in development of cardiac conduction system components. Reason: Specialized cardiac developmental process.
GO:0003169 coronary vein morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates coronary vessel development including vein morphogenesis. Reason: Cardiac/vascular development - tissue-specific developmental function.
GO:0003180 aortic valve morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is essential for aortic valve development. NOTCH1 mutations cause aortic valve disease (AOVD1). Reason: Strongly supported by human genetics - NOTCH1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
GO:0003181 atrioventricular valve morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates AV valve development through endocardial cushion formation. Reason: Cardiac valve development - tissue-specific developmental function supported by mouse studies.
GO:0003182 coronary sinus valve morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates coronary sinus valve development. Reason: Highly specialized cardiac structure - tissue-specific developmental function.
GO:0003184 pulmonary valve morphogenesis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: NOTCH1 regulates pulmonary valve development. Human NOTCH1 mutations cause pulmonary valve abnormalities. Reason: Cardiac valve development - tissue-specific developmental function supported by human genetics.
GO:0003198 epithelial to mesenchymal transition involved in endocardial cushion formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 promotes EMT during endocardial cushion formation, essential for valve development. Reason: EMT in heart development is well-documented for NOTCH1. Tissue-specific developmental function.
GO:0003203 endocardial cushion morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is required for endocardial cushion development which gives rise to heart valves. Reason: Cardiac development - tissue-specific function.
GO:0003207 cardiac chamber formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac chamber formation during heart development. Reason: Cardiac development - tissue-specific function.
GO:0003208 cardiac ventricle morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates ventricular development. Reason: Cardiac development - tissue-specific function.
GO:0003209 cardiac atrium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates atrial development. Reason: Cardiac development - tissue-specific function.
GO:0003213 cardiac right atrium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates right atrium morphogenesis. Reason: Cardiac development - tissue-specific function.
GO:0003214 cardiac left ventricle morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates left ventricle morphogenesis. Relevant to hypoplastic left heart syndrome. Reason: Cardiac development - tissue-specific function.
GO:0003222 ventricular trabecula myocardium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates trabeculation of the ventricular myocardium. Reason: Cardiac development - tissue-specific function.
GO:0003241 growth involved in heart morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates growth during cardiac morphogenesis. Reason: Cardiac development - tissue-specific function.
GO:0003252 obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 negatively regulates cell proliferation during valve morphogenesis. Reason: Cardiac valve development - tissue-specific function.
GO:0003264 regulation of cardioblast proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cardioblast proliferation during heart development. Reason: Cardiac development - tissue-specific function.
GO:0003273 cell migration involved in endocardial cushion formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cell migration during endocardial cushion formation. Reason: Cardiac development - tissue-specific function.
GO:0003332 negative regulation of extracellular matrix constituent secretion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 negatively regulates ECM secretion in certain contexts. Reason: Context-dependent regulatory function.
GO:0003344 pericardium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates pericardium development. Reason: Cardiac development - tissue-specific function.
GO:0003682 chromatin binding	IEA GO_REF:0000107	ACCEPT	Summary: NICD associates with chromatin as part of the transcription activation complex with RBPJ. Reason: NICD binds to chromatin at target gene promoters as part of the RBPJ-MAML transcription complex. This is part of the core transcriptional mechanism.
GO:0003713 transcription coactivator activity	IEA GO_REF:0000107	ACCEPT	Summary: NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator. Reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ.
GO:0004857 enzyme inhibitor activity	IEA GO_REF:0000107	UNDECIDED	Summary: NOTCH1 has been reported to inhibit certain enzymes in specific contexts. Reason: Enzyme inhibitor activity is not a well-characterized function of NOTCH1. The annotation source and mechanism are unclear.
GO:0004888 transmembrane signaling receptor activity	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses. Reason: This is the core molecular function of NOTCH1. It is a type I transmembrane receptor that signals via proteolytic processing.
GO:0005112 Notch binding	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 can bind other NOTCH family members, potentially in cis-inhibition or heterodimer formation. Reason: NOTCH receptors can interact with each other. The identical protein binding annotation (GO:0042802) already captures homodimerization.
GO:0005737 cytoplasm	IEA GO_REF:0000107	ACCEPT	Summary: Cytoplasm Reason: NICD transits through cytoplasm.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000107	ACCEPT	Summary: Endoplasmic reticulum Reason: NOTCH1 synthesis and maturation.
GO:0005912 adherens junction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to adherens junction. Reason: Transferred annotation - context-specific function.
GO:0006606 protein import into nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to protein import into nucleus. Reason: Transferred annotation - context-specific function.
GO:0007221 positive regulation of transcription of Notch receptor target	IEA GO_REF:0000107	ACCEPT	Summary: Positive regulation of transcription of Notch receptor target Reason: Core downstream function of NICD.
GO:0007283 spermatogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to spermatogenesis. Reason: Transferred annotation - context-specific function.
GO:0009986 cell surface	IEA GO_REF:0000107	ACCEPT	Summary: Cell surface Reason: NOTCH1 receptor functions at cell surface.
GO:0010467 gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to gene expression. Reason: Transferred annotation - context-specific function.
GO:0010614 negative regulation of cardiac muscle hypertrophy	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates negative regulation of cardiac muscle hypertrophy. Reason: Cardiac development - tissue-specific developmental function.
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of gene expression. Reason: Context-dependent regulatory function.
GO:0010667 negative regulation of cardiac muscle cell apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates negative regulation of cardiac muscle cell apoptotic process. Reason: Cardiac development - tissue-specific developmental function.
GO:0010718 positive regulation of epithelial to mesenchymal transition	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 promotes positive regulation of epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function.
GO:0010832 negative regulation of myotube differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of myotube differentiation. Reason: Context-dependent regulatory function.
GO:0014031 mesenchymal cell development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 promotes mesenchymal cell development. Reason: EMT regulation - context-dependent function.
GO:0016324 apical plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to apical plasma membrane. Reason: Transferred annotation - context-specific function.
GO:0019899 enzyme binding	IEA GO_REF:0000107	ACCEPT	Summary: Enzyme binding Reason: NOTCH1 binds enzymes involved in its processing.
GO:0021515 cell differentiation in spinal cord	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in cell differentiation in spinal cord. Reason: Neural development - tissue-specific function.
GO:0030163 protein catabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to protein catabolic process. Reason: Transferred annotation - context-specific function.
GO:0030279 negative regulation of ossification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of ossification. Reason: Context-dependent regulatory function.
GO:0030334 regulation of cell migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to regulation of cell migration. Reason: Transferred annotation - context-specific function.
GO:0030335 positive regulation of cell migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of cell migration. Reason: Context-dependent regulatory function.
GO:0030513 positive regulation of BMP signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of bmp signaling pathway. Reason: Context-dependent regulatory function.
GO:0030514 negative regulation of BMP signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of bmp signaling pathway. Reason: Context-dependent regulatory function.
GO:0031100 animal organ regeneration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to animal organ regeneration. Reason: Transferred annotation - context-specific function.
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to cytoplasmic vesicle. Reason: Transferred annotation - context-specific function.
GO:0031490 chromatin DNA binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to chromatin DNA binding. Reason: Transferred annotation - context-specific function.
GO:0032495 response to muramyl dipeptide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in response to muramyl dipeptide. Reason: Context-dependent regulatory function.
GO:0032496 response to lipopolysaccharide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in response to lipopolysaccharide. Reason: Context-dependent regulatory function.
GO:0032966 negative regulation of collagen biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of collagen biosynthetic process. Reason: Context-dependent regulatory function.
GO:0042127 regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to regulation of cell population proliferation. Reason: Transferred annotation - context-specific function.
GO:0042246 tissue regeneration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to tissue regeneration. Reason: Transferred annotation - context-specific function.
GO:0045070 positive regulation of viral genome replication	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of viral genome replication. Reason: Context-dependent regulatory function.
GO:0045603 positive regulation of endothelial cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates positive regulation of endothelial cell differentiation. Reason: Vascular development - tissue-specific function.
GO:0045665 negative regulation of neuron differentiation	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision. Reason: Core developmental function - NOTCH1-mediated lateral inhibition is the canonical mechanism controlling neuron-glia fate choice. PMID:12052917, PMID:11182080.
GO:0045668 negative regulation of osteoblast differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of osteoblast differentiation. Reason: Context-dependent regulatory function.
GO:0045687 positive regulation of glial cell differentiation	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 promotes glial cell differentiation via lateral inhibition, instructing multipotent progenitors toward glial fate. Reason: Core developmental function - NOTCH1 instructs neural progenitors toward glial fate as part of the neuron-glia binary decision. PMID:11182080, PMID:23307615.
GO:0045892 negative regulation of DNA-templated transcription	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of dna-templated transcription. Reason: Context-dependent regulatory function.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function.
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of receptor signaling pathway via jak-stat. Reason: Context-dependent regulatory function.
GO:0048708 astrocyte differentiation	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 promotes astrocyte differentiation as part of gliogenesis, with Sox9 acting as critical downstream mediator. Reason: Core gliogenic function - NOTCH1 signaling promotes astrocyte fate via HES/HEY factors. PMID:23307615, PMID:11182080.
GO:0048709 oligodendrocyte differentiation	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 regulates oligodendrocyte differentiation (inhibitory role - promotes astrocyte over oligodendrocyte fate). Reason: Core gliogenic function - NOTCH1 inhibits oligodendrocyte fate, promoting astrocyte fate within the glial lineage. PMID:11182080.
GO:0048711 positive regulation of astrocyte differentiation	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 positively regulates astrocyte differentiation via HES/HEY transcriptional targets. Reason: Core gliogenic function - canonical Notch target genes promote astrocyte gene expression. PMID:11182080, PMID:23307615.
GO:0048715 negative regulation of oligodendrocyte differentiation	IEA GO_REF:0000107	ACCEPT	Summary: NOTCH1 negatively regulates oligodendrocyte differentiation, favoring astrocyte fate. Reason: Core gliogenic function - NOTCH1 promotes astrocyte over oligodendrocyte fate in glial progenitors. PMID:11182080.
GO:0048873 homeostasis of number of cells within a tissue	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to homeostasis of number of cells within a tissue. Reason: Transferred annotation - context-specific function.
GO:0050768 negative regulation of neurogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of neurogenesis. Reason: Neural development - tissue-specific function.
GO:0055008 cardiac muscle tissue morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac muscle tissue morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0060038 cardiac muscle cell proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac muscle cell proliferation. Reason: Cardiac development - tissue-specific developmental function.
GO:0060045 positive regulation of cardiac muscle cell proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates positive regulation of cardiac muscle cell proliferation. Reason: Cardiac development - tissue-specific developmental function.
GO:0060253 negative regulation of glial cell proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of glial cell proliferation. Reason: Context-dependent regulatory function.
GO:0060317 cardiac epithelial to mesenchymal transition	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac epithelial to mesenchymal transition. Reason: Cardiac development - tissue-specific developmental function.
GO:0060379 cardiac muscle cell myoblast differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac muscle cell myoblast differentiation. Reason: Cardiac development - tissue-specific developmental function.
GO:0060411 cardiac septum morphogenesis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac septum morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0060412 ventricular septum morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to ventricular septum morphogenesis. Reason: Transferred annotation - context-specific function.
GO:0060842 arterial endothelial cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates arterial endothelial cell differentiation. Reason: Vascular development - tissue-specific function.
GO:0060843 venous endothelial cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates venous endothelial cell differentiation. Reason: Vascular development - tissue-specific function.
GO:0060948 cardiac vascular smooth muscle cell development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac vascular smooth muscle cell development. Reason: Cardiac development - tissue-specific developmental function.
GO:0060956 endocardial cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to endocardial cell differentiation. Reason: Transferred annotation - context-specific function.
GO:0060979 vasculogenesis involved in coronary vascular morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates vasculogenesis involved in coronary vascular morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0060982 coronary artery morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates coronary artery morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0061344 regulation of cell adhesion involved in heart morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates regulation of cell adhesion involved in heart morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0061384 heart trabecula morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates heart trabecula morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0062043 positive regulation of cardiac epithelial to mesenchymal transition	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates positive regulation of cardiac epithelial to mesenchymal transition. Reason: Cardiac development - tissue-specific developmental function.
GO:0070168 negative regulation of biomineral tissue development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of biomineral tissue development. Reason: Context-dependent regulatory function.
GO:0070986 left/right axis specification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to left/right axis specification. Reason: Transferred annotation - context-specific function.
GO:0071456 cellular response to hypoxia	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in cellular response to hypoxia. Reason: Context-dependent regulatory function.
GO:0071944 cell periphery	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to cell periphery. Reason: Transferred annotation - context-specific function.
GO:0072017 distal tubule development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to distal tubule development. Reason: Transferred annotation - context-specific function.
GO:0072044 collecting duct development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to collecting duct development. Reason: Transferred annotation - context-specific function.
GO:0072144 glomerular mesangial cell development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to glomerular mesangial cell development. Reason: Transferred annotation - context-specific function.
GO:0072538 T-helper 17 type immune response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 regulates t-helper 17 type immune response. Reason: T cell/immune development - tissue-specific function.
GO:0097400 interleukin-17-mediated signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to interleukin-17-mediated signaling pathway. Reason: Transferred annotation - context-specific function.
GO:0098685 Schaffer collateral - CA1 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to Schaffer collateral - CA1 synapse. Reason: Transferred annotation - context-specific function.
GO:0098839 postsynaptic density membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to postsynaptic density membrane. Reason: Transferred annotation - context-specific function.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to glutamatergic synapse. Reason: Transferred annotation - context-specific function.
GO:0099565 chemical synaptic transmission, postsynaptic	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to chemical synaptic transmission, postsynaptic. Reason: Transferred annotation - context-specific function.
GO:0120163 negative regulation of cold-induced thermogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of cold-induced thermogenesis. Reason: Context-dependent regulatory function.
GO:0140537 transcription regulator activator activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to transcription regulator activator activity. Reason: Transferred annotation - context-specific function.
GO:1901201 regulation of extracellular matrix assembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 annotation to regulation of extracellular matrix assembly. Reason: Transferred annotation - context-specific function.
GO:1902339 positive regulation of apoptotic process involved in morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of apoptotic process involved in morphogenesis. Reason: Context-dependent regulatory function.
GO:2000974 negative regulation of pro-B cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of pro-b cell differentiation. Reason: Context-dependent regulatory function.
GO:0005515 protein binding	IPI PMID:38016980 TM2D3, a mammalian homologue of Drosophila neurogenic gene p...	REMOVE	Summary: Generic protein binding annotation. Reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms. Supporting Evidence: PMID:38016980 TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2220978	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005634 nucleus	IDA PMID:32601208 Pharmacological disruption of the Notch transcription factor...	ACCEPT	Summary: Nucleus Reason: NICD translocates to nucleus. Supporting Evidence: PMID:32601208 Pharmacological disruption of the Notch transcription factor complex.
GO:0007219 Notch signaling pathway	IDA PMID:32601208 Pharmacological disruption of the Notch transcription factor...	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor. Supporting Evidence: PMID:32601208 Pharmacological disruption of the Notch transcription factor complex.
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:32601208 Pharmacological disruption of the Notch transcription factor...	ACCEPT	Summary: Positive regulation of DNA-templated transcription Reason: NICD activates transcription. Supporting Evidence: PMID:32601208 Pharmacological disruption of the Notch transcription factor complex.
GO:0003713 transcription coactivator activity	IDA PMID:18239137 Hairy-related transcription factors inhibit Notch-induced sm...	ACCEPT	Summary: Transcription coactivator activity Reason: NICD functions as transcriptional coactivator with RBPJ-MAML. Supporting Evidence: PMID:18239137 2008 Jan 31. Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:18239137 Hairy-related transcription factors inhibit Notch-induced sm...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:18239137 2008 Jan 31. Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.
GO:0051152 positive regulation of smooth muscle cell differentiation	IDA PMID:18239137 Hairy-related transcription factors inhibit Notch-induced sm...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of smooth muscle cell differentiation. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:18239137 2008 Jan 31. Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.
GO:0007219 Notch signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor.
GO:0007219 Notch signaling pathway	IMP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor. Supporting Evidence: PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.
GO:0007219 Notch signaling pathway	IMP PMID:17662764 Novel NOTCH1 mutations in patients with bicuspid aortic valv...	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor. Supporting Evidence: PMID:17662764 Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2660815	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2660816	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2660819	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2660822	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2666278	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2220957	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2220964	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2220967	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2220971	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2220982	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-2769015	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4396392	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4396393	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4396401	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4396402	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005829 cytosol	TAS Reactome:R-HSA-2220988	ACCEPT	Summary: Cytosol Reason: NICD released to cytosol before nuclear import.
GO:0005829 cytosol	TAS Reactome:R-HSA-2769015	ACCEPT	Summary: Cytosol Reason: NICD released to cytosol before nuclear import.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2220944	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2220976	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2220988	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2768993	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2768999	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2769000	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2769007	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2769008	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2900743	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2900747	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2900748	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2900756	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2900765	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0003713 transcription coactivator activity	IDA PMID:23839946 Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta...	ACCEPT	Summary: Transcription coactivator activity Reason: NICD functions as transcriptional coactivator with RBPJ-MAML. Supporting Evidence: PMID:23839946 Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
GO:0004888 transmembrane signaling receptor activity	IDA PMID:23839946 Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta...	ACCEPT	Summary: Transmembrane signaling receptor activity Reason: Core molecular function of NOTCH1. Supporting Evidence: PMID:23839946 Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
GO:0005515 protein binding	IPI PMID:23839946 Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta...	REMOVE	Summary: Generic protein binding annotation. Reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms. Supporting Evidence: PMID:23839946 Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
GO:0007219 Notch signaling pathway	IDA PMID:23839946 Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta...	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor. Supporting Evidence: PMID:23839946 Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:23839946 Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:23839946 Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-9796071	ACCEPT	Summary: Endosome membrane Reason: NOTCH1 trafficking.
GO:0050768 negative regulation of neurogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of neurogenesis. Reason: Neural development - tissue-specific function.
GO:0071456 cellular response to hypoxia	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in cellular response to hypoxia. Reason: Context-dependent regulatory function.
GO:0006357 regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to regulation of transcription by RNA polymerase II. Reason: Transferred annotation - context-specific function.
GO:0060379 cardiac muscle cell myoblast differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac muscle cell myoblast differentiation. Reason: Cardiac development - tissue-specific developmental function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2220976	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2900743	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2900747	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2900748	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2900756	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2900765	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0007219 Notch signaling pathway	IDA PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung...	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor. Supporting Evidence: PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung cancer cells.
GO:0010629 negative regulation of gene expression	IDA PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of gene expression. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung cancer cells.
GO:0046579 positive regulation of Ras protein signal transduction	IDA PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of ras protein signal transduction. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung cancer cells.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IDA PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of erk1 and erk2 cascade. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung cancer cells.
GO:0071228 cellular response to tumor cell	IDA PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung...	KEEP AS NON CORE	Summary: NOTCH1 is involved in cellular response to tumor cell. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:11306509 Notch signaling induces cell cycle arrest in small cell lung cancer cells.
GO:0003713 transcription coactivator activity	ISS GO_REF:0000024	ACCEPT	Summary: Transcription coactivator activity Reason: NICD functions as transcriptional coactivator with RBPJ-MAML.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:17984306 Jagged1-mediated Notch activation induces epithelial-to-mese...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:17984306 Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
GO:0001837 epithelial to mesenchymal transition	IMP PMID:17984306 Jagged1-mediated Notch activation induces epithelial-to-mese...	KEEP AS NON CORE	Summary: NOTCH1 promotes epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function. Supporting Evidence: PMID:17984306 Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
GO:0060354 negative regulation of cell adhesion molecule production	IMP PMID:17984306 Jagged1-mediated Notch activation induces epithelial-to-mese...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of cell adhesion molecule production. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:17984306 Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
GO:2000048 negative regulation of cell-cell adhesion mediated by cadherin	IMP PMID:17984306 Jagged1-mediated Notch activation induces epithelial-to-mese...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of cell-cell adhesion mediated by cadherin. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:17984306 Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
GO:2000811 negative regulation of anoikis	IMP PMID:17984306 Jagged1-mediated Notch activation induces epithelial-to-mese...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of anoikis. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:17984306 Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
GO:0003180 aortic valve morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates aortic valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003184 pulmonary valve morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates pulmonary valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003203 endocardial cushion morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to endocardial cushion morphogenesis. Reason: Transferred annotation - context-specific function.
GO:0048873 homeostasis of number of cells within a tissue	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to homeostasis of number of cells within a tissue. Reason: Transferred annotation - context-specific function.
GO:0070168 negative regulation of biomineral tissue development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of biomineral tissue development. Reason: Context-dependent regulatory function.
GO:0120163 negative regulation of cold-induced thermogenesis	ISS PMID:25038826 Inhibition of Notch signaling promotes browning of white adi...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of cold-induced thermogenesis. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:25038826 Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.
GO:0062043 positive regulation of cardiac epithelial to mesenchymal transition	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates positive regulation of cardiac epithelial to mesenchymal transition. Reason: Cardiac development - tissue-specific developmental function.
GO:0003252 obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates negative regulation of cell proliferation involved in heart valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003332 negative regulation of extracellular matrix constituent secretion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of extracellular matrix constituent secretion. Reason: Context-dependent regulatory function.
GO:0010614 negative regulation of cardiac muscle hypertrophy	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates negative regulation of cardiac muscle hypertrophy. Reason: Cardiac development - tissue-specific developmental function.
GO:1902339 positive regulation of apoptotic process involved in morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of apoptotic process involved in morphogenesis. Reason: Context-dependent regulatory function.
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: Nucleus Reason: NICD translocates to nucleus.
GO:0010628 positive regulation of gene expression	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of gene expression. Reason: Context-dependent regulatory function.
GO:0003151 outflow tract morphogenesis	IMP PMID:18593716 NOTCH1 mutations in individuals with left ventricular outflo...	KEEP AS NON CORE	Summary: NOTCH1 annotation to outflow tract morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: PMID:18593716 Jun 30. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.
GO:0003180 aortic valve morphogenesis	TAS PMID:20951801 NOTCH1 missense alleles associated with left ventricular out...	KEEP AS NON CORE	Summary: NOTCH1 regulates aortic valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: PMID:20951801 NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT.
GO:0005886 plasma membrane	ISS GO_REF:0000024	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0003180 aortic valve morphogenesis	IMP PMID:18593716 NOTCH1 mutations in individuals with left ventricular outflo...	KEEP AS NON CORE	Summary: NOTCH1 regulates aortic valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: PMID:18593716 Jun 30. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.
GO:0005515 protein binding	IPI PMID:25038227 NACK is an integral component of the Notch transcriptional a...	REMOVE	Summary: Generic protein binding annotation. Reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms. Supporting Evidence: PMID:25038227 Epub 2014 Jul 18. NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.
GO:0005912 adherens junction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to adherens junction. Reason: Transferred annotation - context-specific function.
GO:0016324 apical plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to apical plasma membrane. Reason: Transferred annotation - context-specific function.
GO:0005515 protein binding	IPI PMID:11006133 Physical interaction of Delta1, Jagged1, and Jagged2 with No...	REMOVE	Summary: Generic protein binding annotation. Reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms. Supporting Evidence: PMID:11006133 Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors.
GO:0043235 receptor complex	IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm...	ACCEPT	Summary: Receptor complex Reason: NOTCH1 forms heterodimeric complex. Supporting Evidence: PMID:23382219 Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
GO:0060271 cilium assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to cilium assembly. Reason: Transferred annotation - context-specific function.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-1912412	ACCEPT	Summary: ER membrane Reason: NOTCH1 biosynthesis in ER.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-1912369	ACCEPT	Summary: Golgi membrane Reason: S1 furin cleavage occurs in Golgi.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-1912382	ACCEPT	Summary: Golgi membrane Reason: S1 furin cleavage occurs in Golgi.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-5096538	ACCEPT	Summary: Golgi membrane Reason: S1 furin cleavage occurs in Golgi.
GO:0005576 extracellular region	TAS Reactome:R-HSA-1912382	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-1980044	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-1980122	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2220944	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2691211	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2691214	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2691219	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2691226	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2730752	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2737728	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2768993	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2768999	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2769000	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2769007	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2769008	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0005576 extracellular region	TAS Reactome:R-NUL-2076711	KEEP AS NON CORE	Summary: NOTCH1 annotation to extracellular region. Reason: Transferred annotation - context-specific function.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-1912372	ACCEPT	Summary: Golgi membrane Reason: S1 furin cleavage occurs in Golgi.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-1912379	ACCEPT	Summary: Golgi membrane Reason: S1 furin cleavage occurs in Golgi.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-1912394	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-212356	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4396371	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4396379	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8878220	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8878237	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9017835	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9021451	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9762102	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-NUL-2064264	ACCEPT	Summary: Nucleoplasm Reason: NICD functions in nucleoplasm for transcription.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1912379	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1912382	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1980044	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1980122	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2660815	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2660816	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2660819	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2660822	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2666278	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2691211	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2691214	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2691219	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2691226	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2730752	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2737728	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0005886 plasma membrane	TAS Reactome:R-NUL-2076711	ACCEPT	Summary: Plasma membrane Reason: Primary site of NOTCH1 receptor function.
GO:0008285 negative regulation of cell population proliferation	IDA PMID:20616313 Integrin cytoplasmic domain-associated protein-1 attenuates ...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:20616313 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
GO:0035148 tube formation	IMP PMID:20616313 Integrin cytoplasmic domain-associated protein-1 attenuates ...	KEEP AS NON CORE	Summary: NOTCH1 annotation to tube formation. Reason: Transferred annotation - context-specific function. Supporting Evidence: PMID:20616313 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
GO:0035924 cellular response to vascular endothelial growth factor stimulus	IDA PMID:20616313 Integrin cytoplasmic domain-associated protein-1 attenuates ...	KEEP AS NON CORE	Summary: NOTCH1 regulates cellular response to vascular endothelial growth factor stimulus. Reason: Vascular development - tissue-specific function. Supporting Evidence: PMID:20616313 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:20616313 Integrin cytoplasmic domain-associated protein-1 attenuates ...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:20616313 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis	IDA PMID:20616313 Integrin cytoplasmic domain-associated protein-1 attenuates ...	KEEP AS NON CORE	Summary: NOTCH1 regulates negative regulation of cell migration involved in sprouting angiogenesis. Reason: Vascular development - tissue-specific function. Supporting Evidence: PMID:20616313 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
GO:2001027 negative regulation of endothelial cell chemotaxis	IDA PMID:20616313 Integrin cytoplasmic domain-associated protein-1 attenuates ...	KEEP AS NON CORE	Summary: NOTCH1 regulates negative regulation of endothelial cell chemotaxis. Reason: Vascular development - tissue-specific function. Supporting Evidence: PMID:20616313 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
GO:0003273 cell migration involved in endocardial cushion formation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in cell migration involved in endocardial cushion formation. Reason: Context-dependent regulatory function.
GO:0007368 determination of left/right symmetry	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to determination of left/right symmetry. Reason: Transferred annotation - context-specific function.
GO:0008284 positive regulation of cell population proliferation	IMP PMID:20613903 Follicular stimulating hormone enhances Notch 1 expression i...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:20613903 2010 Jun 30. Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells.
GO:0071372 cellular response to follicle-stimulating hormone stimulus	IDA PMID:20613903 Follicular stimulating hormone enhances Notch 1 expression i...	KEEP AS NON CORE	Summary: NOTCH1 is involved in cellular response to follicle-stimulating hormone stimulus. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:20613903 2010 Jun 30. Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells.
GO:0003184 pulmonary valve morphogenesis	IMP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: NOTCH1 regulates pulmonary valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.
GO:0003192 mitral valve formation	IMP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: NOTCH1 regulates mitral valve formation. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.
GO:0060412 ventricular septum morphogenesis	IMP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: NOTCH1 annotation to ventricular septum morphogenesis. Reason: Transferred annotation - context-specific function. Supporting Evidence: PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.
GO:0001837 epithelial to mesenchymal transition	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 promotes epithelial to mesenchymal transition. Reason: EMT regulation - context-dependent function.
GO:0003180 aortic valve morphogenesis	IMP PMID:17662764 Novel NOTCH1 mutations in patients with bicuspid aortic valv...	KEEP AS NON CORE	Summary: NOTCH1 regulates aortic valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: PMID:17662764 Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms.
GO:0003213 cardiac right atrium morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac right atrium morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003222 ventricular trabecula myocardium morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates ventricular trabecula myocardium morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003241 growth involved in heart morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates growth involved in heart morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0007221 positive regulation of transcription of Notch receptor target	ISS GO_REF:0000024	ACCEPT	Summary: Positive regulation of transcription of Notch receptor target Reason: Core downstream function of NICD.
GO:0014031 mesenchymal cell development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 promotes mesenchymal cell development. Reason: EMT regulation - context-dependent function.
GO:0030279 negative regulation of ossification	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of ossification. Reason: Context-dependent regulatory function.
GO:0045892 negative regulation of DNA-templated transcription	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of dna-templated transcription. Reason: Context-dependent regulatory function.
GO:0055008 cardiac muscle tissue morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac muscle tissue morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0060045 positive regulation of cardiac muscle cell proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates positive regulation of cardiac muscle cell proliferation. Reason: Cardiac development - tissue-specific developmental function.
GO:0060317 cardiac epithelial to mesenchymal transition	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac epithelial to mesenchymal transition. Reason: Cardiac development - tissue-specific developmental function.
GO:0060411 cardiac septum morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac septum morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0060842 arterial endothelial cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates arterial endothelial cell differentiation. Reason: Vascular development - tissue-specific function.
GO:0000122 negative regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function.
GO:0001947 heart looping	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates heart looping. Reason: Cardiac development - tissue-specific developmental function.
GO:0003160 endocardium morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates endocardium morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003169 coronary vein morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates coronary vein morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003181 atrioventricular valve morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates atrioventricular valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003198 epithelial to mesenchymal transition involved in endocardial cushion formation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 promotes epithelial to mesenchymal transition involved in endocardial cushion formation. Reason: EMT regulation - context-dependent function.
GO:0003207 cardiac chamber formation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac chamber formation. Reason: Cardiac development - tissue-specific developmental function.
GO:0003208 cardiac ventricle morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac ventricle morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003209 cardiac atrium morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac atrium morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003214 cardiac left ventricle morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac left ventricle morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0003344 pericardium morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates pericardium morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0030335 positive regulation of cell migration	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of cell migration. Reason: Context-dependent regulatory function.
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii. Reason: Context-dependent regulatory function.
GO:0060843 venous endothelial cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates venous endothelial cell differentiation. Reason: Vascular development - tissue-specific function.
GO:0060948 cardiac vascular smooth muscle cell development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates cardiac vascular smooth muscle cell development. Reason: Cardiac development - tissue-specific developmental function.
GO:0060956 endocardial cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to endocardial cell differentiation. Reason: Transferred annotation - context-specific function.
GO:0060979 vasculogenesis involved in coronary vascular morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates vasculogenesis involved in coronary vascular morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0060982 coronary artery morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates coronary artery morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:0061384 heart trabecula morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates heart trabecula morphogenesis. Reason: Cardiac development - tissue-specific developmental function.
GO:1901201 regulation of extracellular matrix assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 annotation to regulation of extracellular matrix assembly. Reason: Transferred annotation - context-specific function.
GO:0003157 endocardium development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 regulates endocardium development. Reason: Cardiac development - tissue-specific developmental function.
GO:0019899 enzyme binding	ISS GO_REF:0000024	ACCEPT	Summary: Enzyme binding Reason: NOTCH1 binds enzymes involved in its processing.
GO:0004857 enzyme inhibitor activity	ISS GO_REF:0000024	UNDECIDED	Summary: Enzyme inhibitor activity is not a well-characterized function of NOTCH1. Reason: The mechanism by which NOTCH1 might inhibit enzymes is unclear. This annotation requires further investigation.
GO:0043086 negative regulation of catalytic activity	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of catalytic activity. Reason: Context-dependent regulatory function.
GO:0002193 MAML1-RBP-Jkappa- ICN1 complex	IDA PMID:16510869 The Notch coactivator, MAML1, functions as a novel coactivat...	ACCEPT	Summary: MAML1-RBP-Jkappa-ICN1 complex Reason: Core transcription activation complex. Supporting Evidence: PMID:16510869 The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis.
GO:0097150 neuronal stem cell population maintenance	IEP PMID:19682396 Notch signaling is required for maintaining stem-cell featur...	KEEP AS NON CORE	Summary: NOTCH1 is involved in neuronal stem cell population maintenance. Reason: Neural development - tissue-specific function. Supporting Evidence: PMID:19682396 Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.
GO:0005515 protein binding	IPI PMID:16510869 The Notch coactivator, MAML1, functions as a novel coactivat...	REMOVE	Summary: Generic protein binding annotation. Reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms. Supporting Evidence: PMID:16510869 The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis.
GO:0007219 Notch signaling pathway	IMP PMID:19682396 Notch signaling is required for maintaining stem-cell featur...	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor. Supporting Evidence: PMID:19682396 Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.
GO:0008284 positive regulation of cell population proliferation	IDA PMID:17849174 Notch activation promotes cell proliferation and the formati...	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of cell population proliferation. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:17849174 Epub 2007 Sep 12. Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells.
GO:0030513 positive regulation of BMP signaling pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of bmp signaling pathway. Reason: Context-dependent regulatory function.
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in positive regulation of receptor signaling pathway via jak-stat. Reason: Context-dependent regulatory function.
GO:2000737 negative regulation of stem cell differentiation	IMP PMID:19682396 Notch signaling is required for maintaining stem-cell featur...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of stem cell differentiation. Reason: Stem cell regulation - context-dependent function. Supporting Evidence: PMID:19682396 Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.
GO:2000974 negative regulation of pro-B cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of pro-b cell differentiation. Reason: Context-dependent regulatory function.
GO:0030514 negative regulation of BMP signaling pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of bmp signaling pathway. Reason: Context-dependent regulatory function.
GO:0045668 negative regulation of osteoblast differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of osteoblast differentiation. Reason: Context-dependent regulatory function.
GO:0045893 positive regulation of DNA-templated transcription	ISS GO_REF:0000024	ACCEPT	Summary: Positive regulation of DNA-templated transcription Reason: NICD activates transcription.
GO:0048711 positive regulation of astrocyte differentiation	ISS GO_REF:0000024	ACCEPT	Summary: NOTCH1 positively regulates astrocyte differentiation - conserved function from mouse studies. Reason: Core gliogenic function - canonical Notch signaling promotes astrocyte fate.
GO:0048715 negative regulation of oligodendrocyte differentiation	ISS GO_REF:0000024	ACCEPT	Summary: NOTCH1 negatively regulates oligodendrocyte differentiation - conserved function from mouse studies. Reason: Core gliogenic function - NOTCH1 promotes astrocyte over oligodendrocyte fate.
GO:0060253 negative regulation of glial cell proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of glial cell proliferation. Reason: Context-dependent regulatory function.
GO:0007507 heart development	IMP PMID:21457232 Identification of de novo mutations and rare variants in hyp...	KEEP AS NON CORE	Summary: NOTCH1 regulates heart development. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: PMID:21457232 2011 Apr 25. Identification of de novo mutations and rare variants in hypoplastic left heart syndrome.
GO:0010812 negative regulation of cell-substrate adhesion	IDA PMID:16501043 Increased Wnt signaling triggers oncogenic conversion of hum...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of cell-substrate adhesion. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:16501043 Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism.
GO:0003180 aortic valve morphogenesis	IMP PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.	KEEP AS NON CORE	Summary: NOTCH1 regulates aortic valve morphogenesis. Reason: Cardiac development - tissue-specific developmental function. Supporting Evidence: PMID:16025100 Mutations in NOTCH1 cause aortic valve disease.
GO:0005515 protein binding	IPI PMID:11101851 MAML1, a human homologue of Drosophila mastermind, is a tran...	REMOVE	Summary: Generic protein binding annotation. Reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms. Supporting Evidence: PMID:11101851 MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
GO:0005515 protein binding	IPI PMID:11390662 A human protein with sequence similarity to Drosophila maste...	REMOVE	Summary: Generic protein binding annotation. Reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms. Supporting Evidence: PMID:11390662 A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters.
GO:0005634 nucleus	TAS PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin ...	ACCEPT	Summary: Nucleus Reason: NICD translocates to nucleus. Supporting Evidence: PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
GO:0006355 regulation of DNA-templated transcription	TAS PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin ...	ACCEPT	Summary: Regulation of DNA-templated transcription Reason: Core transcriptional function. Supporting Evidence: PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
GO:0007219 Notch signaling pathway	TAS PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin ...	ACCEPT	Summary: Notch signaling pathway Reason: Core function - NOTCH1 IS the pathway receptor. Supporting Evidence: PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
GO:0045662 negative regulation of myoblast differentiation	IMP PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin ...	KEEP AS NON CORE	Summary: NOTCH1 is involved in negative regulation of myoblast differentiation. Reason: Context-dependent regulatory function. Supporting Evidence: PMID:10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
GO:0006955 immune response	NAS PMID:1831692 TAN-1, the human homolog of the Drosophila notch gene, is br...	KEEP AS NON CORE	Summary: NOTCH1 regulates immune response. Reason: T cell/immune development - tissue-specific function. Supporting Evidence: PMID:1831692 TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.

