NOTCH1

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

Notch 1

Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4+ and CD8+ cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).

Animal organ regeneration Source: Ensembl
Aortic valve morphogenesis Source: BHF-UCL
Apoptotic process involved in embryonic digit morphogenesis Source: Ensembl
Arterial endothelial cell differentiation Source: BHF-UCL
Astrocyte differentiation Source: Ensembl
Atrioventricular node development Source: Ensembl
Atrioventricular valve morphogenesis Source: BHF-UCL
Auditory receptor cell fate commitment Source: Ensembl
Axon guidance Source: GO_Central
Branching morphogenesis of an epithelial tube Source: Ensembl
Cardiac atrium morphogenesis Source: BHF-UCL
Cardiac chamber formation Source: BHF-UCL
Cardiac epithelial to mesenchymal transition Source: BHF-UCL
Cardiac left ventricle morphogenesis Source: BHF-UCL
Cardiac muscle cell proliferation Source: Ensembl
Cardiac muscle tissue morphogenesis Source: BHF-UCL
Cardiac right atrium morphogenesis Source: BHF-UCL
Cardiac right ventricle formation Source: Ensembl
Cardiac septum morphogenesis Source: BHF-UCL
Cardiac vascular smooth muscle cell development Source: BHF-UCL
Cardiac ventricle morphogenesis Source: BHF-UCL
Cell cycle arrest Source: UniProtKB
Cell differentiation in spinal cord Source: Ensembl
Cell fate specification Source: Ensembl
Cell migration involved in endocardial cushion formation Source: BHF-UCL
Cellular response to follicle-stimulating hormone stimulus Source: BHF-UCL
Cellular response to vascular endothelial growth factor stimulus Source: UniProtKB
Cilium assembly Source: UniProtKB
Collecting duct development Source: Ensembl
Compartment pattern specification Source: Ensembl
Coronary artery morphogenesis Source: BHF-UCL
Coronary sinus valve morphogenesis Source: Ensembl
Coronary vein morphogenesis Source: BHF-UCL
Determination of left/right symmetry Source: BHF-UCL
Distal tubule development Source: Ensembl
Embryonic hindlimb morphogenesis Source: Ensembl
Endocardial cell differentiation Source: BHF-UCL
Endocardial cushion morphogenesis Source: BHF-UCL
Endocardium development Source: BHF-UCL
Endocardium morphogenesis Source: BHF-UCL
Endoderm development Source: Ensembl
Epithelial to mesenchymal transition Source: BHF-UCL
Epithelial to mesenchymal transition involved in endocardial cushion formation Source: BHF-UCL
Forebrain development Source: Ensembl
Foregut morphogenesis Source: Ensembl
Glomerular mesangial cell development Source: Ensembl
Growth involved in heart morphogenesis Source: BHF-UCL
Hair follicle morphogenesis Source: Ensembl
Heart development Source: DFLAT
Heart looping Source: BHF-UCL
Heart trabecula morphogenesis Source: BHF-UCL
Homeostasis of number of cells within a tissue Source: BHF-UCL
Humoral immune response Source: Ensembl
Immune response Source: UniProtKB
Inflammatory response to antigenic stimulus Source: Ensembl
In utero embryonic development Source: Ensembl
Keratinocyte differentiation Source: Ensembl
Left/right axis specification Source: Ensembl
Liver development Source: Ensembl
Lung development Source: Ensembl
Mesenchymal cell development Source: BHF-UCL
Mitral valve formation Source: BHF-UCL
Negative regulation of anoikis Source: BHF-UCL
Negative regulation of biomineral tissue development Source: BHF-UCL
Negative regulation of BMP signaling pathway Source: BHF-UCL
Negative regulation of calcium ion-dependent exocytosis Source: Ensembl
Negative regulation of canonical Wnt signaling pathway Source: Ensembl
Negative regulation of cardiac muscle hypertrophy Source: BHF-UCL
Negative regulation of catalytic activity Source: UniProtKB
Negative regulation of cell adhesion molecule production Source: ARUK-UCL
Negative regulation of cell-cell adhesion mediated by cadherin Source: ARUK-UCL
Negative regulation of cell migration involved in sprouting angiogenesis Source: UniProtKB
Negative regulation of cell population proliferation Source: UniProtKB
Negative regulation of cell proliferation involved in heart valve morphogenesis Source: BHF-UCL
Negative regulation of cell-substrate adhesion Source: BHF-UCL