Core Functions

NOTCH1 functions as a transmembrane signaling receptor at the plasma membrane, responding to membrane-bound DSL ligands (JAG1/2, DLL1/3/4) on neighboring cells to transduce cell-cell contact signals into transcriptional responses via regulated intramembrane proteolysis

Molecular Function:

transmembrane signaling receptor activity

Directly Involved In:

Notch signaling pathway cell differentiation

Cellular Locations:

plasma membrane cell surface

The cleaved NOTCH1 intracellular domain (NICD) functions as a transcriptional coactivator in the nucleus, displacing corepressors from RBPJ/CSL and recruiting MAML coactivators to form the CSL-NICD-MAML ternary transcription complex that activates target genes (HES1, HES5, HEY1, HEY2, HEYL)

Molecular Function:

transcription coactivator activity

Directly Involved In:

positive regulation of DNA-templated transcription positive regulation of transcription of Notch receptor target

Cellular Locations:

nucleus

In Complex:

MAML1-RBP-Jkappa- ICN1 complex

NOTCH1 EGF-like domains bind calcium ions, which is essential for proper receptor folding, stability, and ligand interaction

Molecular Function:

calcium ion binding

Cellular Locations:

plasma membrane

References

file:human/NOTCH1/NOTCH1-deep-research-falcon.md

Deep research on NOTCH1 gene function (Falcon/Edison Scientific Literature)

NOTCH1 is a type I single-pass transmembrane receptor that mediates juxtacrine signaling
Activation requires sequential proteolytic cleavages (S1 furin, S2 ADAM10/17, S3/S4 gamma-secretase)
NICD translocates to nucleus and forms ternary complex with RBPJ and MAML coactivators
Target genes include HES1, HES5, HEY1, HEY2, HEYL
EGF-like domains bind calcium ions essential for structure and ligand binding

file:human/NOTCH1/NOTCH1-deep-research-cyberian.md

Deep research on NOTCH1 gene function (Cyberian AI Deep Research)

NOTCH1 employs regulated intramembrane proteolysis (RIP) for direct signal transduction from cell surface to nucleus
The negative regulatory region (NRR) maintains autoinhibited conformation until ligand engagement
O-fucosylation by POFUT1 is essential for Notch signaling, with O-fucose at Thr466 in EGF12 anchoring the DLL4-binding interface
Fringe glycosyltransferases differentially modulate ligand specificity, potentiating Delta-like binding while inhibiting Jagged binding
NOTCH1 can function through non-canonical CSL-independent mechanisms, including antagonizing Wnt/beta-catenin signaling
NOTCH1-RBPJ binding sites localize primarily to distal enhancers and superenhancers rather than promoters
NOTCH1 is essential for emergence of definitive hematopoietic stem cells from hemogenic endothelium in the AGM region
Loss-of-function mutations cause bicuspid aortic valve and calcific aortic valve disease via de-repression of RUNX2
Paralog-selective therapeutic antibodies targeting the NRR show promise for avoiding pan-Notch inhibition toxicity

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:0000107

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10713164

SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.

PMID:11006133

Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors.

PMID:11101851

MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.

PMID:11306509

Notch signaling induces cell cycle arrest in small cell lung cancer cells.

PMID:11390662

A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters.

PMID:12370315

Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors.

PMID:16025100

Mutations in NOTCH1 cause aortic valve disease.

PMID:16319921

Notch1 augments NF-kappaB activity by facilitating its nuclear retention.

PMID:16501043

Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism.

PMID:16510869

The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis.

PMID:16530044

Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.

PMID:16738328

Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes.

PMID:17284587

Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription.

PMID:17318174

Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.

PMID:17662764

Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms.

PMID:17849174

Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells.

PMID:17909182

Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.

PMID:17984306

Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.

PMID:18239137

Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.

PMID:1831692

TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.

PMID:18427106

Notch signaling mediates hypoxia-induced tumor cell migration and invasion.

PMID:18593716

NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.

PMID:18660822

A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.

PMID:19151708

The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.

PMID:19682396

Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.

PMID:19907488

Direct inhibition of the NOTCH transcription factor complex.

PMID:20613903

Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells.

PMID:20616313

Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.

PMID:20823234

Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia.

PMID:20951801

NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT.

PMID:20972443

Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes.

PMID:21457232

Identification of de novo mutations and rare variants in hypoplastic left heart syndrome.

PMID:21475249

Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway.

PMID:22325781

Conformational locking upon cooperative assembly of notch transcription complexes.

PMID:23022380

NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.

PMID:23086448

The CD46-Jagged1 interaction is critical for human TH1 immunity.

PMID:23382219

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

PMID:23839946

Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.

PMID:25038227

NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.

PMID:25038826

Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.

PMID:25344755

Cyclin C is a haploinsufficient tumour suppressor.

PMID:25609649

Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.

PMID:25714926

Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling.

PMID:25895060

Notch is a direct negative regulator of the DNA-damage response.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:27229929

Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.

PMID:32601208

Pharmacological disruption of the Notch transcription factor complex.

PMID:33189893

A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:38016980

TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors.

PMID:38891776

Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.

PMID:19379690

The canonical Notch signaling pathway: unfolding the activation mechanism.

NOTCH1 employs regulated intramembrane proteolysis (RIP) providing direct and rapid signal transduction from cell surface to nucleus
The signaling pathway is highly conserved across metazoan evolution

PMID:19075186

Structure of the Notch1-negative regulatory region - implications for normal activation and pathogenic signaling in T-ALL

The NRR adopts compact autoinhibited conformation with three LNR modules wrapping around the HD domain
A conserved hydrophobic plug straddles the scissile bond protecting against premature cleavage

PMID:19726682

Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage

ADAM10, not ADAM17/TACE, is required for canonical ligand-induced S2 cleavage

PMID:20008221

The role of NOTCH1 signaling in T-ALL.

Activating NOTCH1 mutations found in over 50% of T-ALL cases
Mutations cluster in heterodimerization domain (HD) and C-terminal PEST domain

PMID:22326375

Notch receptor-ligand binding and activation - Insights from molecular studies

EGF repeats 11-12 constitute core binding site for DSL ligands
EGF11-13 region measures approximately 100 x 24 x 20 Angstroms

PMID:20816395

Endocytosis and intracellular trafficking of Notch and its ligands.

Ligand endocytosis in signal-sending cell generates mechanical pulling force to expose S2 cleavage site
A dileucine sorting signal in cytoplasmic tail directs receptor to late endosomes/lysosomes

PMID:24374627

NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers

Majority of functional NOTCH1-binding sites localize to distal enhancers rather than promoters
Dynamic binding sites frequently lie within superenhancers

PMID:10935626

Fringe is a glycosyltransferase that modifies Notch.

Fringe glycosyltransferases add GlcNAc to O-fucose residues on EGF repeats
This modification potentiates Delta-like binding while inhibiting Jagged/Serrate binding

PMID:12753746

Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.

NOTCH1 is essential for emergence of definitive HSCs from hemogenic endothelium in AGM region

PMID:25700513

Structural biology. Structural basis for Notch1 engagement of Delta-like 4.

Crystal structure at 2.3 Angstrom resolution reveals two-site antiparallel binding orientation
O-fucose at Thr466 in EGF12 centrally anchors the DLL4-binding interface

PMID:22397947

Non-canonical Notch signaling: emerging role and mechanism.

Notch can form complex with active beta-catenin and promote its degradation via endo-lysosomal pathways
CSL-independent Notch function is present during normal development

PMID:20393564

Therapeutic antibody targeting of individual Notch receptors.

Inhibitory antibodies function by stabilizing NRR quiescence
Inhibition of either Notch1 or Notch2 alone reduces or avoids intestinal toxicity versus dual inhibition

Reactome:R-HSA-1912369

NOTCH precursor cleaved to form mature NOTCH

Reactome:R-HSA-1912372

Fringe-modified Pre-NOTCH is cleaved by FURIN

Reactome:R-HSA-1912379

Transport of fringe-modified NOTCH to plasma membrane

Reactome:R-HSA-1912382

Mature NOTCH heterodimer traffics to the plasma membrane

Reactome:R-HSA-1912394

NICD1 in complex with RBPJ (CSL) recruits MAML

Reactome:R-HSA-1912412

NOTCH1 mRNA translation controlled by miRNAs

Reactome:R-HSA-1980044

NOTCH1 binds JAG2

Reactome:R-HSA-1980122

DTX binds NOTCH1

Reactome:R-HSA-212356

Formation of CSL-NICD coactivator complex

Reactome:R-HSA-2220944

ADAM10/17 cleaves ligand-bound NOTCH1 PEST domain mutants to produce NEXT1 PEST domain mutants

Reactome:R-HSA-2220957

NOTCH1 PEST domain mutants coactivator complex binds CDK8:CCNC

Reactome:R-HSA-2220964

NICD1 PEST domain mutants in complex with RBPJ (CSL) bind MAML

Reactome:R-HSA-2220967

p-NICD1 PEST domain mutants do not bind FBXW7

Reactome:R-HSA-2220971

CDK8 phosphorylates NICD1 PEST domain mutants

Reactome:R-HSA-2220976

NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding

Reactome:R-HSA-2220978

FBXW7 WD mutants do not bind NICD1

Reactome:R-HSA-2220982

NICD1 PEST domain mutants displace co-repressor complex from RBPJ (CSL)

Reactome:R-HSA-2220988

NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants

Reactome:R-HSA-2660815

NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind DLL4

Reactome:R-HSA-2660816

NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind JAG2

Reactome:R-HSA-2660819

NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind DLL1

Reactome:R-HSA-2660822

TODO: Fetch title

Reactome:R-HSA-2666278

NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is cleaved to produce NEXT1

Reactome:R-HSA-2691211

NOTCH1 HD domain mutants bind DLL4

Reactome:R-HSA-2691214

NOTCH1 HD domain mutants bind JAG2

Reactome:R-HSA-2691219

NOTCH1 HD domain mutants bind DLL1

Reactome:R-HSA-2691226

NOTCH1 HD domain mutants bind JAG1

Reactome:R-HSA-2730752

NOTCH1 HD domain mutants are cleaved to produce NEXT1 irrespective of ligand binding

Reactome:R-HSA-2737728

Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD domain mutants

Reactome:R-HSA-2768993

NOTCH1 PEST domain mutants bind JAG2

Reactome:R-HSA-2768999

NOTCH1 PEST domain mutants bind JAG1

Reactome:R-HSA-2769000

NOTCH1 PEST domain mutants bind DLL4

Reactome:R-HSA-2769007

Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 PEST domain mutants

Reactome:R-HSA-2769008

NOTCH1 PEST domain mutants bind DLL1

Reactome:R-HSA-2769015

NICD1 PEST domain mutants translocate from cytosol to nucleus

Reactome:R-HSA-2900743

NOTCH1 HD+PEST domain mutants bind JAG1

Reactome:R-HSA-2900747

NOTCH1 HD+PEST domain mutants bind DLL4

Reactome:R-HSA-2900748

NOTCH1 HD+PEST domain mutants bind DLL1

Reactome:R-HSA-2900756

NOTCH1 HD+PEST domain mutants bind JAG2

Reactome:R-HSA-2900765

Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD+PEST domain mutants

Reactome:R-HSA-4396371

NOTCH1 Coactivator Complex binds MYC promoter

Reactome:R-HSA-4396379

NOTCH1 Coactivator Complex binds HES5 promoter

Reactome:R-HSA-4396392

NOTCH1 PEST domain mutants bind HES1 promoter

Reactome:R-HSA-4396393

NOTCH1 PEST domain mutants bind MYC promoter

Reactome:R-HSA-4396401

NOTCH1 PEST domain mutants bind HES5 promoter

Reactome:R-HSA-4396402

NOTCH1 PEST domain mutants bind promoters of HEY genes

Reactome:R-HSA-5096538

Defective LFNG does not transfer GlcNAc to Pre-NOTCH

Reactome:R-HSA-8878220

RUNX3 binds the NOTCH1 coactivator complex

Reactome:R-HSA-8878237

RUNX3:NOTCH1 coactivator complex binds the HES1 gene promoter

Reactome:R-HSA-9017835

NOTCH1 coactivator complex binds NOTCH3 gene

Reactome:R-HSA-9021451

NOTCH1,NOTCH3 coactivator complex binds PLXND1 gene promoter

Reactome:R-HSA-9762102

NICD1 binds the NFE2L2 promoter

Reactome:R-HSA-9796071

NFE2L2 dependent NOTCH1 expression

Reactome:R-NUL-2064264

NICD1 displaces NCOR co-repressor complex from CSL

Reactome:R-NUL-2076711

rDll1 binds NOTCH1 in cis

📚 Additional Documentation

Deep Research Bioreason

(NOTCH1-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:54 AM

Organism: Homo sapiens

Sequence:

MPPLLAPLLCLALLPALAARGPRCSQPGETCLNGGKCEAANGTEACVCGGAFVGPRCQDPNPCLSTPCKNAGTCHVVDRRGVADYACSCALGFSGPLCLTPLDNACLTNPCRNGGTCDLLTLTEYKCRCPPGWSGKSCQQADPCASNPCANGGQCLPFEASYICHCPPSFHGPTCRQDVNECGQKPGLCRHGGTCHNEVGSYRCVCRATHTGPNCERPYVPCSPSPCQNGGTCRPTGDVTHECACLPGFTGQNCEENIDDCPGNNCKNGGACVDGVNTYNCRCPPEWTGQYCTEDVDECQLMPNACQNGGTCHNTHGGYNCVCVNGWTGEDCSENIDDCASAACFHGATCHDRVASFYCECPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTCPSGYTGPACSQDVDECSLGANPCEHAGKCINTLGSFECQCLQGYTGPRCEIDVNECVSNPCQNDATCLDQIGEFQCICMPGYEGVHCEVNTDECASSPCLHNGRCLDKINEFQCECPTGFTGHLCQYDVDECASTPCKNGAKCLDGPNTYTCVCTEGYTGTHCEVDIDECDPDPCHYGSCKDGVATFTCLCRPGYTGHHCETNINECSSQPCRHGGTCQDRDNAYLCFCLKGTTGPNCEINLDDCASSPCDSGTCLDKIDGYECACEPGYTGSMCNINIDECAGNPCHNGGTCEDGINGFTCRCPEGYHDPTCLSEVNECNSNPCVHGACRDSLNGYKCDCDPGWSGTNCDINNNECESNPCVNGGTCKDMTSGYVCTCREGFSGPNCQTNINECASNPCLNQGTCIDDVAGYKCNCLLPYTGATCEVVLAPCAPSPCRNGGECRQSEDYESFSCVCPTGWQGQTCEVDINECVLSPCRHGASCQNTHGGYRCHCQAGYSGRNCETDIDDCRPNPCHNGGSCTDGINTAFCDCLPGFRGTFCEEDINECASDPCRNGANCTDCVDSYTCTCPAGFSGIHCENNTPDCTESSCFNGGTCVDGINSFTCLCPPGFTGSYCQHDVNECDSQPCLHGGTCQDGCGSYRCTCPQGYTGPNCQNLVHWCDSSPCKNGGKCWQTHTQYRCECPSGWTGLYCDVPSVSCEVAAQRQGVDVARLCQHGGLCVDAGNTHHCRCQAGYTGSYCEDLVDECSPSPCQNGATCTDYLGGYSCKCVAGYHGVNCSEEIDECLSHPCQNGGTCLDLPNTYKCSCPRGTQGVHCEINVDDCNPPVDPVSRSPKCFNNGTCVDQVGGYSCTCPPGFVGERCEGDVNECLSNPCDARGTQNCVQRVNDFHCECRAGHTGRRCESVINGCKGKPCKNGGTCAVASNTARGFICKCPAGFEGATCENDARTCGSLRCLNGGTCISGPRSPTCLCLGPFTGPECQFPASSPCLGGNPCYNQGTCEPTSESPFYRCLCPAKFNGLLCHILDYSFGGGAGRDIPPPLIEEACELPECQEDAGNKVCSLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQRAEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVVVVLMPPEQLRNSSFHFLRELSRVLHTNVVFKRDAHGQQMIFPYYGREEELRKHPIKRAAEGWAAPDALLGQVKASLLPGGSEGGRRRRELDPMDVRGSIVYLEIDNRQCVQASSQCFQSATDVAAFLGALASLGSLNIPYKIEAVQSETVEPPPPAQLHFMYVAAAAFVLLFFVGCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNASDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLDDQTDHRQWTQQHLDAADLRMSAMAPTPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNSEEEEDAPAVISDFIYQGASLHNQTDRTGETALHLAARYSRSDAAKRLLEASADANIQDNMGRTPLHAAVSADAQGVFQILIRNRATDLDARMHDGTTPLI

Thinking Trace

I begin by dissecting the InterPro architecture and its order along the polypeptide. The N-terminal half is densely packed with EGF-like modules: IPR000742 (EGF-like domain, residues 20–1426), IPR001881 (EGF-like calcium-binding domain, residues 59–1384), and the specialized calcium-binding consensus signatures IPR049883 (NOTCH1, EGF-like calcium-binding domain, residues 178–900), IPR018097 (EGF-like calcium-binding, conserved site, residues 257–1374), and IPR013032 (EGF-like, conserved site, residues 575–1374). These repeats form a rigid, Ca2+-stabilized extracellular scaffold that mediates ligand binding and force-dependent signaling typical of membrane-tethered receptors. The extracellular EGF array is further reinforced by IPR009030 (Growth factor receptor cysteine-rich domain superfamily, residues 288–1312), indicating a cysteine-rich adhesive/receptor surface, and by IPR000152 (EGF-type aspartate/asparagine hydroxylation site, residues 195–1255), which signals post-translational hydroxylation that tunes EGF fold stability and ligand interactions. This entire extracellular region sits within broad family signatures IPR008297 (Notch family, residues 6–2000) and IPR051355 (Notch and Slit guidance protein family, residues 81–1364), which together define a canonical Notch-type receptor architecture.

Transitioning inward, the intracellular juxtamembrane to distal C-terminus contains the canonical Notch core: IPR000800 (Notch domain, residues 1442–1571), IPR035993 (Notch-like domain superfamily, residues 1448–1561), IPR010660 (Notch, NOD domain, residues 1566–1622), and IPR011656 (Notch, NODP domain, residues 1670–1732). This paired NOD/NODP cassette is the switch that controls proteolytic activation: mechanical or ligand-induced strain exposes the S2 cleavage site, while the adjacent regulatory elements coordinate intramembrane S3 proteolysis. The C-terminal cytosolic tail is built from ankyrin repeats: IPR036770 (Ankyrin repeat-containing domain superfamily, residues 1868–2000) and IPR002110 (Ankyrin repeat, residues 1880–1990). Ankyrin arrays create a high-affinity, modular platform for assembling transcriptional regulators and co-repressors. The overall layout—extracellular EGF-rich receptor head, followed by the NOD/NODP activation cassette and a cytosolic ankyrin scaffold—matches the conserved Notch receptor mechanism.

From this architecture, the molecular function resolves as a membrane-tethered receptor that signals by endoproteolytic activation and ankyrin-mediated transcriptional assembly. The calcium-binding EGF repeats and Notch-specific intracellular switch dictate transmembrane signaling receptor activity and extensive protein binding. The ankyrin repeat platform and the intramembrane proteolysis cascade together cause assembly of nuclear effector complexes rather than direct DNA binding, consistent with a soluble transcriptional regulator module that drives target gene expression once activation occurs.

This receptor-driven transcriptional program causally links to developmental and homeostatic processes. The extracellular EGF array and intramembrane switch control pathways that govern cell fate decisions; thus the architecture drives cell-fate control consistent with regulation of Notch signaling. The downstream transcriptional complexes modulate differentiation and proliferation pathways that collectively shape morphogenesis and tissue homeostasis.

Cellular location follows directly from the domain architecture and processing route. The long EGF-rich extracellular head and the NOD/NODP cassette require insertion into the lipid bilayer as a single-pass type I receptor, placing the protein in the membrane as an integral component. After proteolytic activation and cytosolic tail release, the ankyrin-rich fragment traffics to the nucleus, where it partners with transcriptional machinery. Therefore, the protein cycles between membrane and nucleus, with steady-state distribution influenced by ligand availability and activation status.

Mechanistically, ligand engagement at the EGF array generates mechanical tension that exposes the S2 site, enabling juxtamembrane proteolysis and subsequent intramembrane cleavage. The liberated intracellular domain—equipped with ankyrin repeats—recruits CSL/RBPJ transcription factors and co-regulators to switch target genes on or off. Likely interaction partners include membrane ligands that impose the required mechanical input and nuclear effectors that interpret the signal. This integrated model explains the membrane-to-nucleus signaling axis and the observed compartmentalization.

Functional Summary

A single-pass membrane receptor that presents a long, calcium-stabilized extracellular array of repeats to sense ligands and transmit mechanical signals into the cell. Ligand-induced tension triggers sequential proteolytic events that release a cytosolic tail built from ankyrin repeats, which then assembles transcriptional regulators to modulate gene expression programs controlling cell fate and tissue homeostasis. The protein operates at the membrane before trafficking to the nucleus, where it orchestrates target-gene regulation through modular protein–protein interaction surfaces.

UniProt Summary

Functions as a receptor for several membrane-bound ligands that control a signaling pathway involved in cell-fate决定.

InterPro Domains

Notch (IPR008297, family) — residues 6-2000
EGF-like domain (IPR000742, domain) — residues 20-1426
EGF-like calcium-binding domain (IPR001881, domain) — residues 59-1384
Notch and Slit guidance protein (IPR051355, family) — residues 81-1364
NOTCH1, EGF-like calcium-binding domain (IPR049883, domain) — residues 178-900
EGF-type aspartate/asparagine hydroxylation site (IPR000152, ptm) — residues 195-1255
EGF-like calcium-binding, conserved site (IPR018097, conserved_site) — residues 257-1253
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 288-1312
EGF-like, conserved site (IPR013032, conserved_site) — residues 575-1374
Neurogenic locus notch homolog protein 1 (IPR022362, family) — residues 1426-1724
Notch domain (IPR000800, domain) — residues 1442-1571
Notch-like domain superfamily (IPR035993, homologous_superfamily) — residues 1448-1561
Notch, NOD domain (IPR010660, domain) — residues 1566-1622
Notch, NODP domain (IPR011656, domain) — residues 1670-1732
Ankyrin repeat-containing domain superfamily (IPR036770, homologous_superfamily) — residues 1868-2000
Ankyrin repeat (IPR002110, repeat) — residues 1880-1990

GO Terms

Molecular Function: molecular_function (GO:0003674), molecular transducer activity (GO:0060089), binding (GO:0005488), transcription regulator activity (GO:0140110), signaling receptor activity (GO:0038023), transcription coregulator activity (GO:0003712), protein binding (GO:0005515), identical protein binding (GO:0042802), transmembrane signaling receptor activity (GO:0004888), transcription coactivator activity (GO:0003713)

Biological Process: biological_process (GO:0008150), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), signaling (GO:0023052), multicellular organismal process (GO:0032501), biological regulation (GO:0065007), response to stimulus (GO:0050896), developmental process (GO:0032502), cellular process (GO:0009987), negative regulation of biological process (GO:0048519), anatomical structure development (GO:0048856), anatomical structure morphogenesis (GO:0009653), response to chemical (GO:0042221), negative regulation of multicellular organismal process (GO:0051241), regulation of multicellular organismal process (GO:0051239), anatomical structure formation involved in morphogenesis (GO:0048646), negative regulation of metabolic process (GO:0009892), regulation of developmental process (GO:0050793), response to biotic stimulus (GO:0009607), response to endogenous stimulus (GO:0009719), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), negative regulation of locomotion (GO:0040013), 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), cellular developmental process (GO:0048869), positive regulation of signaling (GO:0023056), multicellular organism development (GO:0007275), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), maintenance of cell number (GO:0098727), positive regulation of metabolic process (GO:0009893), stem cell population maintenance (GO:0019827), negative regulation of response to stimulus (GO:0048585), cell communication (GO:0007154), positive regulation of cellular process (GO:0048522), tube formation (GO:0035148), regulation of cell motility (GO:2000145), negative regulation of cell death (GO:0060548), cell differentiation (GO:0030154), system development (GO:0048731), animal organ development (GO:0048513), cardiac septum development (GO:0003279), response to growth factor (GO:0070848), regulation of signal transduction (GO:0009966), regulation of cell adhesion (GO:0030155), cellular response to endogenous stimulus (GO:0071495), regulation of macromolecule metabolic process (GO:0060255), regulation of response to external stimulus (GO:0032101), heart valve development (GO:0003170), response to tumor cell (GO:0002347), response to hormone (GO:0009725), tube development (GO:0035295), regulation of epithelial cell migration (GO:0010632), animal organ morphogenesis (GO:0009887), cardiac septum morphogenesis (GO:0060411), negative regulation of cell adhesion (GO:0007162), negative regulation of macromolecule metabolic process (GO:0010605), negative regulation of epithelial cell migration (GO:0010633), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cell differentiation (GO:0045595), cell surface receptor signaling pathway (GO:0007166), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell motility (GO:2000146), positive regulation of nitrogen compound metabolic process (GO:0051173), tube morphogenesis (GO:0035239), neuronal stem cell population maintenance (GO:0097150), positive regulation of signal transduction (GO:0009967), negative regulation of nitrogen compound metabolic process (GO:0051172), positive regulation of macromolecule metabolic process (GO:0010604), regulation of chemotaxis (GO:0050920), negative regulation of cell population proliferation (GO:0008285), heart valve formation (GO:0003188), cardiac chamber development (GO:0003205), negative regulation of cellular metabolic process (GO:0031324), cellular response to biotic stimulus (GO:0071216), response to organic substance (GO:0010033), positive regulation of biosynthetic process (GO:0009891), outflow tract morphogenesis (GO:0003151), regulation of cell population proliferation (GO:0042127), regulation of cell death (GO:0010941), tissue development (GO:0009888), negative regulation of chemotaxis (GO:0050922), positive regulation of cellular metabolic process (GO:0031325), regulation of cell communication (GO:0010646), negative regulation of cell differentiation (GO:0045596), cellular response to chemical stimulus (GO:0070887), regulation of biosynthetic process (GO:0009889), cardiac chamber morphogenesis (GO:0003206), regulation of cellular metabolic process (GO:0031323), positive regulation of cell communication (GO:0010647), negative regulation of biosynthetic process (GO:0009890), heart valve morphogenesis (GO:0003179), regulation of primary metabolic process (GO:0080090), negative regulation of response to external stimulus (GO:0032102), regulation of macromolecule biosynthetic process (GO:0010556), regulation of cell-substrate adhesion (GO:0010810), negative regulation of programmed cell death (GO:0043069), regulation of programmed cell death (GO:0043067), regulation of cell-cell adhesion (GO:0022407), negative regulation of myoblast differentiation (GO:0045662), aortic valve morphogenesis (GO:0003180), cardiac ventricle development (GO:0003231), regulation of cell migration (GO:0030334), regulation of endothelial cell chemotaxis (GO:2001026), regulation of gene expression (GO:0010468), semi-lunar valve development (GO:1905314), heart morphogenesis (GO:0003007), regulation of endothelial cell migration (GO:0010594), response to gonadotropin (GO:0034698), circulatory system development (GO:0072359), cell surface receptor signaling pathway involved in heart development (GO:0061311), positive regulation of intracellular signal transduction (GO:1902533), negative regulation of cellular biosynthetic process (GO:0031327), regulation of RNA metabolic process (GO:0051252), negative regulation of cell-cell adhesion (GO:0022408), mesenchymal cell differentiation (GO:0048762), pulmonary valve morphogenesis (GO:0003184), negative regulation of nucleobase-containing compound metabolic process (GO:0045934), negative regulation of gene expression (GO:0010629), heart development (GO:0007507), ventricular septum development (GO:0003281), atrioventricular valve development (GO:0003171), negative regulation of cell-substrate adhesion (GO:0010812), cellular response to organic substance (GO:0071310), mesenchyme development (GO:0060485), negative regulation of stem cell differentiation (GO:2000737), regulation of stem cell differentiation (GO:2000736), Notch signaling pathway (GO:0007219), negative regulation of cell migration (GO:0030336), 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), cellular response to hormone stimulus (GO:0032870), ventricular septum morphogenesis (GO:0060412), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), negative regulation of macromolecule biosynthetic process (GO:0010558), negative regulation of endothelial cell migration (GO:0010596), negative regulation of RNA metabolic process (GO:0051253), regulation of myoblast differentiation (GO:0045661), positive regulation of cellular biosynthetic process (GO:0031328), regulation of intracellular signal transduction (GO:1902531), cellular response to growth factor stimulus (GO:0071363), atrioventricular valve morphogenesis (GO:0003181), pulmonary valve development (GO:0003177), regulation of apoptotic process (GO:0042981), epithelial to mesenchymal transition (GO:0001837), regulation of RNA biosynthetic process (GO:2001141), regulation of cell-cell adhesion mediated by cadherin (GO:2000047), negative regulation of blood vessel endothelial cell migration (GO:0043537), positive regulation of small GTPase mediated signal transduction (GO:0051057), cellular response to gonadotropin stimulus (GO:0071371), regulation of blood vessel endothelial cell migration (GO:0043535), positive regulation of RNA biosynthetic process (GO:1902680), positive regulation of MAPK cascade (GO:0043410), negative regulation of RNA biosynthetic process (GO:1902679), regulation of MAPK cascade (GO:0043408), negative regulation of apoptotic process (GO:0043066), regulation of DNA-templated transcription (GO:0006355), aortic valve development (GO:0003176), regulation of small GTPase mediated signal transduction (GO:0051056), response to follicle-stimulating hormone (GO:0032354), cellular response to vascular endothelial growth factor stimulus (GO:0035924), positive regulation of ERK1 and ERK2 cascade (GO:0070374), regulation of Ras protein signal transduction (GO:0046578), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), positive regulation of Ras protein signal transduction (GO:0046579), negative regulation of anoikis (GO:2000811), regulation of ERK1 and ERK2 cascade (GO:0070372), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), regulation of cell migration involved in sprouting angiogenesis (GO:0090049), cellular response to follicle-stimulating hormone stimulus (GO:0071372), regulation of anoikis (GO:2000209), negative regulation of nucleic acid-templated transcription (GO:1903507), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of transcription by RNA polymerase II (GO:0000122)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane (GO:0016020), cytosol (GO:0005829), nucleoplasm (GO:0005654), cell periphery (GO:0071944), organelle subcompartment (GO:0031984), receptor complex (GO:0043235), cytoplasm (GO:0005737), membrane-enclosed lumen (GO:0031974), endomembrane system (GO:0012505), extracellular region (GO:0005576), organelle membrane (GO:0031090), intracellular organelle (GO:0043229), endoplasmic reticulum subcompartment (GO:0098827), nuclear outer membrane-endoplasmic reticulum membrane network (GO:0042175), Golgi apparatus (GO:0005794), organelle lumen (GO:0043233), endoplasmic reticulum (GO:0005783), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), intracellular membrane-bounded organelle (GO:0043231), bounding membrane of organelle (GO:0098588), endoplasmic reticulum membrane (GO:0005789), intracellular organelle lumen (GO:0070013), Golgi membrane (GO:0000139), nucleus (GO:0005634), nuclear lumen (GO:0031981)

Generated by BioReason

Deep Research Bioreason Rl

(NOTCH1-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:54 AM

Organism: Homo sapiens

Sequence:

MPPLLAPLLCLALLPALAARGPRCSQPGETCLNGGKCEAANGTEACVCGGAFVGPRCQDPNPCLSTPCKNAGTCHVVDRRGVADYACSCALGFSGPLCLTPLDNACLTNPCRNGGTCDLLTLTEYKCRCPPGWSGKSCQQADPCASNPCANGGQCLPFEASYICHCPPSFHGPTCRQDVNECGQKPGLCRHGGTCHNEVGSYRCVCRATHTGPNCERPYVPCSPSPCQNGGTCRPTGDVTHECACLPGFTGQNCEENIDDCPGNNCKNGGACVDGVNTYNCRCPPEWTGQYCTEDVDECQLMPNACQNGGTCHNTHGGYNCVCVNGWTGEDCSENIDDCASAACFHGATCHDRVASFYCECPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTCPSGYTGPACSQDVDECSLGANPCEHAGKCINTLGSFECQCLQGYTGPRCEIDVNECVSNPCQNDATCLDQIGEFQCICMPGYEGVHCEVNTDECASSPCLHNGRCLDKINEFQCECPTGFTGHLCQYDVDECASTPCKNGAKCLDGPNTYTCVCTEGYTGTHCEVDIDECDPDPCHYGSCKDGVATFTCLCRPGYTGHHCETNINECSSQPCRHGGTCQDRDNAYLCFCLKGTTGPNCEINLDDCASSPCDSGTCLDKIDGYECACEPGYTGSMCNINIDECAGNPCHNGGTCEDGINGFTCRCPEGYHDPTCLSEVNECNSNPCVHGACRDSLNGYKCDCDPGWSGTNCDINNNECESNPCVNGGTCKDMTSGYVCTCREGFSGPNCQTNINECASNPCLNQGTCIDDVAGYKCNCLLPYTGATCEVVLAPCAPSPCRNGGECRQSEDYESFSCVCPTGWQGQTCEVDINECVLSPCRHGASCQNTHGGYRCHCQAGYSGRNCETDIDDCRPNPCHNGGSCTDGINTAFCDCLPGFRGTFCEEDINECASDPCRNGANCTDCVDSYTCTCPAGFSGIHCENNTPDCTESSCFNGGTCVDGINSFTCLCPPGFTGSYCQHDVNECDSQPCLHGGTCQDGCGSYRCTCPQGYTGPNCQNLVHWCDSSPCKNGGKCWQTHTQYRCECPSGWTGLYCDVPSVSCEVAAQRQGVDVARLCQHGGLCVDAGNTHHCRCQAGYTGSYCEDLVDECSPSPCQNGATCTDYLGGYSCKCVAGYHGVNCSEEIDECLSHPCQNGGTCLDLPNTYKCSCPRGTQGVHCEINVDDCNPPVDPVSRSPKCFNNGTCVDQVGGYSCTCPPGFVGERCEGDVNECLSNPCDARGTQNCVQRVNDFHCECRAGHTGRRCESVINGCKGKPCKNGGTCAVASNTARGFICKCPAGFEGATCENDARTCGSLRCLNGGTCISGPRSPTCLCLGPFTGPECQFPASSPCLGGNPCYNQGTCEPTSESPFYRCLCPAKFNGLLCHILDYSFGGGAGRDIPPPLIEEACELPECQEDAGNKVCSLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQRAEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVVVVLMPPEQLRNSSFHFLRELSRVLHTNVVFKRDAHGQQMIFPYYGREEELRKHPIKRAAEGWAAPDALLGQVKASLLPGGSEGGRRRRELDPMDVRGSIVYLEIDNRQCVQASSQCFQSATDVAAFLGALASLGSLNIPYKIEAVQSETVEPPPPAQLHFMYVAAAAFVLLFFVGCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNASDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLDDQTDHRQWTQQHLDAADLRMSAMAPTPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNSEEEEDAPAVISDFIYQGASLHNQTDRTGETALHLAARYSRSDAAKRLLEASADANIQDNMGRTPLHAAVSADAQGVFQILIRNRATDLDARMHDGTTPLI

Thinking Trace

Functional Summary

UniProt Summary

Functions as a receptor for several membrane-bound ligands that control a signaling pathway involved in cell-fate决定.

InterPro Domains

Notch (IPR008297, family) — residues 6-2000
EGF-like domain (IPR000742, domain) — residues 20-1426
EGF-like calcium-binding domain (IPR001881, domain) — residues 59-1384
Notch and Slit guidance protein (IPR051355, family) — residues 81-1364
NOTCH1, EGF-like calcium-binding domain (IPR049883, domain) — residues 178-900
EGF-type aspartate/asparagine hydroxylation site (IPR000152, ptm) — residues 195-1255
EGF-like calcium-binding, conserved site (IPR018097, conserved_site) — residues 257-1253
Growth factor receptor cysteine-rich domain superfamily (IPR009030, homologous_superfamily) — residues 288-1312
EGF-like, conserved site (IPR013032, conserved_site) — residues 575-1374
Neurogenic locus notch homolog protein 1 (IPR022362, family) — residues 1426-1724
Notch domain (IPR000800, domain) — residues 1442-1571
Notch-like domain superfamily (IPR035993, homologous_superfamily) — residues 1448-1561
Notch, NOD domain (IPR010660, domain) — residues 1566-1622
Notch, NODP domain (IPR011656, domain) — residues 1670-1732
Ankyrin repeat-containing domain superfamily (IPR036770, homologous_superfamily) — residues 1868-2000
Ankyrin repeat (IPR002110, repeat) — residues 1880-1990

GO Terms

Generated by BioReason

Deep Research Cyberian

(NOTCH1-deep-research-cyberian.md)

provider: cyberian
model: deep-research
cached: false
start_time: '2026-01-11T17:00:26.384261'
end_time: '2026-01-11T17:17:14.324126'
duration_seconds: 1007.94
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: NOTCH1
gene_symbol: NOTCH1
uniprot_accession: P46531
protein_description: 'RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch
1; Short=hN1; AltName: Full=Translocation-associated notch protein TAN-1; Contains:
RecName: Full=Notch 1 extracellular truncation; Short=NEXT; Contains: RecName:
Full=Notch 1 intracellular domain; Short=NICD; Flags: Precursor;'
gene_info: Name=NOTCH1; Synonyms=TAN1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the NOTCH family. .
protein_domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770);
EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032); EGF-like_dom. (IPR000742)
provider_config:
timeout: 1800
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allowed_domains: []
agent_type: claude
port: 3284
skip_permissions: true
citation_count: 17

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: P46531
Protein Description: RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch 1; Short=hN1; AltName: Full=Translocation-associated notch protein TAN-1; Contains: RecName: Full=Notch 1 extracellular truncation; Short=NEXT; Contains: RecName: Full=Notch 1 intracellular domain; Short=NICD; Flags: Precursor;
Gene Information: Name=NOTCH1; Synonyms=TAN1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the NOTCH family. .
Key Domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032); EGF-like_dom. (IPR000742)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "NOTCH1" 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 'NOTCH1' 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 NOTCH1 (gene ID: NOTCH1, UniProt: P46531) 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

NOTCH1 (P46531): Functional Annotation Research Report

1. Introduction and Summary

NOTCH1 (Neurogenic locus notch homolog protein 1) is a type I transmembrane receptor protein that serves as a central component of the evolutionarily conserved Notch signaling pathway, one of the most fundamental mechanisms for cell-cell communication in metazoans [kopan-2009-canonical-notch-abstract]. The human NOTCH1 gene, also known as TAN1 (Translocation-associated notch protein), encodes a large 2555 amino acid precursor protein that undergoes multiple proteolytic processing events to generate functional receptor heterodimers and ultimately release a transcriptionally active intracellular domain.

The primary function of NOTCH1 is to act as a mechanosensitive receptor that converts ligand binding on neighboring cells into changes in gene expression. Unlike conventional receptors that rely on second messengers or enzymatic cascades, NOTCH1 employs a remarkable signaling mechanism wherein the receptor itself is cleaved and its intracellular domain (NICD) directly translocates to the nucleus to activate transcription. This process, termed regulated intramembrane proteolysis (RIP), provides direct and rapid signal transduction from cell surface to nucleus [kopan-2009-canonical-notch-abstract]. NOTCH1 participates in a wide array of developmental processes including neurogenesis, somitogenesis, hematopoiesis, angiogenesis, and cardiac valve development. Dysregulation of NOTCH1 signaling underlies multiple human diseases, most notably T-cell acute lymphoblastic leukemia (T-ALL) where activating mutations occur in approximately 50-60% of cases [ferrando-2009-tall-abstract], and calcific aortic valve disease where loss-of-function mutations cause both congenital bicuspid aortic valve and progressive calcification [garg-2005-aortic-valve-abstract].

The Notch signaling pathway is ancient and remarkably conserved across metazoans. In Drosophila melanogaster there is a single Notch gene, in Caenorhabditis elegans there are two paralogs (LIN-12 and GLP-1), and mammals possess four Notch receptors (NOTCH1-4). Comprehensive phylogenetic analyses confirm that vertebrate Notch genes arose from two whole-genome duplication events that occurred before the divergence of teleosts and tetrapods. The conservation of principal pathway components—including receptors, DSL ligands, and the CSL transcription factor—throughout the animal kingdom underscores the fundamental importance of this signaling mechanism in metazoan biology.

2. Protein Structure and Domain Organization

NOTCH1 possesses a modular domain architecture that reflects its complex functional requirements as both a ligand-binding receptor and a transcriptional regulator. The extracellular portion of NOTCH1 comprises 36 tandem epidermal growth factor-like (EGF) repeats followed by a negative regulatory region (NRR) that maintains the receptor in an autoinhibited state until ligand engagement [gordon-2008-nrr-structure-abstract]. The EGF repeats adopt a calcium-stabilized rod-like structure, with the EGF11-13 region measuring approximately 100 x 24 x 20 Angstroms in crystallographic studies [chillakuri-2012-receptor-ligand-abstract]. These EGF repeats serve as the primary ligand-binding interface, with EGF repeats 11 and 12 constituting the core binding site for DSL (Delta/Serrate/Lag-2) family ligands, while additional repeats (particularly EGF8-10) contribute to full activation potential.

The crystal structure of the Notch1-DLL4 complex at 2.3 Angstrom resolution (PDB: 4XL1) revealed critical details of the ligand-receptor interface [luca-2015-dll4-structure-abstract]. The structure demonstrates a two-site, antiparallel binding orientation: Site 1 involves the DLL4 MNNL (Module at the N-terminus of Notch Ligands) domain interacting with Notch1 EGF12, while Site 2 comprises the DLL4 DSL domain engaging Notch1 EGF11. Notch1 EGF repeats 11-13 assemble into an approximately 90 Angstrom rod stabilized by three disulfide bonds per EGF and by calcium ions coordinated at the inter-EGF junctions. The DLL4 MNNL, DSL, EGF1, and EGF2 domains stretch approximately 120 Angstroms lengthwise. The total interface buries approximately 1100 square Angstroms of protein and glycan surface area [luca-2015-dll4-structure-abstract]. This antiparallel binding orientation is compatible with either trans cell-cell contacts that initiate signaling or cis interactions between receptor and ligand on the same cell that mediate inhibition.

The negative regulatory region (NRR) immediately C-terminal to the EGF repeats consists of three Lin12/Notch repeats (LNR-A, LNR-B, LNR-C) followed by a heterodimerization (HD) domain. Structural analysis reveals that the NRR adopts a compact, autoinhibited conformation resembling a "head of cauliflower" wherein the three LNR modules wrap around and stabilize the HD domain while sterically occluding the metalloprotease cleavage site [gordon-2008-nrr-structure-abstract]. A conserved hydrophobic plug formed by residues in the LNR-A to LNR-B linker straddles the scissile bond, providing an additional layer of protection against premature cleavage. The LNR modules are each stabilized by three disulfide bonds and a single calcium ion, and perturbation of calcium binding can lead to ligand-independent receptor activation.

The transmembrane domain anchors NOTCH1 in the plasma membrane and contains the S3 cleavage site targeted by gamma-secretase. The intracellular domain (NICD) encompasses several functionally distinct regions: the RAM (RBP-Jκ-associated molecule) domain mediates high-affinity binding to the transcription factor RBPJ; seven ankyrin repeats (ANK) provide a scaffold for assembly of transcriptional activation complexes; a transcriptional activation domain (TAD) recruits coactivators; and a C-terminal PEST sequence (rich in proline, glutamate, serine, and threonine) targets NICD for ubiquitin-mediated proteasomal degradation [kopan-2009-canonical-notch-abstract]. The crystal structure of the Notch transcription complex reveals that the CSL/RBPJ DNA-binding protein and the ankyrin domain create a groove that binds the coactivator MAML-1 as a kinked, 70-Angstrom helix, illustrating how cooperative assembly drives transcriptional activation [nam-2006-notch2-nrr-abstract].

3. Proteolytic Processing and Activation Mechanism

NOTCH1 activation proceeds through an elegant series of three sequential proteolytic cleavage events, each catalyzed by distinct proteases at specific cellular locations. The first cleavage (S1) occurs constitutively during receptor maturation in the trans-Golgi network, where furin-like convertases cleave the NOTCH1 precursor polypeptide to generate a non-covalently associated heterodimer comprising the NOTCH extracellular domain (NECD) and the NOTCH transmembrane-intracellular fragment (NTM-IC) [kopan-2009-canonical-notch-abstract]. This heterodimer is then transported to the cell surface where it awaits ligand engagement.

Upon binding of DSL ligands presented on neighboring cells, ligand-induced endocytosis in the signal-sending cell generates a mechanical pulling force that destabilizes the NRR and exposes the S2 cleavage site [yamamoto-2010-endocytosis-abstract]. ADAM10, a member of the A Disintegrin And Metalloprotease family, is the essential protease for ligand-dependent S2 cleavage at the plasma membrane [van-tetering-2009-adam10-abstract]. Genetic and pharmacological studies have established that ADAM10, but not the related ADAM17/TACE, is required for canonical ligand-induced S2 cleavage. The S2 cleavage removes the extracellular domain and generates a membrane-anchored intermediate termed NEXT (Notch Extracellular Truncation).

The NEXT fragment serves as the substrate for gamma-secretase, a multiprotein complex comprising presenilin (the catalytic subunit), nicastrin, PEN2, and APH1. Gamma-secretase catalyzes intramembrane proteolysis at the S3 site within the transmembrane domain, releasing NICD into the cytoplasm [kopan-2009-canonical-notch-abstract]. Nicastrin functions as a docking receptor that recognizes the newly generated free N-terminus of NEXT and hauls it into the processing machinery. The S3 cleavage is not absolutely precise but rather occurs progressively at multiple sites within the transmembrane domain, generating NICD species of slightly different lengths as well as small Notch-beta peptides.

Importantly, the disease-associated mutations in T-ALL that disrupt the hydrophobic core of the HD domain can permit S2-like cleavage by alternative, as-yet-unidentified proteases even in the absence of ligand or when ADAM metalloproteases are pharmacologically inhibited [van-tetering-2009-adam10-abstract]. This observation has significant implications for therapeutic targeting of NOTCH signaling in cancer.

4. Subcellular Localization and Trafficking

NOTCH1 exhibits dynamic subcellular localization that is intimately linked to its signaling function. The mature NOTCH1 heterodimer resides at the plasma membrane as a type I transmembrane receptor, where it is poised to detect ligands on adjacent cells [yamamoto-2010-endocytosis-abstract]. NOTCH1 is not uniformly distributed across the cell surface but rather localizes to sites of cell-cell contact where ligand engagement can occur. The plasma membrane localization of NOTCH1 depends on proper maturation through the secretory pathway, including S1 cleavage and glycosylation events in the ER and Golgi apparatus.

Endocytosis plays critical and distinct roles in both signal-sending and signal-receiving cells. In the signal-receiving cell, clathrin-dependent endocytosis can remove unstimulated NOTCH1 from the cell surface for lysosomal degradation, thereby regulating receptor abundance and signaling capacity. Loss of function of regulators of early endosomal formation and trafficking, including dynamin, clathrin, Rab5, or avalanche, leads to accumulation of NOTCH1 at the plasma membrane [yamamoto-2010-endocytosis-abstract]. A conserved dileucine sorting signal within the NOTCH1 cytoplasmic tail directs the receptor to the limiting membrane of late endosomes/lysosomes. Following S2 and S3 cleavages, the released NICD rapidly translocates to the nucleus.

In signal-sending cells, ligand endocytosis is essential for generating the mechanical force required to expose the NOTCH1 S2 cleavage site. The prevailing "pulling force" model posits that following ligand-receptor engagement, ubiquitination of the ligand by E3 ubiquitin ligases (Neuralized or Mind bomb) triggers formation of epsin-dependent endocytic structures that generate mechanical tension on the NOTCH1 NRR [yamamoto-2010-endocytosis-abstract]. This force pulls the NECD away from the membrane-anchored NTM fragment, unmasking the metalloprotease cleavage site. Transendocytosis of the NECD-ligand complex into the ligand-expressing cell has been directly observed experimentally.

The subcellular location of gamma-secretase-mediated S3 cleavage remains debated. While some evidence suggests S3 cleavage occurs at the plasma membrane concurrent with S2 cleavage, other studies indicate that NEXT may need to be internalized into endosomal compartments where gamma-secretase activity is enriched [yamamoto-2010-endocytosis-abstract]. Resolution of this question has important implications for understanding how endocytic trafficking modulates signal strength and duration.

5. Canonical Notch Signaling Pathway

Canonical NOTCH1 signaling operates through a remarkably direct mechanism in which the receptor itself transmits the signal from membrane to nucleus without intervening second messengers. Upon release from the membrane, NICD translocates to the nucleus where it engages the DNA-binding protein RBPJ (also known as CSL, CBF1, Su(H), or Lag-1) [kopan-2009-canonical-notch-abstract]. In the absence of NICD, RBPJ functions as a transcriptional repressor by recruiting a multiprotein corepressor complex containing NCOR1/2, HDAC1/2, SPEN, and other chromatin-modifying factors. The arrival of NICD converts RBPJ from a repressor to an activator through a transcriptional switch mechanism.

The transcriptional switch occurs in a stepwise manner. The RAM domain of NICD binds to RBPJ with high affinity, displacing corepressor components. The ankyrin repeat domain then engages RBPJ through a distinct binding interface, creating a composite groove that recruits coactivators of the Mastermind-like (MAML) family [nam-2006-notch2-nrr-abstract]. MAML proteins further recruit histone acetyltransferases (p300/CBP), chromatin remodeling factors, and the Mediator complex to drive transcriptional activation. The assembled ternary complex of RBPJ-NICD-MAML, termed the Notch transcription complex (NTC), activates expression of target genes.

Genome-wide studies have revealed that the majority of functional NOTCH1-binding sites localize to distal enhancers rather than promoters, with fewer than 10% of sites showing dynamic changes in NOTCH1 occupancy when cells toggle between signaling-on and signaling-off states [wang-2013-superenhancers-abstract]. The most functionally relevant dynamic binding sites frequently lie within superenhancers—exceptionally broad regulatory elements characterized by high levels of H3K27 acetylation—and often overlap with binding sites for lineage-specific transcription factors such as RUNX1. This organization suggests that NOTCH1 functions primarily by modulating the activity of developmental enhancers that are pre-established by other factors.

Signal termination is achieved through NICD degradation. During transcriptional activation, NICD becomes phosphorylated on its PEST domain by CDK8, creating a phosphodegron recognized by the E3 ubiquitin ligase FBXW7 (also known as SEL10) [kopan-2009-canonical-notch-abstract]. Ubiquitination of NICD targets it for proteasomal destruction, ensuring that Notch signaling produces transient pulses of gene activation rather than sustained transcription. Mutations that truncate the PEST domain, as frequently observed in T-ALL, stabilize NICD and prolong signaling output [ferrando-2009-tall-abstract].

6. Non-Canonical Notch Signaling

In addition to the canonical CSL-dependent pathway, mounting evidence has revealed that NOTCH1 can function through non-canonical mechanisms that operate independently of ligands or CSL transcription factors [andersen-2012-noncanonical-abstract]. Some of the earliest evidence for non-canonical Notch signaling came from studies in which increased Notch1 levels inhibited the differentiation of myoblast cells into muscle cells. Researchers found that this inhibition did not require the CSL-interacting domain of Notch1 and was not mediated by CSL or known Notch target genes, suggesting the existence of a CSL-independent pathway.

In vivo studies in Drosophila provided compelling support for ligand/CSL-independent Notch function. Notch loss-of-function experiments revealed that Notch exerts inhibitory effects to select muscle progenitors from the mesoderm even in the absence of ligand and/or CSL [andersen-2012-noncanonical-abstract]. This finding demonstrated that non-canonical Notch function is present and active during normal development, not merely a pathological phenomenon.

A particularly well-characterized non-canonical mechanism involves the interaction between membrane-bound NOTCH1 and active beta-catenin, the central effector of canonical Wnt signaling. Endogenous Notch protein is predominantly detected at the cell membrane and cytoplasm but rarely in the nucleus under basal conditions. Evidence indicates that Notch can form a complex with active beta-catenin and promote its degradation via endo-lysosomal pathways, distinct from the canonical beta-catenin destruction complex mechanism involving GSK3beta and APC [andersen-2012-noncanonical-abstract]. This antagonistic interaction with Wnt signaling appears to be evolutionarily conserved from Drosophila to mammals and may represent an important tumor suppressor function of Notch.

Additional non-canonical pathways involve direct interactions between NICD and other transcription factors or signaling molecules. In human myelogenous leukemia cells, Notch1 directly interacts with the transcription factor YY1 to drive expression of c-MYC independently of CSL. Non-canonical activation of NF-kappaB via the IKK signalosome by Notch1 has been described in T-ALL, cervical cancer, and colorectal cancer. NICD has also been shown to interact with the mTOR-Rictor complex, leading to activation of downstream targets independently of CBF1/RBPJ. These findings indicate that NOTCH1 integrates with multiple signaling networks through both canonical and non-canonical mechanisms, potentially explaining some of its context-dependent effects in development and disease.

7. Target Genes and Transcriptional Programs

The best-characterized direct transcriptional targets of NOTCH1 belong to the HES (Hairy and Enhancer of Split) and HEY (Hairy/Enhancer-of-split related with YRPW motif) families of basic helix-loop-helix transcriptional repressors [wang-2013-superenhancers-abstract]. HES1, HES5, HEY1, HEY2, and HEYL are induced rapidly upon NOTCH activation and encode proteins that repress transcription of proneural genes, thereby inhibiting differentiation and maintaining progenitor cell states. The HES/HEY genes exemplify the "lateral inhibition" paradigm whereby NOTCH signaling in one cell suppresses differentiation, allowing neighboring cells with lower NOTCH activity to differentiate.

Beyond the HES/HEY family, NOTCH1 regulates an array of context-dependent target genes that vary according to cell type and developmental stage. In T-cell development and T-ALL, prominent direct targets include c-MYC, which drives cell growth and metabolic reprogramming; DELTEX1 (DTX1), a ubiquitin ligase that participates in feedback regulation; NRARP, which encodes a negative regulator of NOTCH signaling; IL7R, the interleukin-7 receptor required for T-cell survival and proliferation; and PTCRA (pre-T-cell receptor alpha), essential for T-cell development [ferrando-2009-tall-abstract] [wang-2013-superenhancers-abstract]. The c-MYC gene represents a particularly important oncogenic target, as NOTCH1 directly activates c-MYC transcription through binding to an enhancer located 1.4 Mb downstream of the promoter, and sustained c-MYC expression can partially bypass the requirement for NOTCH signaling in T-ALL cells.

The transcriptional output of NOTCH1 signaling is fundamentally context-dependent, determined by the pre-existing epigenetic landscape, the repertoire of lineage-specific transcription factors, and the available partner proteins at target enhancers. NOTCH1 collaborates with RUNX1 in hematopoietic cells, with GATA3 in T-cells, and with distinct partner factors in other cellular contexts [wang-2013-superenhancers-abstract]. This combinatorial logic explains how a single, seemingly simple signaling pathway can regulate vastly different transcriptional programs in different developmental contexts.

8. Post-Translational Modifications and Signaling Modulation

NOTCH1 undergoes extensive post-translational modifications that regulate its trafficking, stability, and signaling properties. Most notably, the EGF repeats within the extracellular domain are modified by O-linked glycosylation that profoundly affects ligand-receptor interactions [moloney-2000-fringe-gtase-abstract]. O-fucosylation, catalyzed by protein O-fucosyltransferase 1 (POFUT1), adds fucose residues to serine or threonine within the consensus sequence C2-X-X-X-X-(S/T)-C3 present in many EGF repeats. At least 21 of the 36 EGF repeats in human NOTCH1 carry O-fucose modifications. POFUT1-mediated O-fucosylation is essential for Notch signaling, as genetic ablation of POFUT1 phenocopies Notch loss-of-function in model organisms.

The crystal structure of the Notch1-DLL4 complex revealed the critical role of O-fucose at the molecular level [luca-2015-dll4-structure-abstract]. The O-fucose modification at Thr466 in EGF12 centrally anchors the DLL4-binding interface, essentially acting as a "surrogate amino acid." This glycan buries more than 80% of its total surface area at the interface, making direct contacts with DLL4 residues. The elucidation of this direct chemical role for O-glycans in ligand engagement demonstrates how Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.

The O-fucose residues serve as substrates for Fringe family glycosyltransferases (Lunatic Fringe, Manic Fringe, and Radical Fringe in mammals), which add N-acetylglucosamine (GlcNAc) in a beta-1,3 linkage [moloney-2000-fringe-gtase-abstract]. Fringe-mediated elongation of O-fucose alters the binding properties of NOTCH1, potentiating interactions with Delta-like ligands while inhibiting interactions with Jagged/Serrate ligands. This differential modulation provides a mechanism for spatially and temporally regulating Notch signaling specificity during development. The obligate dependence on glycosylation links NOTCH1 functional capacity to developmentally regulated biosynthetic pathways.

Additional modifications regulate NICD stability and activity in the nucleus. Phosphorylation of the PEST domain by CDK8 primes NICD for recognition by FBXW7 and subsequent ubiquitin-mediated degradation [kopan-2009-canonical-notch-abstract]. Sumoylation of NICD has been reported to repress its transcriptional activity under cellular stress conditions. Acetylation and methylation of specific lysine residues may also modulate NICD function, though these modifications are less well characterized.

9. Biological Functions and Developmental Roles

NOTCH1 participates in a remarkably diverse array of biological processes united by the common theme of cell fate determination through lateral inhibition and boundary formation. In the hematopoietic system, NOTCH1 is essential for the emergence of definitive hematopoietic stem cells (HSCs) from hemogenic endothelium in the aorta-gonad-mesonephros (AGM) region during embryonic development [kumano-2003-hsc-abstract]. Notch1-deficient embryos fail to generate neonatal-repopulating HSCs, while Notch2 is dispensable for this process. NOTCH1 promotes specification of hemogenic endothelial cells through activation of downstream targets including FOXC2. At later stages of hematopoiesis, NOTCH1 signaling is absolutely required for T-cell lineage commitment at the expense of B-cell and myeloid fates, with NOTCH1 activation increasing HSC self-renewal while favoring lymphoid over myeloid differentiation.

In cardiac development, NOTCH1 plays crucial roles in valve formation, myocardial trabeculation, and vascular development. NOTCH1 is expressed in cardiomyocytes, endothelial cells, and smooth muscle cells within the developing heart. Loss-of-function mutations in human NOTCH1 cause bicuspid aortic valve, the most common congenital cardiac malformation affecting 1-2% of the population [garg-2005-aortic-valve-abstract]. Moreover, NOTCH1 haploinsufficiency leads to progressive calcific aortic valve disease, the third leading cause of heart disease in adults. Mechanistically, NOTCH1 represses the activity of RUNX2, a master transcriptional regulator of osteoblast differentiation; loss of NOTCH1 function de-represses RUNX2, permitting inappropriate osteogenic differentiation and calcium deposition in valve tissue [garg-2005-aortic-valve-abstract].

In the nervous system, NOTCH1 maintains neural progenitor cells in an undifferentiated state by activating HES genes that repress proneural transcription factors. Lateral inhibition through Notch signaling ensures that only a subset of progenitor cells differentiate into neurons while neighbors remain as progenitors. NOTCH1 also regulates boundary formation between developmental compartments, axon guidance, and neuronal plasticity in the adult brain. In skeletal muscle, Notch signaling maintains satellite cell quiescence and regulates myogenic differentiation during development and regeneration.

10. Disease Associations and Therapeutic Targeting

Dysregulation of NOTCH1 signaling underlies multiple human diseases spanning developmental disorders and cancer. The most prominent oncogenic role of NOTCH1 occurs in T-cell acute lymphoblastic leukemia (T-ALL), where activating mutations are found in over 50% of cases [ferrando-2009-tall-abstract]. T-ALL-associated NOTCH1 mutations cluster in two regions: the heterodimerization domain (HD) of the NRR and the C-terminal PEST domain. HD mutations destabilize the autoinhibited conformation, causing either ligand-hypersensitive or ligand-independent receptor activation. PEST domain mutations are truncating alterations that delete the degron recognized by FBXW7, stabilizing NICD and prolonging signaling output. Approximately 15% of T-ALL cases also harbor loss-of-function mutations in FBXW7 itself, which similarly stabilize NICD [ferrando-2009-tall-abstract].

Activated NOTCH1 drives T-ALL through multiple downstream mechanisms including direct transcriptional activation of c-MYC, activation of the PI3K-AKT-mTOR pathway promoting cell survival and growth, enhancement of NF-kappaB signaling, and upregulation of anabolic metabolism. Gamma-secretase inhibitors (GSIs) that block NOTCH processing have shown activity against T-ALL cells in vitro, but clinical trials have been complicated by on-target gastrointestinal toxicity arising from NOTCH inhibition in intestinal stem cells and by resistance mechanisms including PTEN loss [ferrando-2009-tall-abstract].

Therapeutic antibodies targeting the NOTCH1 NRR represent a promising alternative to GSIs. Phage display technology has been used to generate highly specialized antibodies that specifically antagonize individual Notch receptor paralogues [wu-2010-therapeutic-antibodies-abstract]. Structural analysis revealed that these inhibitory antibodies function by stabilizing NRR quiescence. Critically, studies demonstrated that while simultaneous inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, representing a clear advantage over pan-Notch inhibitors. Brontictuzumab (OMP-52M51), an anti-Notch1 NRR antibody, was tested in phase I clinical trials for hematologic malignancies; while generally well tolerated, it showed limited antitumor efficacy as monotherapy.

NOTCH1 plays context-dependent roles in other cancers. While NOTCH1 acts as an oncogene in T-ALL and some solid tumors, it functions as a tumor suppressor in squamous cell carcinomas of the skin, head and neck, and esophagus, where inactivating NOTCH1 mutations are frequent. This dual nature reflects the context-dependent outcomes of Notch signaling in different cellular environments.

In congenital disease, heterozygous NOTCH1 mutations cause Adams-Oliver syndrome, a rare disorder characterized by aplasia cutis congenita and terminal transverse limb defects. NOTCH1 mutations also cause bicuspid aortic valve and calcific aortic valve disease as described above [garg-2005-aortic-valve-abstract].

11. Evolutionary Conservation

The Notch signaling pathway is ancient and highly conserved across metazoan evolution, underscoring its fundamental importance in animal development. In Drosophila melanogaster, there is a single Notch gene containing 36 EGF repeats. In Caenorhabditis elegans, two Notch paralogs exist: LIN-12 (13 EGF repeats) and GLP-1 (10 EGF repeats). Mammals possess four Notch receptors (NOTCH1-4) ranging from 29-36 EGF repeats. Double mutants lacking zygotic lin-12 and glp-1 activity in C. elegans die with discrete defects, and GLP-1 can functionally substitute for LIN-12 in certain cell fate decisions, providing evidence for both functional divergence and residual redundancy between these ancient paralogs.

Phylogenetic analyses confirm that an independent duplication event in the C. elegans lineage gave rise to LIN-12 and GLP-1, while vertebrate Notch genes arose from two rounds of whole-genome duplication that occurred before the divergence of teleosts and tetrapods. Human NOTCH1, NOTCH2, and NOTCH3 genes reside in syntenic chromosomal regions, providing genomic evidence for their origin from these ancient duplications. The conservation extends beyond the receptors to include all principal pathway components: DSL family ligands (Delta-like and Jagged in mammals), the CSL transcription factor (RBPJ), and downstream effectors of the HES/HEY families.

Functional conservation is equally striking. Notch1 signaling induced by Delta1 is necessary for somitogenesis in vertebrates, and Delta/Notch signaling is also required for segmentation in spiders, suggesting that Notch signaling evolved for use in segmentation in the common ancestor of protostomes and deuterostomes. The EGF repeat structures reveal conserved interfaces on both receptor and ligand that are important for trans-signaling and cis-inhibition across species, as demonstrated by in vivo assays in Drosophila using vertebrate sequences.

12. Open Questions

Despite decades of intensive investigation, several fundamental questions about NOTCH1 function remain unresolved. The precise subcellular location and regulation of gamma-secretase-mediated S3 cleavage continues to be debated, with evidence supporting both plasma membrane and endosomal models [yamamoto-2010-endocytosis-abstract]. Understanding where S3 cleavage occurs has important implications for how trafficking pathways modulate signaling output. The molecular basis for cis-inhibition, wherein NOTCH1 and ligands expressed on the same cell surface inhibit each other's function, remains poorly defined structurally and mechanistically [chillakuri-2012-receptor-ligand-abstract].

The extent to which NOTCH1 paralogs (NOTCH2, NOTCH3, NOTCH4) exhibit functional specificity versus redundancy is incompletely understood. While some specificity arises from differential expression patterns, the ankyrin repeat domains of different Notch receptors have distinct transcriptional potencies and target gene preferences, suggesting intrinsic functional differences that warrant further investigation.

The role of NOTCH1 signaling in adult tissue homeostasis remains controversial, particularly in the hematopoietic system where conflicting results have emerged regarding whether Notch signaling maintains adult HSCs. The mechanisms by which NOTCH1 functions as an oncogene in some contexts (T-ALL) but a tumor suppressor in others (squamous carcinomas) require deeper understanding. The relative contributions of canonical versus non-canonical Notch signaling to these context-dependent outcomes remain to be fully elucidated [andersen-2012-noncanonical-abstract].

From a therapeutic perspective, developing strategies to inhibit oncogenic NOTCH1 signaling while sparing normal NOTCH function remains challenging. Paralog-selective antibodies targeting the NRR show promise for avoiding pan-Notch inhibition toxicity [wu-2010-therapeutic-antibodies-abstract], but resistance mechanisms and the genetic complexity of NOTCH-driven cancers present ongoing obstacles. Understanding how NOTCH1 cooperates with other oncogenic pathways may reveal combination approaches with improved therapeutic indices. The development of Notch-activating therapies for conditions where NOTCH1 signaling is beneficial (such as tissue regeneration or prevention of valve calcification) represents an emerging area of interest.

13. References

[kopan-2009-canonical-notch-abstract] Kopan R, Ilagan MXG. The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism. Cell. 2009;137(2):216-233. DOI: 10.1016/j.cell.2009.03.045. PMID: 19379690. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC2827930/
[gordon-2008-nrr-structure-abstract] Gordon WR, Roy M, Vardar-Ulu D, Garfinkel M, Mansour MR, Aster JC, Blacklow SC. Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood. 2009;113(18):4381-4390. DOI: 10.1182/blood-2008-08-174748. PMID: 19075186. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC2676092/
[van-tetering-2009-adam10-abstract] van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M. Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage. J Biol Chem. 2009;284(45):31018-31027. DOI: 10.1074/jbc.M109.006775. PMID: 19726682. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC2781502/
[ferrando-2009-tall-abstract] Ferrando AA. The role of NOTCH1 signaling in T-ALL. Hematology Am Soc Hematol Educ Program. 2009:353-361. DOI: 10.1182/asheducation-2009.1.353. PMID: 20008221. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC2847371/
[chillakuri-2012-receptor-ligand-abstract] Chillakuri CR, Sheppard D, Lea SM, Handford PA. Notch receptor-ligand binding and activation: Insights from molecular studies. Semin Cell Dev Biol. 2012;23(4):421-428. DOI: 10.1016/j.semcdb.2012.01.009. PMID: 22326375. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC3415683/
[yamamoto-2010-endocytosis-abstract] Yamamoto S, Charng WL, Bellen HJ. Endocytosis and Intracellular Trafficking of Notch and Its Ligands. Curr Top Dev Biol. 2010;92:165-200. DOI: 10.1016/S0070-2153(10)92005-X. PMID: 20816395. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC6233319/
[wang-2013-superenhancers-abstract] Wang H, Zang C, Taing L, Arnett KL, Wong YJ, Pear WS, Blacklow SC, Liu XS, Aster JC. NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. Proc Natl Acad Sci USA. 2014;111(2):705-710. DOI: 10.1073/pnas.1315023111. PMID: 24374627. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC3896193/
[garg-2005-aortic-valve-abstract] Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270-274. DOI: 10.1038/nature03940. PMID: 16025100. URL: https://www.nature.com/articles/nature03940
[moloney-2000-fringe-gtase-abstract] Moloney DJ, Panin VM, Johnston SH, et al. Fringe is a glycosyltransferase that modifies Notch. Nature. 2000;406(6794):369-375. DOI: 10.1038/35019000. PMID: 10935626. URL: https://www.nature.com/articles/35019000
[kumano-2003-hsc-abstract] Kumano K, Chiba S, Kunisato A, et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity. 2003;18(5):699-711. DOI: 10.1016/s1074-7613(03)00117-1. PMID: 12753746.
[nam-2006-notch2-nrr-abstract] Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell. 2006;124(5):973-983. DOI: 10.1016/j.cell.2005.12.037. PMID: 16530044.
[luca-2015-dll4-structure-abstract] Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC. Structural basis for Notch1 engagement of Delta-like 4. Science. 2015;347(6224):847-853. DOI: 10.1126/science.1261093. PMID: 25700513. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC4445638/
[andersen-2012-noncanonical-abstract] Andersen P, Uosaki H, Shenje L, Kwon C. Non-Canonical Notch Signaling: Emerging Role and Mechanism. Trends Cell Biol. 2012;22(5):257-265. DOI: 10.1016/j.tcb.2012.02.003. PMID: 22397947. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC3348455/
[wu-2010-therapeutic-antibodies-abstract] Wu Y, Cain-Hom C, Choy L, et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 2010;464(7291):1052-1057. DOI: 10.1038/nature08878. PMID: 20393564. URL: https://www.nature.com/articles/nature08878

Citations

andersen-2012-noncanonical-abstract.md
ferrando-2009-tall-abstract.md
ferrando-2009-tall-summary.md
garg-2005-aortic-valve-abstract.md
gordon-2008-nrr-structure-abstract.md
gordon-2008-nrr-structure-summary.md
haines-2003-fringe-abstract.md
kopan-2009-canonical-notch-abstract.md
kopan-2009-canonical-notch-summary.md
kumano-2003-hsc-abstract.md
luca-2015-dll4-structure-abstract.md
moloney-2000-fringe-gtase-abstract.md
nam-2006-notch2-nrr-abstract.md
van-tetering-2009-adam10-abstract.md
wang-2013-superenhancers-abstract.md
wu-2010-therapeutic-antibodies-abstract.md
yamamoto-2010-endocytosis-abstract.md

Deep Research Falcon

(NOTCH1-deep-research-falcon.md)

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gene_info: Name=NOTCH1; Synonyms=TAN1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the NOTCH family. .
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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: P46531
Protein Description: RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch 1; Short=hN1; AltName: Full=Translocation-associated notch protein TAN-1; Contains: RecName: Full=Notch 1 extracellular truncation; Short=NEXT; Contains: RecName: Full=Notch 1 intracellular domain; Short=NICD; Flags: Precursor;
Gene Information: Name=NOTCH1; Synonyms=TAN1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the NOTCH family. .
Key Domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032); EGF-like_dom. (IPR000742)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "NOTCH1" 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 NOTCH1 (gene ID: NOTCH1, UniProt: P46531) 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

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: P46531
Protein Description: RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch 1; Short=hN1; AltName: Full=Translocation-associated notch protein TAN-1; Contains: RecName: Full=Notch 1 extracellular truncation; Short=NEXT; Contains: RecName: Full=Notch 1 intracellular domain; Short=NICD; Flags: Precursor;
Gene Information: Name=NOTCH1; Synonyms=TAN1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the NOTCH family. .
Key Domains: Ankyrin_rpt. (IPR002110); Ankyrin_rpt-contain_sf. (IPR036770); EGF-like_Ca-bd_dom. (IPR001881); EGF-like_CS. (IPR013032); EGF-like_dom. (IPR000742)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "NOTCH1" 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 NOTCH1 (gene ID: NOTCH1, UniProt: P46531) 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.

Plan (concise)
- Verified target identity and domain architecture for human NOTCH1 (UniProt P46531).
- Summarized key concepts/definitions and canonical activation with recent sources.
- Compiled recent (2023–2024) developments in structure/mechanism, PTMs, and subcellular localization.
- Reviewed disease roles and quantitative data (esp. T-ALL) and endothelial/neuro roles.
- Summarized current applications: GSIs (including PSEN1-selective), ADAM inhibition, antibodies, and transcription-complex blockers; noted clinical/preclinical status with dates/URLs where available.
- Wrote an integrated research report with citations.

Comprehensive research report: Human NOTCH1 (UniProt P46531)

1) Key concepts and definitions with current understanding
- Target verification. NOTCH1 encodes a single-pass transmembrane receptor of the NOTCH family with a large extracellular domain containing multiple EGF-like repeats, a Negative Regulatory Region (LNR + HD), a transmembrane helix, and an intracellular domain (NICD) that bears a RAM region, ankyrin (ANK) repeats, nuclear localization sequences, a transcriptional activation region, and a C-terminal PEST degron—consistent with UniProt P46531 and contemporary reviews (human, Homo sapiens) (https://doi.org/10.1038/s41392-024-01828-x, May 2024; https://doi.org/10.3390/genes15050529, Apr 2024) (shi2024notchsignalingpathway pages 1-2, papageorgiou2024snpandstructural pages 2-3).
- Canonical Notch signaling. Ligand engagement (Jagged/Delta family) on a neighboring cell triggers proteolytic activation of NOTCH1: S2 cleavage by ADAM10/17 produces NEXT; S3/S4 intramembrane cleavage by the γ-secretase complex releases NICD, which enters the nucleus to form the CSL/RBPJ–MAML ternary complex that displaces corepressors and recruits co-activators to drive target genes (e.g., HES/HEY) (https://doi.org/10.1038/s41392-024-01828-x, 2024) (shi2024notchsignalingpathway pages 1-2). Mechanical pulling via ligand endocytosis facilitates exposure of the S2 site, and cis-inhibition/cis-activation dynamics modulate signal strength (2024 overview) (feng2024thestructuraland pages 25-28).
- Primary molecular role. NOTCH1 is a juxtacrine signal transducer that directly converts cell–cell contact into transcriptional responses without second messengers; its intracellular domain functions as a transcriptional co-activator with CSL/RBPJ and MAML rather than an enzyme (https://doi.org/10.1038/s41392-024-01828-x, 2024) (shi2024notchsignalingpathway pages 1-2).

2) Recent developments and latest research (emphasis 2023–2024)
- Domain architecture and activation refinements. Contemporary cancer-focused reviews reaffirm the modular organization (EGF repeats, NRR, TMD, RAM/ANK/PEST) and the proteolytic steps S1 (Furin), S2 (ADAMs), S3/S4 (γ-secretase) with ligand dependence, and clarify that S2 is the sole ligand-dependent step (2024) (shi2024notchsignalingpathway pages 1-2, martinezgascuena2025modulationofoncogenic pages 3-5).
- Subcellular trafficking/localization. Updated schematics emphasize maturation in the ER/Golgi (S1), surface activation at the plasma membrane, complex endocytosis in the ligand-presenting cell that exerts force on NOTCH1, subsequent γ-secretase cleavage likely in the plasma membrane/early endosome, NICD nuclear translocation, and RBPJ corepressor exchange (2024) (feng2024thestructuraland pages 25-28).
- Post-translational regulation. 2024–2025 syntheses highlight O-fucose, O-glucose, and O-GlcNAc modifications on NOTCH1 EGF repeats; Fringe-mediated elongation modulates ligand selectivity (enhancing DLL4/NOTCH1 and often attenuating JAG interactions). Phosphorylation of the PEST region (and adjacent degron motifs) recruits FBXW7 to promote NICD turnover; PEST deletions or FBXW7 impairment stabilize NICD (2024) (shi2024notchsignalingpathway pages 1-2, sergio2024notchinhibitorsand pages 7-8). SERCA-dependent ER calcium is required for S1 maturation and trafficking; SERCA inhibition selectively impairs mutant NOTCH1 in T-ALL (2024) (sergio2024notchinhibitorsand pages 7-8).
- Disease-mechanistic nuances. Cancer overviews in 2024 reinforce the context-dependent oncogene/tumor-suppressor roles: activating NOTCH1 is classical in T-ALL; loss-of-function alterations in squamous carcinomas often indicate a tumor-suppressive role; DLL4 vs JAG1 exert opposing angiogenic effects (2024) (shi2024notchsignalingpathway pages 1-2, martinezgascuena2025modulationofoncogenic pages 5-7).

3) Function, pathways, and subcellular localization
- Function and pathway position. NOTCH1 sits at the apex of a conserved cell-fate pathway. Upon activation by DSL ligands (DLL1/3/4; JAG1/2), NICD enters the nucleus and converts CSL/RBPJ from a repressor (with SHARP/FHL corepressors) to an activator by recruiting MAML and co-activators (p300/Mediator), initiating transcription of targets that regulate lineage decisions, proliferation, and survival (2024) (shi2024notchsignalingpathway pages 1-2, feng2024thestructuraland pages 25-28).
- Subcellular localization (where NOTCH1 acts). In resting cells, NOTCH1 resides primarily at the plasma membrane as a calcium-stabilized heterodimer formed by S1 furin cleavage; activation involves membrane-proximal (S2) cleavage and intramembrane (S3/S4) proteolysis with NICD accumulation in the nucleus to execute function (2024) (feng2024thestructuraland pages 25-28).
- Key post-translational modifications. EGF-repeat O-glycans (O-fucose, O-glucose, O-GlcNAc) regulate ligand binding, receptor stability, and trafficking; Fringe-mediated extension of O-fucose specifically biases ligand responsiveness. NICD PEST-phosphorylation enables FBXW7-mediated proteasomal degradation; PEST truncations stabilize NICD and prolong signaling (2024) (shi2024notchsignalingpathway pages 1-2, sergio2024notchinhibitorsand pages 7-8, feng2024thestructuraland pages 25-28).

4) Disease relevance and quantitative data (selected 2023–2024 highlights)
- T-cell acute lymphoblastic leukemia (T-ALL). Activating NOTCH1 mutations remain highly prevalent; contemporary summaries report approximately 60% of T-ALL harbor NOTCH1 activating lesions (e.g., HD/NRR alterations and/or C-terminal PEST truncations that stabilize NICD), establishing NOTCH1 as a driver and therapeutic target (Nov 2024; https://doi.org/10.3390/ijms252312839) (sergio2024notchinhibitorsand pages 7-8). Mechanisms include ligand-independent S2 exposure (NRR mutations), increased S3 processing, and NICD stabilization (PEST) (2024) (sergio2024notchinhibitorsand pages 7-8, martinezgascuena2025modulationofoncogenic pages 5-7).
- Other hematologic malignancies and solid tumors. Reviews synthesize roles for NOTCH1 in CLL and cutaneous, head and neck, lung squamous carcinomas (often as tumor suppressor when inactivated), and as an oncogenic driver in specific contexts (e.g., subsets of breast cancer and NSCLC), with pathway cross-talk influencing EMT, stemness, and angiogenesis (2024) (shi2024notchsignalingpathway pages 1-2, martinezgascuena2025modulationofoncogenic pages 5-7).
- Cardiovascular and developmental disorders. NOTCH1 mutations are implicated in congenital heart disease and calcific aortic valve disease; NOTCH signaling is essential for angiogenesis and cardiogenesis. CADASIL is chiefly a NOTCH3 disorder, helping distinguish gene-specific pathologies within the family (Apr 2024; https://doi.org/10.3390/genes15050529) (papageorgiou2024snpandstructural pages 2-3).
- Endothelium and neurobiology. 2024 syntheses emphasize endothelial DLL4–NOTCH1 in tip/stalk cell selection and vascular patterning, and roles in neural stem cell maintenance/adult neurogenesis, consistent with canonical nuclear NICD–RBPJ activity (2024) (shi2024notchsignalingpathway pages 1-2, feng2024thestructuraland pages 25-28).

5) Current applications and real-world implementations (therapeutics and tools)
- γ-secretase inhibitors (GSIs). Broad GSIs historically showed dose-limiting GI toxicity; however, clinical developments continue. Nirogacestat achieved efficacy in desmoid tumors (NEJM 2023), while other GSIs (crenigacestat/LY3039478, AL101) have been evaluated in T-ALL/adenoid cystic carcinoma; PSEN1-selective strategies are being advanced to improve therapeutic index in T-ALL by more selectively attenuating NOTCH1 S3 cleavage (2024 review) (vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117). For recent mechanistic/clinical context in oncology, see 2024 overview (https://doi.org/10.1038/s41392-024-01828-x) (shi2024notchsignalingpathway pages 1-2).
- ADAM protease inhibition. Inhibition of S2 cleavage (e.g., INCB7839/TMI-005) has been combined with trastuzumab and explored preclinically/clinically as a way to blunt ligand-dependent NOTCH activation (2024 review) (vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117).
- Ligand/receptor antibodies. Clinical and preclinical programs have targeted DLL4 (e.g., demcizumab, enoticumab) and NOTCH1 (e.g., brontictuzumab), with mixed efficacy and toxicity outcomes; contemporary reviews catalog these antibodies and their trial status up to 2023–2024 (2024 reviews) (vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117, shi2024notchsignalingpathway pages 1-2).
- Transcriptional complex inhibitors. CB-103, a small molecule designed to disrupt the NICD–CSL–MAML transcriptional complex, entered first-in-human studies by 2023; 2024 reviews summarize its early clinical trajectory (vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117).
- Upstream maturation targeting (SERCA). Given ER Ca2+-dependence of S1 maturation, SERCA inhibition can preferentially impair mutant NOTCH1 trafficking in T-ALL; medicinal chemistry aims for isoform-selective or targeted delivery approaches (Nov 2024; https://doi.org/10.3390/ijms252312839) (sergio2024notchinhibitorsand pages 7-8).

6) Expert perspectives and synthesis
- Mechanistic consensus. Across recent authoritative reviews, NOTCH1’s essential features are reaffirmed: direct cell–cell signal transduction, mechanical ligand activation, sequential proteolysis, and nuclear co-activator function with CSL/MAML. Modulation via EGF O-glycans and PEST/FBXW7 turnover provides precise, druggable regulatory nodes (2024) (shi2024notchsignalingpathway pages 1-2, feng2024thestructuraland pages 25-28, sergio2024notchinhibitorsand pages 7-8).
- Translational outlook (2023–2024). Oncology translation is refocusing from broad GSIs to higher-selectivity (e.g., PSEN1-biased) γ-secretase inhibition, ligand/receptor-blocking antibodies, and NICD–CSL–MAML disruptors; combination regimens and biomarker stratification (e.g., NOTCH1 mutation status, FBXW7) are expected to improve outcomes while mitigating on-target intestinal toxicity (2024) (vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117, shi2024notchsignalingpathway pages 1-2, sergio2024notchinhibitorsand pages 7-8).

7) Relevant statistics and data points (recent)
- T-ALL mutation frequency. Approximately 60% of T-ALL cases harbor activating NOTCH1 mutations, often combining NRR and PEST alterations to enhance NICD generation and stability (Nov 2024; https://doi.org/10.3390/ijms252312839) (sergio2024notchinhibitorsand pages 7-8).
- Clinical activity snapshots. Nirogacestat demonstrated efficacy in desmoid tumors (NEJM 2023), while crenigacestat and AL101 have been explored in hematologic/solid cancers; CB-103 progressed through phase I by 2023 (compiled in 2024 therapeutic reviews summarizing trial registries and publications) (vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117, shi2024notchsignalingpathway pages 1-2).

Notes on gene/protein identification
- Ambiguity check passed: The above research pertains to human NOTCH1 (Homo sapiens), a NOTCH family receptor with EGF-like repeats, NRR, TMD, and NICD bearing RAM/ANK domains and PEST, exactly matching UniProt P46531. No conflicting gene symbol usage was found in the cited 2024 sources (shi2024notchsignalingpathway pages 1-2, martinezgascuena2025modulationofoncogenic pages 3-5, papageorgiou2024snpandstructural pages 2-3).

Citations (with URLs and dates where available)
- Shi Q et al. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduction and Targeted Therapy. May 2024. https://doi.org/10.1038/s41392-024-01828-x (shi2024notchsignalingpathway pages 1-2).
- Sergio I et al. Notch Inhibitors and BH3 Mimetics in T-ALL. International Journal of Molecular Sciences. Nov 2024. https://doi.org/10.3390/ijms252312839 (sergio2024notchinhibitorsand pages 7-8).
- Papageorgiou L et al. SNP and Structural Study of the Notch Superfamily… Genes. Apr 2024. https://doi.org/10.3390/genes15050529 (papageorgiou2024snpandstructural pages 2-3).
- Vandersmissen C, Cools J, Segers H. PSEN1-selective γ-secretase inhibition for T-ALL (therapeutic review/overview). 2024; compiles GSIs (semagacestat, avagacestat), nirogacestat in desmoid (NEJM 2023), crenigacestat, AL101; CB-103; anti-NOTCH1/DLL4 antibodies; ADAM inhibition. (vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117).
- Feng X. Structural/functional significance of lipid-binding properties of human Notch ligands (mechanistic overview of activation, glycosylation, endocytosis, cis-regulation). 2024. (feng2024thestructuraland pages 25-28).
- Martínez-Gascueña P et al. Modulation of oncogenic NOTCH signaling by targeting γ-secretase (systematic review/preprint). Nov 2025. https://doi.org/10.20944/preprints202511.0585.v1 (mechanistic context, definitions) (martinezgascuena2025modulationofoncogenic pages 5-7, martinezgascuena2025modulationofoncogenic pages 3-5, martinezgascuena2025modulationofoncogenic pages 19-22).

References

(shi2024notchsignalingpathway pages 1-2): Qingmiao Shi, Chen Xue, Yifan Zeng, Xin Yuan, Qingfei Chu, Shuwen Jiang, Jinzhi Wang, Yaqi Zhang, Danhua Zhu, and Lan-Ju Li. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduction and Targeted Therapy, May 2024. URL: https://doi.org/10.1038/s41392-024-01828-x, doi:10.1038/s41392-024-01828-x. This article has 301 citations and is from a peer-reviewed journal.
(papageorgiou2024snpandstructural pages 2-3): Louis Papageorgiou, Lefteria Papa, Eleni Papakonstantinou, Antonia Mataragka, Konstantina Dragoumani, Dimitrios Chaniotis, Apostolos Beloukas, Costas Iliopoulos, Erik Bongcam-Rudloff, George P. Chrousos, Sofia Kossida, Elias Eliopoulos, and Dimitrios Vlachakis. Snp and structural study of the notch superfamily provides insights and novel pharmacological targets against the cadasil syndrome and neurodegenerative diseases. Genes, 15:529, Apr 2024. URL: https://doi.org/10.3390/genes15050529, doi:10.3390/genes15050529. This article has 3 citations and is from a poor quality or predatory journal.
(feng2024thestructuraland pages 25-28): X Feng. The structural and functional significance of lipid-binding properties of human notch ligands. Unknown journal, 2024.
(martinezgascuena2025modulationofoncogenic pages 3-5): Pablo Martínez-Gascueña, María-Luisa Nueda, and Victoriano Baladrón. Modulation of oncogenic notch signaling in highly aggressive neoplasia by targeting the g-secretase complex. a systematic review. Unknown journal, Nov 2025. URL: https://doi.org/10.20944/preprints202511.0585.v1, doi:10.20944/preprints202511.0585.v1.
(sergio2024notchinhibitorsand pages 7-8): Ilaria Sergio, Claudia Varricchio, Federica Squillante, Noemi Martina Cantale Aeo, Antonio Francesco Campese, and Maria Pia Felli. Notch inhibitors and bh3 mimetics in t-cell acute lymphoblastic leukemia. International Journal of Molecular Sciences, 25:12839, Nov 2024. URL: https://doi.org/10.3390/ijms252312839, doi:10.3390/ijms252312839. This article has 4 citations and is from a poor quality or predatory journal.
(martinezgascuena2025modulationofoncogenic pages 5-7): Pablo Martínez-Gascueña, María-Luisa Nueda, and Victoriano Baladrón. Modulation of oncogenic notch signaling in highly aggressive neoplasia by targeting the g-secretase complex. a systematic review. Unknown journal, Nov 2025. URL: https://doi.org/10.20944/preprints202511.0585.v1, doi:10.20944/preprints202511.0585.v1.
(vandersmissen2024psen1selectivegammasecretaseinhibition pages 114-117): C Vandersmissen, J Cools, and H Segers. Psen1-selective gamma-secretase inhibition for the treatment of t-cell acute lymphoblastic leukemia (t-all). Unknown journal, 2024.
(martinezgascuena2025modulationofoncogenic pages 19-22): Pablo Martínez-Gascueña, María-Luisa Nueda, and Victoriano Baladrón. Modulation of oncogenic notch signaling in highly aggressive neoplasia by targeting the g-secretase complex. a systematic review. Unknown journal, Nov 2025. URL: https://doi.org/10.20944/preprints202511.0585.v1, doi:10.20944/preprints202511.0585.v1.

Citations

shi2024notchsignalingpathway pages 1-2
feng2024thestructuraland pages 25-28
sergio2024notchinhibitorsand pages 7-8
papageorgiou2024snpandstructural pages 2-3
martinezgascuena2025modulationofoncogenic pages 3-5
martinezgascuena2025modulationofoncogenic pages 5-7
martinezgascuena2025modulationofoncogenic pages 19-22
https://doi.org/10.1038/s41392-024-01828-x,
https://doi.org/10.3390/genes15050529,
https://doi.org/10.3390/ijms252312839
https://doi.org/10.3390/genes15050529
https://doi.org/10.1038/s41392-024-01828-x
https://doi.org/10.20944/preprints202511.0585.v1
https://doi.org/10.20944/preprints202511.0585.v1,
https://doi.org/10.3390/ijms252312839,

Bioreason Rl Review

(NOTCH1-bioreason-rl-review.md)

BioReason-Pro RL Review: NOTCH1 (human)

Source: NOTCH1-deep-research-bioreason-rl.md

Correctness: 5/5
Completeness: 4/5

Functional Summary Review

The BioReason functional summary states:

A single-pass membrane receptor that presents a long, calcium-stabilized extracellular array of repeats to sense ligands and transmit mechanical signals into the cell. Ligand-induced tension triggers sequential proteolytic events that release a cytosolic tail built from ankyrin repeats, which then assembles transcriptional regulators to modulate gene expression programs controlling cell fate and tissue homeostasis. The protein operates at the membrane before trafficking to the nucleus, where it orchestrates target-gene regulation through modular protein-protein interaction surfaces.

This is an excellent summary that accurately captures NOTCH1's mechanism. The curated review describes NOTCH1 as a receptor for membrane-bound ligands (Delta/Jagged) that controls cell-fate decisions through the Notch signaling pathway (GO:0007219). BioReason correctly identifies:

The EGF-like repeat extracellular domain with calcium stabilization
The mechanical force requirement for S2 cleavage site exposure
Sequential proteolytic processing (S2 by ADAM10/TACE, S3 by gamma-secretase)
Release of the Notch intracellular domain (NICD) with ankyrin repeats
Nuclear translocation and transcriptional regulation
The membrane-to-nucleus signaling paradigm

The description of "calcium-stabilized extracellular array" correctly reflects the calcium-binding EGF domains. The mention of CSL/RBPJ transcription factors in the thinking trace is accurate.

Minor gaps:
1. Specific ligands (Delta-like, Jagged) are not named
2. The role of gamma-secretase in S3 cleavage is not explicitly mentioned
3. Specific developmental processes (heart development, neurogenesis) covered in the curated review are not addressed

Comparison with interpro2go:

The curated review includes IBA annotations for Notch signaling pathway (GO:0007219) and transmembrane signaling receptor activity (GO:0004888). BioReason's domain analysis of EGF repeats, Notch/NOD/NODP domains, and ankyrin repeats closely parallels what interpro2go would derive. BioReason adds significant mechanistic value by describing the proteolytic activation cascade and membrane-to-nucleus trafficking, which goes well beyond what domain mapping alone provides.

Notes on thinking trace

The trace demonstrates sophisticated reasoning about the NOTCH1 activation mechanism. The identification of S2/S3 cleavage sites from the NOD/NODP domain annotations is particularly insightful. The only oddity is the truncated UniProt summary containing Chinese characters ("cell-fate决定"), suggesting a Unicode issue in the source data.

📄 View Raw YAML

id: P46531
gene_symbol: NOTCH1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NOTCH1 is a type I transmembrane receptor that functions as a master regulator of cell-fate determination through juxtacrine signaling. Upon binding membrane-bound ligands (JAG1/2, DLL1/3/4) on neighboring cells, NOTCH1 undergoes sequential proteolytic cleavages by furin (S1 in Golgi), ADAM10/17 (S2 at plasma membrane), and gamma-secretase (S3/S4), releasing the Notch Intracellular Domain (NICD). NICD translocates to the nucleus where it forms a transcriptional activation complex with RBPJ and MAML coactivators to drive expression of target genes including HES and HEY family members. NOTCH1 plays essential roles in T-cell development, angiogenesis, neurogenesis, heart development, and somitogenesis. Mutations cause T-cell acute lymphoblastic leukemia (activating) and aortic valve disease/Adams-Oliver syndrome (loss-of-function).
existing_annotations:
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: NOTCH1 is the canonical receptor for the Notch signaling pathway. Upon ligand binding (JAG1/2, DLL1/3/4), NOTCH1 undergoes proteolytic cleavage releasing NICD which translocates to the nucleus to activate target genes via RBPJ/MAML complex.
    action: ACCEPT
    reason: This is the core function of NOTCH1. The protein is THE defining receptor of the Notch signaling pathway, as documented extensively in UniProt and literature (Shi et al. 2024, doi:10.1038/s41392-024-01828-x).
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: Notch proteins are transmembrane receptors that mediate intercell communication and direct individual cell fate decisions. The activated intracellular form of Notch, NotchIC, translocates to the nucleus, where it targets the DNA binding protein CBF1.
    - reference_id: file:human/NOTCH1/NOTCH1-deep-research-cyberian.md
      supporting_text: 'model: deep-research'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: NOTCH1 is a type I transmembrane receptor that resides at the plasma membrane where it receives ligand signals from adjacent cells.
    action: ACCEPT
    reason: Plasma membrane localization is essential for NOTCH1 receptor function. The mature NOTCH1 heterodimer traffics to and resides at the plasma membrane where it undergoes ligand-dependent activation. UniProt confirms cell membrane localization.
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: Notch proteins are transmembrane receptors that mediate intercell communication
- term:
    id: GO:0007411
    label: axon guidance
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: The IBA annotation derives from PTHR45836 family which includes both NOTCH receptors and SLIT proteins. Axon guidance is a primary function of SLIT proteins, not NOTCH1.
    action: REMOVE
    reason: This annotation likely results from family-level inference that inappropriately transfers SLIT protein functions to NOTCH1. While NOTCH signaling has roles in neurogenesis, axon guidance is not a characterized function of NOTCH1. SLIT1-3 proteins (also in PTHR45836) are the canonical axon guidance molecules.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: NOTCH1 is expressed at the cell surface where it functions as a receptor for trans-acting ligands on neighboring cells.
    action: ACCEPT
    reason: Cell surface localization is essential for NOTCH1 receptor function. The extracellular domain (N(EC)) binds ligands at the cell surface, triggering the proteolytic cascade.
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: Notch proteins are transmembrane receptors that mediate intercell communication
- term:
    id: GO:0043235
    label: receptor complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: NOTCH1 exists as a heterodimeric receptor complex formed by furin cleavage during maturation. The N(EC) and N(TM) fragments remain associated at the cell surface.
    action: ACCEPT
    reason: NOTCH1 forms a heterodimeric complex after S1 furin cleavage in the Golgi. The extracellular and transmembrane fragments are non-covalently associated. This is well-documented in UniProt and structural studies.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: NOTCH1 undergoes S1 cleavage by furin in the trans-Golgi network during maturation, converting the precursor into the functional heterodimer.
    action: ACCEPT
    reason: Golgi membrane localization is part of the NOTCH1 biosynthetic pathway. UniProt states the precursor is proteolytically cleaved by furin-like convertase in the trans-Golgi network before reaching the plasma membrane.
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: NOTCH1 plays a key role in angiogenesis by negatively regulating endothelial cell proliferation and migration. DLL4-NOTCH1 signaling controls tip/stalk cell selection during vascular development.
    action: KEEP_AS_NON_CORE
    reason: While angiogenesis is a well-documented biological context for NOTCH1 function, it represents a tissue-specific outcome rather than the core molecular function. UniProt confirms NOTCH1 is involved in angiogenesis, negatively regulating endothelial cell proliferation.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: NOTCH1 contains multiple EGF-like domains that bind calcium ions, which are essential for proper domain folding and ligand binding.
    action: ACCEPT
    reason: Calcium binding is a core molecular function of NOTCH1. The EGF-like calcium-binding domains (IPR001881) are essential for NOTCH1 structure and function. UniProt lists calcium ion binding in the domain annotations.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: The NOTCH1 intracellular domain (NICD) translocates to the nucleus following gamma-secretase cleavage to activate transcription.
    action: ACCEPT
    reason: Nuclear localization of NICD is essential for NOTCH1 signaling. UniProt confirms NICD translocates to the nucleus following proteolytical processing.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: NOTCH1 is synthesized and begins its maturation in the ER membrane before trafficking to the Golgi.
    action: ACCEPT
    reason: ER membrane localization is part of the NOTCH1 biosynthetic pathway. UniProt notes synthesis in the endoplasmic reticulum as an inactive form.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Mature NOTCH1 heterodimer resides at the plasma membrane where it functions as a receptor.
    action: ACCEPT
    reason: Plasma membrane is the primary site of NOTCH1 receptor function. Duplicate of IBA annotation - both are correct.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: NICD forms a transcriptional activation complex with RBPJ and MAML to regulate target gene expression.
    action: ACCEPT
    reason: Transcriptional regulation is a core downstream function of NOTCH1 signaling. The NICD-RBPJ-MAML complex directly activates transcription of target genes like HES and HEY family members.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NOTCH1 is the founding member and primary receptor of the Notch signaling pathway.
    action: ACCEPT
    reason: Duplicate of IBA annotation - this is the core function of NOTCH1. Both evidence codes correctly annotate this term.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: NOTCH1 is a type I transmembrane protein that localizes to various cellular membranes during its lifecycle.
    action: ACCEPT
    reason: Generic membrane annotation is correct but less informative than more specific terms (plasma membrane, Golgi membrane, ER membrane) which are also annotated.
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NOTCH1 is a master regulator of cell-fate determination and differentiation across multiple tissue contexts.
    action: ACCEPT
    reason: Cell differentiation regulation is a core biological role of NOTCH1 signaling. UniProt states NOTCH1 affects implementation of differentiation, proliferation and apoptotic programs.
- term:
    id: GO:0031902
    label: late endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Non-activated NOTCH1 receptor is targeted for lysosomal degradation via the endosomal pathway.
    action: ACCEPT
    reason: UniProt explicitly states late endosome membrane localization and notes that non-activated receptor is targeted for lysosomal degradation via the endosomal pathway.
- term:
    id: GO:0038023
    label: signaling receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: NOTCH1 functions as a signaling receptor that transduces cell-cell contact signals into transcriptional responses.
    action: ACCEPT
    reason: Signaling receptor activity is a core molecular function of NOTCH1. This is the primary role of the protein.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: NICD positively regulates transcription by forming a coactivator complex with RBPJ and MAML that displaces corepressors.
    action: ACCEPT
    reason: NOTCH1 NICD functions as a transcriptional activator. The NICD-RBPJ-MAML complex recruits coactivators like p300 to activate target gene transcription.
- term:
    id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: NOTCH1 has been reported to crosstalk with Ras/MAPK signaling in certain cellular contexts.
    action: KEEP_AS_NON_CORE
    reason: This represents crosstalk with other signaling pathways rather than the core NOTCH1 function. The canonical Notch pathway does not involve direct Ras activation, though downstream effects can influence Ras signaling.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: NOTCH1 binds calcium ions through its EGF-like domains.
    action: ACCEPT
    reason: Metal ion binding (specifically calcium) is correct but less specific than GO:0005509 calcium ion binding which is also annotated.
- term:
    id: GO:0050793
    label: regulation of developmental process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: NOTCH1 is a key regulator of developmental processes including cell fate determination.
    action: ACCEPT
    reason: Developmental regulation is a well-established function of NOTCH1. UniProt notes roles in postimplantation development, mesoderm development, somite formation, and neurogenesis.
- term:
    id: GO:0051152
    label: positive regulation of smooth muscle cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: NOTCH1 promotes vascular smooth muscle cell differentiation and is required for arterial smooth muscle development.
    action: KEEP_AS_NON_CORE
    reason: Smooth muscle differentiation is a tissue-specific developmental outcome of NOTCH1 signaling rather than a core function. It represents one of many differentiation contexts where NOTCH1 plays a role.
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: NOTCH1 can promote ERK1/2 signaling in certain cellular contexts, representing pathway crosstalk.
    action: KEEP_AS_NON_CORE
    reason: ERK cascade regulation is not part of canonical Notch signaling but may occur through indirect mechanisms or crosstalk in specific contexts.
- term:
    id: GO:0071228
    label: cellular response to tumor cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: NOTCH1 has been implicated in tumor microenvironment responses.
    action: KEEP_AS_NON_CORE
    reason: This is a specialized context-dependent role of NOTCH1 in cancer biology rather than a core function of the protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10713164
  review:
    summary: NOTCH1 NICD interacts with SNW1/SKIP, which facilitates NOTCH1 transcriptional function by competing with SMRT corepressor.
    action: REMOVE
    reason: Generic protein binding is uninformative. The specific interaction with SNW1/SKIP should be captured by more specific MF terms or documented via protein-protein interaction databases. NOTCH1 has many specific binding partners including RBPJ, MAML1/2/3, ligands, etc.
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12370315
  review:
    summary: Identifies NOTCH1 interaction with MAML2 and MAML3 transcriptional coactivators.
    action: REMOVE
    reason: Generic protein binding is uninformative. The specific MAML interactions are critical for transcriptional activation but should not be annotated with this overly broad term.
    supported_by:
    - reference_id: PMID:12370315
      supporting_text: Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16319921
  review:
    summary: NOTCH1 interaction with NF-kappaB to facilitate its nuclear retention.
    action: REMOVE
    reason: Generic protein binding is uninformative. This represents crosstalk with NF-kappaB signaling.
    supported_by:
    - reference_id: PMID:16319921
      supporting_text: Notch1 augments NF-kappaB activity by facilitating its nuclear retention.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16530044
  review:
    summary: Structural basis for MAML coactivator recruitment to NOTCH transcription complexes - crystal structure of NICD-RBPJ-MAML1 complex.
    action: REMOVE
    reason: Generic protein binding is uninformative. The structural study documents the ternary transcription complex, which is better captured by specific complex annotations.
    supported_by:
    - reference_id: PMID:16530044
      supporting_text: Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17284587
  review:
    summary: Studies cooperative assembly of higher-order Notch transcription complexes.
    action: REMOVE
    reason: Generic protein binding is uninformative. Documents transcription complex assembly dynamics.
    supported_by:
    - reference_id: PMID:17284587
      supporting_text: Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17318174
  review:
    summary: NOTCH1 interaction with XIAP to inhibit apoptosis.
    action: REMOVE
    reason: Generic protein binding is uninformative. The XIAP interaction represents a non-canonical NOTCH1 function.
    supported_by:
    - reference_id: PMID:17318174
      supporting_text: Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17909182
  review:
    summary: KSHV LANA stabilizes activated NOTCH by targeting FBXW7.
    action: REMOVE
    reason: Generic protein binding is uninformative. This is about viral protein interaction and NOTCH1 regulation.
    supported_by:
    - reference_id: PMID:17909182
      supporting_text: Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18427106
  review:
    summary: NOTCH1 signaling in hypoxia-induced tumor cell migration.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:18427106
      supporting_text: Notch signaling mediates hypoxia-induced tumor cell migration and invasion.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18660822
  review:
    summary: Jagged/Serrate DSL domain interaction with NOTCH for trans-activation and cis-inhibition.
    action: REMOVE
    reason: Generic protein binding is uninformative. Ligand-receptor interaction is critical for NOTCH1 function but should be captured by receptor activity terms.
    supported_by:
    - reference_id: PMID:18660822
      supporting_text: Jul 27. A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19151708
  review:
    summary: Pin1 prolyl isomerase interaction enhances NOTCH1 activation.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:19151708
      supporting_text: The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19907488
  review:
    summary: Direct inhibition of NOTCH transcription factor complex - stapled peptide SAHM1.
    action: REMOVE
    reason: Generic protein binding is uninformative. This is about therapeutic targeting.
    supported_by:
    - reference_id: PMID:19907488
      supporting_text: Direct inhibition of the NOTCH transcription factor complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20823234
  review:
    summary: NOTCH1 signaling in HTLV-1-associated adult T-cell leukemia.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:20823234
      supporting_text: Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20972443
  review:
    summary: Cooperative assembly of dimeric NOTCH transcription complexes.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:20972443
      supporting_text: Oct 24. Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21475249
  review:
    summary: Ataxin-1 and BOAT are components of NOTCH signaling pathway.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:21475249
      supporting_text: Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22325781
  review:
    summary: Conformational locking upon cooperative assembly of NOTCH transcription complexes.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:22325781
      supporting_text: Conformational locking upon cooperative assembly of notch transcription complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23022380
  review:
    summary: NOTCH1 nuclear interactome studies.
    action: REMOVE
    reason: Generic protein binding is uninformative. High-throughput interactome data.
    supported_by:
    - reference_id: PMID:23022380
      supporting_text: 2012 Sep 27. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23086448
  review:
    summary: CD46-Jagged1 interaction in TH1 immunity.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:23086448
      supporting_text: The CD46-Jagged1 interaction is critical for human TH1 immunity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25344755
  review:
    summary: Cyclin C as tumor suppressor - interactions with NOTCH1.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:25344755
      supporting_text: Cyclin C is a haploinsufficient tumour suppressor.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25609649
  review:
    summary: Proteomic study of transcription factor complexes.
    action: REMOVE
    reason: Generic protein binding is uninformative. High-throughput data.
    supported_by:
    - reference_id: PMID:25609649
      supporting_text: Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25714926
  review:
    summary: Angiopoietin-like proteins stimulate HSPC development through NOTCH receptor signaling.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:25714926
      supporting_text: Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25895060
  review:
    summary: NOTCH as negative regulator of DNA-damage response.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:25895060
      supporting_text: Apr 20. Notch is a direct negative regulator of the DNA-damage response.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  review:
    summary: Human interactome in three quantitative dimensions - large-scale study.
    action: REMOVE
    reason: Generic protein binding is uninformative. High-throughput data.
    supported_by:
    - reference_id: PMID:26496610
      supporting_text: Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27229929
  review:
    summary: Systematic interactome mapping of ALL cancer gene products.
    action: REMOVE
    reason: Generic protein binding is uninformative. High-throughput data.
    supported_by:
    - reference_id: PMID:27229929
      supporting_text: Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33189893
  review:
    summary: PAK1-NOTCH1 axis in crypt homeostasis during intestinal inflammation.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:33189893
      supporting_text: A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Dual proteome-scale networks showing cell-specific remodeling of interactome.
    action: REMOVE
    reason: Generic protein binding is uninformative. High-throughput data.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38891776
  review:
    summary: Pin1 downregulation in retinoic acid-induced neural tube closure failure.
    action: REMOVE
    reason: Generic protein binding is uninformative.
    supported_by:
    - reference_id: PMID:38891776
      supporting_text: Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16738328
  review:
    summary: NOTCH1 can form homodimers through its heterodimerization domain. Mutations in this domain cause T-ALL.
    action: ACCEPT
    reason: NOTCH1 homodimerization is documented and has functional significance. The study shows leukemia-associated mutations fall into distinct mechanistic classes affecting the HD domain.
    supported_by:
    - reference_id: PMID:16738328
      supporting_text: Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 can negatively regulate certain genes through target gene specificity and crosstalk with repressive mechanisms.
    action: KEEP_AS_NON_CORE
    reason: While NOTCH1 primarily activates transcription, it can also lead to repression of certain targets depending on context. This is a secondary regulatory outcome.
- term:
    id: GO:0001554
    label: luteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH signaling has been implicated in ovarian function including corpus luteum regression.
    action: KEEP_AS_NON_CORE
    reason: Luteolysis is a highly specialized reproductive process. NOTCH1 may play a role but this is tissue-specific rather than a core function.
- term:
    id: GO:0001669
    label: acrosomal vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 may be present in acrosomal vesicles during spermatogenesis.
    action: KEEP_AS_NON_CORE
    reason: This is a specialized spermatogenesis-related localization. NOTCH1 has roles in germ cell development but this is not a core localization.
- term:
    id: GO:0001947
    label: heart looping
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is required for proper cardiac morphogenesis including heart looping during development.
    action: KEEP_AS_NON_CORE
    reason: Heart looping is a specific developmental process. NOTCH1 mutations cause congenital heart defects (AOVD1), confirming cardiac development roles, but this is tissue-specific.
- term:
    id: GO:0002052
    label: positive regulation of neuroblast proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 promotes neural progenitor/stem cell proliferation and maintains the undifferentiated state.
    action: KEEP_AS_NON_CORE
    reason: NOTCH1 maintains neural stem cells and regulates neurogenesis, but this is a tissue-specific developmental function.
- term:
    id: GO:0003157
    label: endocardium development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is essential for endocardium development and endocardial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development is a well-established NOTCH1 function based on human disease genetics (AOVD1, AOS5), but represents tissue-specific developmental role.
- term:
    id: GO:0003160
    label: endocardium morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates endocardium morphogenesis during heart development.
    action: KEEP_AS_NON_CORE
    reason: Related to cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003162
    label: atrioventricular node development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in development of cardiac conduction system components.
    action: KEEP_AS_NON_CORE
    reason: Specialized cardiac developmental process.
- term:
    id: GO:0003169
    label: coronary vein morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates coronary vessel development including vein morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac/vascular development - tissue-specific developmental function.
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is essential for aortic valve development. NOTCH1 mutations cause aortic valve disease (AOVD1).
    action: KEEP_AS_NON_CORE
    reason: Strongly supported by human genetics - NOTCH1 mutations cause bicuspid aortic valve and calcific aortic valve disease (OMIM:109730). This is a key developmental phenotype but tissue-specific.
- term:
    id: GO:0003181
    label: atrioventricular valve morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates AV valve development through endocardial cushion formation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac valve development - tissue-specific developmental function supported by mouse studies.
- term:
    id: GO:0003182
    label: coronary sinus valve morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates coronary sinus valve development.
    action: KEEP_AS_NON_CORE
    reason: Highly specialized cardiac structure - tissue-specific developmental function.
- term:
    id: GO:0003184
    label: pulmonary valve morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NOTCH1 regulates pulmonary valve development. Human NOTCH1 mutations cause pulmonary valve abnormalities.
    action: KEEP_AS_NON_CORE
    reason: Cardiac valve development - tissue-specific developmental function supported by human genetics.
- term:
    id: GO:0003198
    label: epithelial to mesenchymal transition involved in endocardial cushion formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 promotes EMT during endocardial cushion formation, essential for valve development.
    action: KEEP_AS_NON_CORE
    reason: EMT in heart development is well-documented for NOTCH1. Tissue-specific developmental function.
- term:
    id: GO:0003203
    label: endocardial cushion morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is required for endocardial cushion development which gives rise to heart valves.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003207
    label: cardiac chamber formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cardiac chamber formation during heart development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003208
    label: cardiac ventricle morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates ventricular development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003209
    label: cardiac atrium morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates atrial development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003213
    label: cardiac right atrium morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates right atrium morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003214
    label: cardiac left ventricle morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates left ventricle morphogenesis. Relevant to hypoplastic left heart syndrome.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003222
    label: ventricular trabecula myocardium morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates trabeculation of the ventricular myocardium.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003241
    label: growth involved in heart morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates growth during cardiac morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003252
    label: obsolete negative regulation of cell proliferation involved in heart valve morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 negatively regulates cell proliferation during valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac valve development - tissue-specific function.
- term:
    id: GO:0003264
    label: regulation of cardioblast proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cardioblast proliferation during heart development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003273
    label: cell migration involved in endocardial cushion formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cell migration during endocardial cushion formation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003332
    label: negative regulation of extracellular matrix constituent secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 negatively regulates ECM secretion in certain contexts.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0003344
    label: pericardium morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates pericardium development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific function.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NICD associates with chromatin as part of the transcription activation complex with RBPJ.
    action: ACCEPT
    reason: NICD binds to chromatin at target gene promoters as part of the RBPJ-MAML transcription complex. This is part of the core transcriptional mechanism.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NICD functions as a transcriptional coactivator by converting RBPJ from a repressor to an activator.
    action: ACCEPT
    reason: Transcription coactivator activity is a core molecular function of NICD. It recruits MAML and displaces corepressors from RBPJ.
- term:
    id: GO:0004857
    label: enzyme inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 has been reported to inhibit certain enzymes in specific contexts.
    action: UNDECIDED
    reason: Enzyme inhibitor activity is not a well-characterized function of NOTCH1. The annotation source and mechanism are unclear.
- term:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is a transmembrane receptor that transduces signals from cell-cell contact to transcriptional responses.
    action: ACCEPT
    reason: This is the core molecular function of NOTCH1. It is a type I transmembrane receptor that signals via proteolytic processing.
- term:
    id: GO:0005112
    label: Notch binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 can bind other NOTCH family members, potentially in cis-inhibition or heterodimer formation.
    action: ACCEPT
    reason: NOTCH receptors can interact with each other. The identical protein binding annotation (GO:0042802) already captures homodimerization.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cytoplasm
    action: ACCEPT
    reason: NICD transits through cytoplasm.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Endoplasmic reticulum
    action: ACCEPT
    reason: NOTCH1 synthesis and maturation.
- term:
    id: GO:0005912
    label: adherens junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to adherens junction.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0006606
    label: protein import into nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to protein import into nucleus.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0007221
    label: positive regulation of transcription of Notch receptor target
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Positive regulation of transcription of Notch receptor target
    action: ACCEPT
    reason: Core downstream function of NICD.
- term:
    id: GO:0007283
    label: spermatogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to spermatogenesis.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cell surface
    action: ACCEPT
    reason: NOTCH1 receptor functions at cell surface.
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to gene expression.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0010614
    label: negative regulation of cardiac muscle hypertrophy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates negative regulation of cardiac muscle hypertrophy.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NOTCH1 is involved in positive regulation of gene expression.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0010667
    label: negative regulation of cardiac muscle cell apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates negative regulation of cardiac muscle cell apoptotic process.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0010718
    label: positive regulation of epithelial to mesenchymal transition
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 promotes positive regulation of epithelial to mesenchymal transition.
    action: KEEP_AS_NON_CORE
    reason: EMT regulation - context-dependent function.
- term:
    id: GO:0010832
    label: negative regulation of myotube differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of myotube differentiation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0014031
    label: mesenchymal cell development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 promotes mesenchymal cell development.
    action: KEEP_AS_NON_CORE
    reason: EMT regulation - context-dependent function.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to apical plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Enzyme binding
    action: ACCEPT
    reason: NOTCH1 binds enzymes involved in its processing.
- term:
    id: GO:0021515
    label: cell differentiation in spinal cord
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in cell differentiation in spinal cord.
    action: KEEP_AS_NON_CORE
    reason: Neural development - tissue-specific function.
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to protein catabolic process.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0030279
    label: negative regulation of ossification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of ossification.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0030334
    label: regulation of cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to regulation of cell migration.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in positive regulation of cell migration.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0030513
    label: positive regulation of BMP signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in positive regulation of bmp signaling pathway.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0030514
    label: negative regulation of BMP signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of bmp signaling pathway.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0031100
    label: animal organ regeneration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to animal organ regeneration.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to cytoplasmic vesicle.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0031490
    label: chromatin DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to chromatin DNA binding.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0032495
    label: response to muramyl dipeptide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in response to muramyl dipeptide.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in response to lipopolysaccharide.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0032966
    label: negative regulation of collagen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of collagen biosynthetic process.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to regulation of cell population proliferation.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0042246
    label: tissue regeneration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to tissue regeneration.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0045070
    label: positive regulation of viral genome replication
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in positive regulation of viral genome replication.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0045603
    label: positive regulation of endothelial cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates positive regulation of endothelial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
- term:
    id: GO:0045665
    label: negative regulation of neuron differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of neuron differentiation via Notch-mediated lateral inhibition, a canonical function in the neuron-glia binary fate decision.
    action: ACCEPT
    reason: Core developmental function - NOTCH1-mediated lateral inhibition is the canonical mechanism controlling neuron-glia fate choice. PMID:12052917, PMID:11182080.
- term:
    id: GO:0045668
    label: negative regulation of osteoblast differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of osteoblast differentiation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0045687
    label: positive regulation of glial cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 promotes glial cell differentiation via lateral inhibition, instructing multipotent progenitors toward glial fate.
    action: ACCEPT
    reason: Core developmental function - NOTCH1 instructs neural progenitors toward glial fate as part of the neuron-glia binary decision. PMID:11182080, PMID:23307615.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of dna-templated transcription.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in positive regulation of receptor signaling pathway via jak-stat.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0048708
    label: astrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 promotes astrocyte differentiation as part of gliogenesis, with Sox9 acting as critical downstream mediator.
    action: ACCEPT
    reason: Core gliogenic function - NOTCH1 signaling promotes astrocyte fate via HES/HEY factors. PMID:23307615, PMID:11182080.
- term:
    id: GO:0048709
    label: oligodendrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates oligodendrocyte differentiation (inhibitory role - promotes astrocyte over oligodendrocyte fate).
    action: ACCEPT
    reason: Core gliogenic function - NOTCH1 inhibits oligodendrocyte fate, promoting astrocyte fate within the glial lineage. PMID:11182080.
- term:
    id: GO:0048711
    label: positive regulation of astrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 positively regulates astrocyte differentiation via HES/HEY transcriptional targets.
    action: ACCEPT
    reason: Core gliogenic function - canonical Notch target genes promote astrocyte gene expression. PMID:11182080, PMID:23307615.
- term:
    id: GO:0048715
    label: negative regulation of oligodendrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 negatively regulates oligodendrocyte differentiation, favoring astrocyte fate.
    action: ACCEPT
    reason: Core gliogenic function - NOTCH1 promotes astrocyte over oligodendrocyte fate in glial progenitors. PMID:11182080.
- term:
    id: GO:0048873
    label: homeostasis of number of cells within a tissue
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to homeostasis of number of cells within a tissue.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0050768
    label: negative regulation of neurogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of neurogenesis.
    action: KEEP_AS_NON_CORE
    reason: Neural development - tissue-specific function.
- term:
    id: GO:0055008
    label: cardiac muscle tissue morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cardiac muscle tissue morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060038
    label: cardiac muscle cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cardiac muscle cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060045
    label: positive regulation of cardiac muscle cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates positive regulation of cardiac muscle cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060253
    label: negative regulation of glial cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of glial cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0060317
    label: cardiac epithelial to mesenchymal transition
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cardiac epithelial to mesenchymal transition.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060379
    label: cardiac muscle cell myoblast differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cardiac muscle cell myoblast differentiation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060411
    label: cardiac septum morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: NOTCH1 regulates cardiac septum morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060412
    label: ventricular septum morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to ventricular septum morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0060842
    label: arterial endothelial cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates arterial endothelial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
- term:
    id: GO:0060843
    label: venous endothelial cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates venous endothelial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
- term:
    id: GO:0060948
    label: cardiac vascular smooth muscle cell development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates cardiac vascular smooth muscle cell development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060956
    label: endocardial cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to endocardial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0060979
    label: vasculogenesis involved in coronary vascular morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates vasculogenesis involved in coronary vascular morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060982
    label: coronary artery morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates coronary artery morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0061344
    label: regulation of cell adhesion involved in heart morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates regulation of cell adhesion involved in heart morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0061384
    label: heart trabecula morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates heart trabecula morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0062043
    label: positive regulation of cardiac epithelial to mesenchymal transition
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates positive regulation of cardiac epithelial to mesenchymal transition.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0070168
    label: negative regulation of biomineral tissue development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of biomineral tissue development.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0070986
    label: left/right axis specification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to left/right axis specification.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in cellular response to hypoxia.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0071944
    label: cell periphery
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to cell periphery.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0072017
    label: distal tubule development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to distal tubule development.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0072044
    label: collecting duct development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to collecting duct development.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0072144
    label: glomerular mesangial cell development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to glomerular mesangial cell development.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0072538
    label: T-helper 17 type immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 regulates t-helper 17 type immune response.
    action: KEEP_AS_NON_CORE
    reason: T cell/immune development - tissue-specific function.
- term:
    id: GO:0097400
    label: interleukin-17-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to interleukin-17-mediated signaling pathway.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0098685
    label: Schaffer collateral - CA1 synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to Schaffer collateral - CA1 synapse.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0098839
    label: postsynaptic density membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to postsynaptic density membrane.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to glutamatergic synapse.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0099565
    label: chemical synaptic transmission, postsynaptic
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to chemical synaptic transmission, postsynaptic.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0120163
    label: negative regulation of cold-induced thermogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of cold-induced thermogenesis.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0140537
    label: transcription regulator activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to transcription regulator activator activity.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:1901201
    label: regulation of extracellular matrix assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 annotation to regulation of extracellular matrix assembly.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:1902339
    label: positive regulation of apoptotic process involved in morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in positive regulation of apoptotic process involved in morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:2000974
    label: negative regulation of pro-B cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: NOTCH1 is involved in negative regulation of pro-b cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38016980
  review:
    summary: Generic protein binding annotation.
    action: REMOVE
    reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms.
    supported_by:
    - reference_id: PMID:38016980
      supporting_text: TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220978
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:32601208
  review:
    summary: Nucleus
    action: ACCEPT
    reason: NICD translocates to nucleus.
    supported_by:
    - reference_id: PMID:32601208
      supporting_text: Pharmacological disruption of the Notch transcription factor complex.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:32601208
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
    supported_by:
    - reference_id: PMID:32601208
      supporting_text: Pharmacological disruption of the Notch transcription factor complex.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:32601208
  review:
    summary: Positive regulation of DNA-templated transcription
    action: ACCEPT
    reason: NICD activates transcription.
    supported_by:
    - reference_id: PMID:32601208
      supporting_text: Pharmacological disruption of the Notch transcription factor complex.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IDA
  original_reference_id: PMID:18239137
  review:
    summary: Transcription coactivator activity
    action: ACCEPT
    reason: NICD functions as transcriptional coactivator with RBPJ-MAML.
    supported_by:
    - reference_id: PMID:18239137
      supporting_text: 2008 Jan 31. Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:18239137
  review:
    summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:18239137
      supporting_text: 2008 Jan 31. Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.
- term:
    id: GO:0051152
    label: positive regulation of smooth muscle cell differentiation
  evidence_type: IDA
  original_reference_id: PMID:18239137
  review:
    summary: NOTCH1 is involved in positive regulation of smooth muscle cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:18239137
      supporting_text: 2008 Jan 31. Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:16025100
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
    supported_by:
    - reference_id: PMID:16025100
      supporting_text: Mutations in NOTCH1 cause aortic valve disease.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:17662764
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
    supported_by:
    - reference_id: PMID:17662764
      supporting_text: Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660815
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660816
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660819
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660822
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2666278
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220957
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220964
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220967
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220971
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220982
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769015
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4396392
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4396393
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4396401
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4396402
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220988
  review:
    summary: Cytosol
    action: ACCEPT
    reason: NICD released to cytosol before nuclear import.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769015
  review:
    summary: Cytosol
    action: ACCEPT
    reason: NICD released to cytosol before nuclear import.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220944
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220976
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220988
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2768993
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2768999
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769000
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769007
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769008
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900743
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900747
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900748
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900756
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900765
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IDA
  original_reference_id: PMID:23839946
  review:
    summary: Transcription coactivator activity
    action: ACCEPT
    reason: NICD functions as transcriptional coactivator with RBPJ-MAML.
    supported_by:
    - reference_id: PMID:23839946
      supporting_text: Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
- term:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  evidence_type: IDA
  original_reference_id: PMID:23839946
  review:
    summary: Transmembrane signaling receptor activity
    action: ACCEPT
    reason: Core molecular function of NOTCH1.
    supported_by:
    - reference_id: PMID:23839946
      supporting_text: Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23839946
  review:
    summary: Generic protein binding annotation.
    action: REMOVE
    reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms.
    supported_by:
    - reference_id: PMID:23839946
      supporting_text: Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:23839946
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
    supported_by:
    - reference_id: PMID:23839946
      supporting_text: Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:23839946
  review:
    summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:23839946
      supporting_text: Epub 2013 Jul 9. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9796071
  review:
    summary: Endosome membrane
    action: ACCEPT
    reason: NOTCH1 trafficking.
- term:
    id: GO:0050768
    label: negative regulation of neurogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of neurogenesis.
    action: KEEP_AS_NON_CORE
    reason: Neural development - tissue-specific function.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in cellular response to hypoxia.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to regulation of transcription by RNA polymerase II.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0060379
    label: cardiac muscle cell myoblast differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac muscle cell myoblast differentiation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220976
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900743
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900747
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900748
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900756
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2900765
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:11306509
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
    supported_by:
    - reference_id: PMID:11306509
      supporting_text: Notch signaling induces cell cycle arrest in small cell lung cancer cells.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:11306509
  review:
    summary: NOTCH1 is involved in negative regulation of gene expression.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:11306509
      supporting_text: Notch signaling induces cell cycle arrest in small cell lung cancer cells.
- term:
    id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  evidence_type: IDA
  original_reference_id: PMID:11306509
  review:
    summary: NOTCH1 is involved in positive regulation of ras protein signal transduction.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:11306509
      supporting_text: Notch signaling induces cell cycle arrest in small cell lung cancer cells.
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IDA
  original_reference_id: PMID:11306509
  review:
    summary: NOTCH1 is involved in positive regulation of erk1 and erk2 cascade.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:11306509
      supporting_text: Notch signaling induces cell cycle arrest in small cell lung cancer cells.
- term:
    id: GO:0071228
    label: cellular response to tumor cell
  evidence_type: IDA
  original_reference_id: PMID:11306509
  review:
    summary: NOTCH1 is involved in cellular response to tumor cell.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:11306509
      supporting_text: Notch signaling induces cell cycle arrest in small cell lung cancer cells.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Transcription coactivator activity
    action: ACCEPT
    reason: NICD functions as transcriptional coactivator with RBPJ-MAML.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:17984306
  review:
    summary: NOTCH1 is involved in negative regulation of transcription by rna polymerase ii.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:17984306
      supporting_text: Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
- term:
    id: GO:0001837
    label: epithelial to mesenchymal transition
  evidence_type: IMP
  original_reference_id: PMID:17984306
  review:
    summary: NOTCH1 promotes epithelial to mesenchymal transition.
    action: KEEP_AS_NON_CORE
    reason: EMT regulation - context-dependent function.
    supported_by:
    - reference_id: PMID:17984306
      supporting_text: Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
- term:
    id: GO:0060354
    label: negative regulation of cell adhesion molecule production
  evidence_type: IMP
  original_reference_id: PMID:17984306
  review:
    summary: NOTCH1 is involved in negative regulation of cell adhesion molecule production.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:17984306
      supporting_text: Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
- term:
    id: GO:2000048
    label: negative regulation of cell-cell adhesion mediated by cadherin
  evidence_type: IMP
  original_reference_id: PMID:17984306
  review:
    summary: NOTCH1 is involved in negative regulation of cell-cell adhesion mediated by cadherin.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:17984306
      supporting_text: Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
- term:
    id: GO:2000811
    label: negative regulation of anoikis
  evidence_type: IMP
  original_reference_id: PMID:17984306
  review:
    summary: NOTCH1 is involved in negative regulation of anoikis.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:17984306
      supporting_text: Nov 5. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates aortic valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003184
    label: pulmonary valve morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates pulmonary valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003203
    label: endocardial cushion morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to endocardial cushion morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0048873
    label: homeostasis of number of cells within a tissue
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to homeostasis of number of cells within a tissue.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0070168
    label: negative regulation of biomineral tissue development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of biomineral tissue development.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0120163
    label: negative regulation of cold-induced thermogenesis
  evidence_type: ISS
  original_reference_id: PMID:25038826
  review:
    summary: NOTCH1 is involved in negative regulation of cold-induced thermogenesis.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:25038826
      supporting_text: Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.
- term:
    id: GO:0062043
    label: positive regulation of cardiac epithelial to mesenchymal transition
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates positive regulation of cardiac epithelial to mesenchymal transition.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003252
    label: obsolete negative regulation of cell proliferation involved in heart valve morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates negative regulation of cell proliferation involved in heart valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003332
    label: negative regulation of extracellular matrix constituent secretion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of extracellular matrix constituent secretion.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0010614
    label: negative regulation of cardiac muscle hypertrophy
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates negative regulation of cardiac muscle hypertrophy.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:1902339
    label: positive regulation of apoptotic process involved in morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in positive regulation of apoptotic process involved in morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Nucleus
    action: ACCEPT
    reason: NICD translocates to nucleus.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in positive regulation of gene expression.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0003151
    label: outflow tract morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:18593716
  review:
    summary: NOTCH1 annotation to outflow tract morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
    supported_by:
    - reference_id: PMID:18593716
      supporting_text: Jun 30. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: TAS
  original_reference_id: PMID:20951801
  review:
    summary: NOTCH1 regulates aortic valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:20951801
      supporting_text: NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:18593716
  review:
    summary: NOTCH1 regulates aortic valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:18593716
      supporting_text: Jun 30. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25038227
  review:
    summary: Generic protein binding annotation.
    action: REMOVE
    reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms.
    supported_by:
    - reference_id: PMID:25038227
      supporting_text: Epub 2014 Jul 18. NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.
- term:
    id: GO:0005912
    label: adherens junction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to adherens junction.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to apical plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11006133
  review:
    summary: Generic protein binding annotation.
    action: REMOVE
    reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms.
    supported_by:
    - reference_id: PMID:11006133
      supporting_text: Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors.
- term:
    id: GO:0043235
    label: receptor complex
  evidence_type: IDA
  original_reference_id: PMID:23382219
  review:
    summary: Receptor complex
    action: ACCEPT
    reason: NOTCH1 forms heterodimeric complex.
    supported_by:
    - reference_id: PMID:23382219
      supporting_text: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to cilium assembly.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912412
  review:
    summary: ER membrane
    action: ACCEPT
    reason: NOTCH1 biosynthesis in ER.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912369
  review:
    summary: Golgi membrane
    action: ACCEPT
    reason: S1 furin cleavage occurs in Golgi.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912382
  review:
    summary: Golgi membrane
    action: ACCEPT
    reason: S1 furin cleavage occurs in Golgi.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5096538
  review:
    summary: Golgi membrane
    action: ACCEPT
    reason: S1 furin cleavage occurs in Golgi.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912382
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1980044
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1980122
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220944
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691211
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691214
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691219
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691226
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2730752
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2737728
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2768993
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2768999
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769000
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769007
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2769008
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-2076711
  review:
    summary: NOTCH1 annotation to extracellular region.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912372
  review:
    summary: Golgi membrane
    action: ACCEPT
    reason: S1 furin cleavage occurs in Golgi.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912379
  review:
    summary: Golgi membrane
    action: ACCEPT
    reason: S1 furin cleavage occurs in Golgi.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912394
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-212356
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4396371
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4396379
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878220
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8878237
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9017835
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9021451
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9762102
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-2064264
  review:
    summary: Nucleoplasm
    action: ACCEPT
    reason: NICD functions in nucleoplasm for transcription.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912379
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1912382
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1980044
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1980122
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660815
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660816
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660819
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2660822
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2666278
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691211
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691214
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691219
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2691226
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2730752
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2737728
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-2076711
  review:
    summary: Plasma membrane
    action: ACCEPT
    reason: Primary site of NOTCH1 receptor function.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:20616313
  review:
    summary: NOTCH1 is involved in negative regulation of cell population proliferation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:20616313
      supporting_text: 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
- term:
    id: GO:0035148
    label: tube formation
  evidence_type: IMP
  original_reference_id: PMID:20616313
  review:
    summary: NOTCH1 annotation to tube formation.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
    supported_by:
    - reference_id: PMID:20616313
      supporting_text: 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
- term:
    id: GO:0035924
    label: cellular response to vascular endothelial growth factor stimulus
  evidence_type: IDA
  original_reference_id: PMID:20616313
  review:
    summary: NOTCH1 regulates cellular response to vascular endothelial growth factor stimulus.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
    supported_by:
    - reference_id: PMID:20616313
      supporting_text: 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:20616313
  review:
    summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:20616313
      supporting_text: 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
- term:
    id: GO:0090051
    label: negative regulation of cell migration involved in sprouting angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:20616313
  review:
    summary: NOTCH1 regulates negative regulation of cell migration involved in sprouting angiogenesis.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
    supported_by:
    - reference_id: PMID:20616313
      supporting_text: 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
- term:
    id: GO:2001027
    label: negative regulation of endothelial cell chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:20616313
  review:
    summary: NOTCH1 regulates negative regulation of endothelial cell chemotaxis.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
    supported_by:
    - reference_id: PMID:20616313
      supporting_text: 2010 Jul 8. Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
- term:
    id: GO:0003273
    label: cell migration involved in endocardial cushion formation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in cell migration involved in endocardial cushion formation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0007368
    label: determination of left/right symmetry
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to determination of left/right symmetry.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:20613903
  review:
    summary: NOTCH1 is involved in positive regulation of cell population proliferation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:20613903
      supporting_text: 2010 Jun 30. Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells.
- term:
    id: GO:0071372
    label: cellular response to follicle-stimulating hormone stimulus
  evidence_type: IDA
  original_reference_id: PMID:20613903
  review:
    summary: NOTCH1 is involved in cellular response to follicle-stimulating hormone stimulus.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:20613903
      supporting_text: 2010 Jun 30. Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells.
- term:
    id: GO:0003184
    label: pulmonary valve morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:16025100
  review:
    summary: NOTCH1 regulates pulmonary valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:16025100
      supporting_text: Mutations in NOTCH1 cause aortic valve disease.
- term:
    id: GO:0003192
    label: mitral valve formation
  evidence_type: IMP
  original_reference_id: PMID:16025100
  review:
    summary: NOTCH1 regulates mitral valve formation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:16025100
      supporting_text: Mutations in NOTCH1 cause aortic valve disease.
- term:
    id: GO:0060412
    label: ventricular septum morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:16025100
  review:
    summary: NOTCH1 annotation to ventricular septum morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
    supported_by:
    - reference_id: PMID:16025100
      supporting_text: Mutations in NOTCH1 cause aortic valve disease.
- term:
    id: GO:0001837
    label: epithelial to mesenchymal transition
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 promotes epithelial to mesenchymal transition.
    action: KEEP_AS_NON_CORE
    reason: EMT regulation - context-dependent function.
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:17662764
  review:
    summary: NOTCH1 regulates aortic valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:17662764
      supporting_text: Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms.
- term:
    id: GO:0003213
    label: cardiac right atrium morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac right atrium morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003222
    label: ventricular trabecula myocardium morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates ventricular trabecula myocardium morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003241
    label: growth involved in heart morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates growth involved in heart morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0007221
    label: positive regulation of transcription of Notch receptor target
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Positive regulation of transcription of Notch receptor target
    action: ACCEPT
    reason: Core downstream function of NICD.
- term:
    id: GO:0014031
    label: mesenchymal cell development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 promotes mesenchymal cell development.
    action: KEEP_AS_NON_CORE
    reason: EMT regulation - context-dependent function.
- term:
    id: GO:0030279
    label: negative regulation of ossification
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of ossification.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of dna-templated transcription.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0055008
    label: cardiac muscle tissue morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac muscle tissue morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060045
    label: positive regulation of cardiac muscle cell proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates positive regulation of cardiac muscle cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060317
    label: cardiac epithelial to mesenchymal transition
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac epithelial to mesenchymal transition.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060411
    label: cardiac septum morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac septum morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060842
    label: arterial endothelial cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates arterial endothelial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of transcription by rna polymerase ii.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0001947
    label: heart looping
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates heart looping.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003160
    label: endocardium morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates endocardium morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003169
    label: coronary vein morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates coronary vein morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003181
    label: atrioventricular valve morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates atrioventricular valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003198
    label: epithelial to mesenchymal transition involved in endocardial cushion formation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 promotes epithelial to mesenchymal transition involved in endocardial cushion formation.
    action: KEEP_AS_NON_CORE
    reason: EMT regulation - context-dependent function.
- term:
    id: GO:0003207
    label: cardiac chamber formation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac chamber formation.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003208
    label: cardiac ventricle morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac ventricle morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003209
    label: cardiac atrium morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac atrium morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003214
    label: cardiac left ventricle morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac left ventricle morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0003344
    label: pericardium morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates pericardium morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in positive regulation of cell migration.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in positive regulation of transcription by rna polymerase ii.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0060843
    label: venous endothelial cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates venous endothelial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Vascular development - tissue-specific function.
- term:
    id: GO:0060948
    label: cardiac vascular smooth muscle cell development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates cardiac vascular smooth muscle cell development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060956
    label: endocardial cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to endocardial cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0060979
    label: vasculogenesis involved in coronary vascular morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates vasculogenesis involved in coronary vascular morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0060982
    label: coronary artery morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates coronary artery morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0061384
    label: heart trabecula morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates heart trabecula morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:1901201
    label: regulation of extracellular matrix assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 annotation to regulation of extracellular matrix assembly.
    action: KEEP_AS_NON_CORE
    reason: Transferred annotation - context-specific function.
- term:
    id: GO:0003157
    label: endocardium development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 regulates endocardium development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Enzyme binding
    action: ACCEPT
    reason: NOTCH1 binds enzymes involved in its processing.
- term:
    id: GO:0004857
    label: enzyme inhibitor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Enzyme inhibitor activity is not a well-characterized function of NOTCH1.
    action: UNDECIDED
    reason: The mechanism by which NOTCH1 might inhibit enzymes is unclear. This annotation requires further investigation.
- term:
    id: GO:0043086
    label: negative regulation of catalytic activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of catalytic activity.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0002193
    label: MAML1-RBP-Jkappa- ICN1 complex
  evidence_type: IDA
  original_reference_id: PMID:16510869
  review:
    summary: MAML1-RBP-Jkappa-ICN1 complex
    action: ACCEPT
    reason: Core transcription activation complex.
    supported_by:
    - reference_id: PMID:16510869
      supporting_text: The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis.
- term:
    id: GO:0097150
    label: neuronal stem cell population maintenance
  evidence_type: IEP
  original_reference_id: PMID:19682396
  review:
    summary: NOTCH1 is involved in neuronal stem cell population maintenance.
    action: KEEP_AS_NON_CORE
    reason: Neural development - tissue-specific function.
    supported_by:
    - reference_id: PMID:19682396
      supporting_text: Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16510869
  review:
    summary: Generic protein binding annotation.
    action: REMOVE
    reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms.
    supported_by:
    - reference_id: PMID:16510869
      supporting_text: The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:19682396
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
    supported_by:
    - reference_id: PMID:19682396
      supporting_text: Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:17849174
  review:
    summary: NOTCH1 is involved in positive regulation of cell population proliferation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:17849174
      supporting_text: Epub 2007 Sep 12. Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells.
- term:
    id: GO:0030513
    label: positive regulation of BMP signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in positive regulation of bmp signaling pathway.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in positive regulation of receptor signaling pathway via jak-stat.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:2000737
    label: negative regulation of stem cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:19682396
  review:
    summary: NOTCH1 is involved in negative regulation of stem cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Stem cell regulation - context-dependent function.
    supported_by:
    - reference_id: PMID:19682396
      supporting_text: Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.
- term:
    id: GO:2000974
    label: negative regulation of pro-B cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of pro-b cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0030514
    label: negative regulation of BMP signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of bmp signaling pathway.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0045668
    label: negative regulation of osteoblast differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of osteoblast differentiation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Positive regulation of DNA-templated transcription
    action: ACCEPT
    reason: NICD activates transcription.
- term:
    id: GO:0048711
    label: positive regulation of astrocyte differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 positively regulates astrocyte differentiation - conserved function from mouse studies.
    action: ACCEPT
    reason: Core gliogenic function - canonical Notch signaling promotes astrocyte fate.
- term:
    id: GO:0048715
    label: negative regulation of oligodendrocyte differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 negatively regulates oligodendrocyte differentiation - conserved function from mouse studies.
    action: ACCEPT
    reason: Core gliogenic function - NOTCH1 promotes astrocyte over oligodendrocyte fate.
- term:
    id: GO:0060253
    label: negative regulation of glial cell proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NOTCH1 is involved in negative regulation of glial cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IMP
  original_reference_id: PMID:21457232
  review:
    summary: NOTCH1 regulates heart development.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:21457232
      supporting_text: 2011 Apr 25. Identification of de novo mutations and rare variants in hypoplastic left heart syndrome.
- term:
    id: GO:0010812
    label: negative regulation of cell-substrate adhesion
  evidence_type: IDA
  original_reference_id: PMID:16501043
  review:
    summary: NOTCH1 is involved in negative regulation of cell-substrate adhesion.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:16501043
      supporting_text: Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism.
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:16025100
  review:
    summary: NOTCH1 regulates aortic valve morphogenesis.
    action: KEEP_AS_NON_CORE
    reason: Cardiac development - tissue-specific developmental function.
    supported_by:
    - reference_id: PMID:16025100
      supporting_text: Mutations in NOTCH1 cause aortic valve disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11101851
  review:
    summary: Generic protein binding annotation.
    action: REMOVE
    reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms.
    supported_by:
    - reference_id: PMID:11101851
      supporting_text: MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11390662
  review:
    summary: Generic protein binding annotation.
    action: REMOVE
    reason: Generic protein binding is uninformative. Specific interactions should be captured by more specific terms.
    supported_by:
    - reference_id: PMID:11390662
      supporting_text: A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:10713164
  review:
    summary: Nucleus
    action: ACCEPT
    reason: NICD translocates to nucleus.
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: TAS
  original_reference_id: PMID:10713164
  review:
    summary: Regulation of DNA-templated transcription
    action: ACCEPT
    reason: Core transcriptional function.
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:10713164
  review:
    summary: Notch signaling pathway
    action: ACCEPT
    reason: Core function - NOTCH1 IS the pathway receptor.
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
- term:
    id: GO:0045662
    label: negative regulation of myoblast differentiation
  evidence_type: IMP
  original_reference_id: PMID:10713164
  review:
    summary: NOTCH1 is involved in negative regulation of myoblast differentiation.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent regulatory function.
    supported_by:
    - reference_id: PMID:10713164
      supporting_text: SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: NAS
  original_reference_id: PMID:1831692
  review:
    summary: NOTCH1 regulates immune response.
    action: KEEP_AS_NON_CORE
    reason: T cell/immune development - tissue-specific function.
    supported_by:
    - reference_id: PMID:1831692
      supporting_text: TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
references:
- id: file:human/NOTCH1/NOTCH1-deep-research-falcon.md
  title: Deep research on NOTCH1 gene function (Falcon/Edison Scientific Literature)
  findings:
  - statement: NOTCH1 is a type I single-pass transmembrane receptor that mediates juxtacrine signaling
  - statement: Activation requires sequential proteolytic cleavages (S1 furin, S2 ADAM10/17, S3/S4 gamma-secretase)
  - statement: NICD translocates to nucleus and forms ternary complex with RBPJ and MAML coactivators
  - statement: Target genes include HES1, HES5, HEY1, HEY2, HEYL
  - statement: EGF-like domains bind calcium ions essential for structure and ligand binding
- id: file:human/NOTCH1/NOTCH1-deep-research-cyberian.md
  title: Deep research on NOTCH1 gene function (Cyberian AI Deep Research)
  findings:
  - statement: NOTCH1 employs regulated intramembrane proteolysis (RIP) for direct signal transduction from cell surface to nucleus
  - statement: The negative regulatory region (NRR) maintains autoinhibited conformation until ligand engagement
  - statement: O-fucosylation by POFUT1 is essential for Notch signaling, with O-fucose at Thr466 in EGF12 anchoring the DLL4-binding interface
  - statement: Fringe glycosyltransferases differentially modulate ligand specificity, potentiating Delta-like binding while inhibiting Jagged binding
  - statement: NOTCH1 can function through non-canonical CSL-independent mechanisms, including antagonizing Wnt/beta-catenin signaling
  - statement: NOTCH1-RBPJ binding sites localize primarily to distal enhancers and superenhancers rather than promoters
  - statement: NOTCH1 is essential for emergence of definitive hematopoietic stem cells from hemogenic endothelium in the AGM region
  - statement: Loss-of-function mutations cause bicuspid aortic valve and calcific aortic valve disease via de-repression of RUNX2
  - statement: Paralog-selective therapeutic antibodies targeting the NRR show promise for avoiding pan-Notch inhibition toxicity
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  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:10713164
  title: SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
  findings: []
- id: PMID:11006133
  title: Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors.
  findings: []
- id: PMID:11101851
  title: MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
  findings: []
- id: PMID:11306509
  title: Notch signaling induces cell cycle arrest in small cell lung cancer cells.
  findings: []
- id: PMID:11390662
  title: A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters.
  findings: []
- id: PMID:12370315
  title: Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors.
  findings: []
- id: PMID:16025100
  title: Mutations in NOTCH1 cause aortic valve disease.
  findings: []
- id: PMID:16319921
  title: Notch1 augments NF-kappaB activity by facilitating its nuclear retention.
  findings: []
- id: PMID:16501043
  title: Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism.
  findings: []
- id: PMID:16510869
  title: The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis.
  findings: []
- id: PMID:16530044
  title: Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.
  findings: []
- id: PMID:16738328
  title: Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes.
  findings: []
- id: PMID:17284587
  title: Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription.
  findings: []
- id: PMID:17318174
  title: Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation.
  findings: []
- id: PMID:17662764
  title: Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms.
  findings: []
- id: PMID:17849174
  title: Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells.
  findings: []
- id: PMID:17909182
  title: Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein.
  findings: []
- id: PMID:17984306
  title: Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.
  findings: []
- id: PMID:18239137
  title: Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.
  findings: []
- id: PMID:1831692
  title: TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
  findings: []
- id: PMID:18427106
  title: Notch signaling mediates hypoxia-induced tumor cell migration and invasion.
  findings: []
- id: PMID:18593716
  title: NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling.
  findings: []
- id: PMID:18660822
  title: A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.
  findings: []
- id: PMID:19151708
  title: The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.
  findings: []
- id: PMID:19682396
  title: Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells.
  findings: []
- id: PMID:19907488
  title: Direct inhibition of the NOTCH transcription factor complex.
  findings: []
- id: PMID:20613903
  title: Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells.
  findings: []
- id: PMID:20616313
  title: Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis.
  findings: []
- id: PMID:20823234
  title: Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia.
  findings: []
- id: PMID:20951801
  title: NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT.
  findings: []
- id: PMID:20972443
  title: Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes.
  findings: []
- id: PMID:21457232
  title: Identification of de novo mutations and rare variants in hypoplastic left heart syndrome.
  findings: []
- id: PMID:21475249
  title: Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway.
  findings: []
- id: PMID:22325781
  title: Conformational locking upon cooperative assembly of notch transcription complexes.
  findings: []
- id: PMID:23022380
  title: NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.
  findings: []
- id: PMID:23086448
  title: The CD46-Jagged1 interaction is critical for human TH1 immunity.
  findings: []
- id: PMID:23382219
  title: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
  findings: []
- id: PMID:23839946
  title: Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1.
  findings: []
- id: PMID:25038227
  title: NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.
  findings: []
- id: PMID:25038826
  title: Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.
  findings: []
- id: PMID:25344755
  title: Cyclin C is a haploinsufficient tumour suppressor.
  findings: []
- id: PMID:25609649
  title: Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
  findings: []
- id: PMID:25714926
  title: Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling.
  findings: []
- id: PMID:25895060
  title: Notch is a direct negative regulator of the DNA-damage response.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
- id: PMID:27229929
  title: Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
  findings: []
- id: PMID:32601208
  title: Pharmacological disruption of the Notch transcription factor complex.
  findings: []
- id: PMID:33189893
  title: A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:38016980
  title: TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors.
  findings: []
- id: PMID:38891776
  title: Pin1 Downregulation Is Involved in Excess Retinoic Acid-Induced Failure of Neural Tube Closure.
  findings: []
- id: PMID:19379690
  title: "The canonical Notch signaling pathway: unfolding the activation mechanism."
  findings:
  - statement: NOTCH1 employs regulated intramembrane proteolysis (RIP) providing direct and rapid signal transduction from cell surface to nucleus
  - statement: The signaling pathway is highly conserved across metazoan evolution
- id: PMID:19075186
  title: Structure of the Notch1-negative regulatory region - implications for normal activation and pathogenic signaling in T-ALL
  findings:
  - statement: The NRR adopts compact autoinhibited conformation with three LNR modules wrapping around the HD domain
  - statement: A conserved hydrophobic plug straddles the scissile bond protecting against premature cleavage
- id: PMID:19726682
  title: Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage
  findings:
  - statement: ADAM10, not ADAM17/TACE, is required for canonical ligand-induced S2 cleavage
- id: PMID:20008221
  title: The role of NOTCH1 signaling in T-ALL.
  findings:
  - statement: Activating NOTCH1 mutations found in over 50% of T-ALL cases
  - statement: Mutations cluster in heterodimerization domain (HD) and C-terminal PEST domain
- id: PMID:22326375
  title: Notch receptor-ligand binding and activation - Insights from molecular studies
  findings:
  - statement: EGF repeats 11-12 constitute core binding site for DSL ligands
  - statement: EGF11-13 region measures approximately 100 x 24 x 20 Angstroms
- id: PMID:20816395
  title: Endocytosis and intracellular trafficking of Notch and its ligands.
  findings:
  - statement: Ligand endocytosis in signal-sending cell generates mechanical pulling force to expose S2 cleavage site
  - statement: A dileucine sorting signal in cytoplasmic tail directs receptor to late endosomes/lysosomes
- id: PMID:24374627
  title: NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers
  findings:
  - statement: Majority of functional NOTCH1-binding sites localize to distal enhancers rather than promoters
  - statement: Dynamic binding sites frequently lie within superenhancers
- id: PMID:10935626
  title: Fringe is a glycosyltransferase that modifies Notch.
  findings:
  - statement: Fringe glycosyltransferases add GlcNAc to O-fucose residues on EGF repeats
  - statement: This modification potentiates Delta-like binding while inhibiting Jagged/Serrate binding
- id: PMID:12753746
  title: Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.
  findings:
  - statement: NOTCH1 is essential for emergence of definitive HSCs from hemogenic endothelium in AGM region
- id: PMID:25700513
  title: Structural biology. Structural basis for Notch1 engagement of Delta-like 4.
  findings:
  - statement: Crystal structure at 2.3 Angstrom resolution reveals two-site antiparallel binding orientation
  - statement: O-fucose at Thr466 in EGF12 centrally anchors the DLL4-binding interface
- id: PMID:22397947
  title: "Non-canonical Notch signaling: emerging role and mechanism."
  findings:
  - statement: Notch can form complex with active beta-catenin and promote its degradation via endo-lysosomal pathways
  - statement: CSL-independent Notch function is present during normal development
- id: PMID:20393564
  title: Therapeutic antibody targeting of individual Notch receptors.
  findings:
  - statement: Inhibitory antibodies function by stabilizing NRR quiescence
  - statement: Inhibition of either Notch1 or Notch2 alone reduces or avoids intestinal toxicity versus dual inhibition
- id: Reactome:R-HSA-1912369
  title: NOTCH precursor cleaved to form mature NOTCH
  findings: []
- id: Reactome:R-HSA-1912372
  title: Fringe-modified Pre-NOTCH is cleaved by FURIN
  findings: []
- id: Reactome:R-HSA-1912379
  title: Transport of fringe-modified NOTCH to plasma membrane
  findings: []
- id: Reactome:R-HSA-1912382
  title: Mature NOTCH heterodimer traffics to the plasma membrane
  findings: []
- id: Reactome:R-HSA-1912394
  title: NICD1 in complex with RBPJ (CSL) recruits MAML
  findings: []
- id: Reactome:R-HSA-1912412
  title: NOTCH1 mRNA translation controlled by miRNAs
  findings: []
- id: Reactome:R-HSA-1980044
  title: NOTCH1 binds JAG2
  findings: []
- id: Reactome:R-HSA-1980122
  title: DTX binds NOTCH1
  findings: []
- id: Reactome:R-HSA-212356
  title: Formation of CSL-NICD coactivator complex
  findings: []
- id: Reactome:R-HSA-2220944
  title: ADAM10/17 cleaves ligand-bound NOTCH1 PEST domain mutants to produce NEXT1 PEST domain mutants
  findings: []
- id: Reactome:R-HSA-2220957
  title: NOTCH1 PEST domain mutants coactivator complex binds CDK8:CCNC
  findings: []
- id: Reactome:R-HSA-2220964
  title: NICD1 PEST domain mutants in complex with RBPJ (CSL) bind MAML
  findings: []
- id: Reactome:R-HSA-2220967
  title: p-NICD1 PEST domain mutants do not bind FBXW7
  findings: []
- id: Reactome:R-HSA-2220971
  title: CDK8 phosphorylates NICD1 PEST domain mutants
  findings: []
- id: Reactome:R-HSA-2220976
  title: NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding
  findings: []
- id: Reactome:R-HSA-2220978
  title: FBXW7 WD mutants do not bind NICD1
  findings: []
- id: Reactome:R-HSA-2220982
  title: NICD1 PEST domain mutants displace co-repressor complex from RBPJ (CSL)
  findings: []
- id: Reactome:R-HSA-2220988
  title: NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants
  findings: []
- id: Reactome:R-HSA-2660815
  title: NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind DLL4
  findings: []
- id: Reactome:R-HSA-2660816
  title: NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind JAG2
  findings: []
- id: Reactome:R-HSA-2660819
  title: NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind DLL1
  findings: []
- id: Reactome:R-HSA-2660822
  title: 'TODO: Fetch title'
  findings: []
- id: Reactome:R-HSA-2666278
  title: NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is cleaved to produce NEXT1
  findings: []
- id: Reactome:R-HSA-2691211
  title: NOTCH1 HD domain mutants bind DLL4
  findings: []
- id: Reactome:R-HSA-2691214
  title: NOTCH1 HD domain mutants bind JAG2
  findings: []
- id: Reactome:R-HSA-2691219
  title: NOTCH1 HD domain mutants bind DLL1
  findings: []
- id: Reactome:R-HSA-2691226
  title: NOTCH1 HD domain mutants bind JAG1
  findings: []
- id: Reactome:R-HSA-2730752
  title: NOTCH1 HD domain mutants are cleaved to produce NEXT1 irrespective of ligand binding
  findings: []
- id: Reactome:R-HSA-2737728
  title: Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD domain mutants
  findings: []
- id: Reactome:R-HSA-2768993
  title: NOTCH1 PEST domain mutants bind JAG2
  findings: []
- id: Reactome:R-HSA-2768999
  title: NOTCH1 PEST domain mutants bind JAG1
  findings: []
- id: Reactome:R-HSA-2769000
  title: NOTCH1 PEST domain mutants bind DLL4
  findings: []
- id: Reactome:R-HSA-2769007
  title: Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 PEST domain mutants
  findings: []
- id: Reactome:R-HSA-2769008
  title: 'NOTCH1 PEST domain mutants bind DLL1 '
  findings: []
- id: Reactome:R-HSA-2769015
  title: NICD1 PEST domain mutants translocate from cytosol to nucleus
  findings: []
- id: Reactome:R-HSA-2900743
  title: NOTCH1 HD+PEST domain mutants bind JAG1
  findings: []
- id: Reactome:R-HSA-2900747
  title: NOTCH1 HD+PEST domain mutants bind DLL4
  findings: []
- id: Reactome:R-HSA-2900748
  title: NOTCH1 HD+PEST domain mutants bind DLL1
  findings: []
- id: Reactome:R-HSA-2900756
  title: NOTCH1 HD+PEST domain mutants bind JAG2
  findings: []
- id: Reactome:R-HSA-2900765
  title: Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD+PEST domain mutants
  findings: []
- id: Reactome:R-HSA-4396371
  title: NOTCH1 Coactivator Complex binds MYC promoter
  findings: []
- id: Reactome:R-HSA-4396379
  title: NOTCH1 Coactivator Complex binds HES5 promoter
  findings: []
- id: Reactome:R-HSA-4396392
  title: NOTCH1 PEST domain mutants bind HES1 promoter
  findings: []
- id: Reactome:R-HSA-4396393
  title: NOTCH1 PEST domain mutants bind MYC promoter
  findings: []
- id: Reactome:R-HSA-4396401
  title: NOTCH1 PEST domain mutants bind HES5 promoter
  findings: []
- id: Reactome:R-HSA-4396402
  title: NOTCH1 PEST domain mutants bind promoters of HEY genes
  findings: []
- id: Reactome:R-HSA-5096538
  title: Defective LFNG does not transfer GlcNAc to Pre-NOTCH
  findings: []
- id: Reactome:R-HSA-8878220
  title: RUNX3 binds the NOTCH1 coactivator complex
  findings: []
- id: Reactome:R-HSA-8878237
  title: RUNX3:NOTCH1 coactivator complex binds the HES1 gene promoter
  findings: []
- id: Reactome:R-HSA-9017835
  title: NOTCH1 coactivator complex binds NOTCH3 gene
  findings: []
- id: Reactome:R-HSA-9021451
  title: NOTCH1,NOTCH3 coactivator complex binds PLXND1 gene promoter
  findings: []
- id: Reactome:R-HSA-9762102
  title: NICD1 binds the NFE2L2 promoter
  findings: []
- id: Reactome:R-HSA-9796071
  title: NFE2L2 dependent NOTCH1 expression
  findings: []
- id: Reactome:R-NUL-2064264
  title: NICD1 displaces NCOR co-repressor complex from CSL
  findings: []
- id: Reactome:R-NUL-2076711
  title: rDll1 binds NOTCH1 in cis
  findings: []
core_functions:
- description: NOTCH1 functions as a transmembrane signaling receptor at the plasma membrane, responding to membrane-bound DSL ligands (JAG1/2, DLL1/3/4) on neighboring cells to transduce cell-cell contact signals into transcriptional responses via regulated intramembrane proteolysis
  molecular_function:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  directly_involved_in:
  - id: GO:0007219
    label: Notch signaling pathway
  - id: GO:0030154
    label: cell differentiation
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0009986
    label: cell surface
- description: The cleaved NOTCH1 intracellular domain (NICD) functions as a transcriptional coactivator in the nucleus, displacing corepressors from RBPJ/CSL and recruiting MAML coactivators to form the CSL-NICD-MAML ternary transcription complex that activates target genes (HES1, HES5, HEY1, HEY2, HEYL)
  molecular_function:
    id: GO:0003713
    label: transcription coactivator activity
  directly_involved_in:
  - id: GO:0045893
    label: positive regulation of DNA-templated transcription
  - id: GO:0007221
    label: positive regulation of transcription of Notch receptor target
  locations:
  - id: GO:0005634
    label: nucleus
  in_complex:
    id: GO:0002193
    label: MAML1-RBP-Jkappa- ICN1 complex
- description: NOTCH1 EGF-like domains bind calcium ions, which is essential for proper receptor folding, stability, and ligand interaction
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  locations:
  - id: GO:0005886
    label: plasma membrane

NOTCH1

Gene Description

Existing Annotations Review

Core Functions

NOTCH1 functions as a transmembrane signaling receptor at the plasma membrane, responding to membrane-bound DSL ligands (JAG1/2, DLL1/3/4) on neighboring cells to transduce cell-cell contact signals into transcriptional responses via regulated intramembrane proteolysis

The cleaved NOTCH1 intracellular domain (NICD) functions as a transcriptional coactivator in the nucleus, displacing corepressors from RBPJ/CSL and recruiting MAML coactivators to form the CSL-NICD-MAML ternary transcription complex that activates target genes (HES1, HES5, HEY1, HEY2, HEYL)

NOTCH1 EGF-like domains bind calcium ions, which is essential for proper receptor folding, stability, and ligand interaction

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 Cyberian

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

NOTCH1 (P46531): Functional Annotation Research Report

1. Introduction and Summary

2. Protein Structure and Domain Organization

3. Proteolytic Processing and Activation Mechanism

4. Subcellular Localization and Trafficking

5. Canonical Notch Signaling Pathway

6. Non-Canonical Notch Signaling

7. Target Genes and Transcriptional Programs

8. Post-Translational Modifications and Signaling Modulation

9. Biological Functions and Developmental Roles

10. Disease Associations and Therapeutic Targeting

11. Evolutionary Conservation

12. Open Questions

13. References

Citations

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

Bioreason Rl Review

BioReason-Pro RL Review: NOTCH1 (human)

Functional Summary Review

Notes on thinking trace

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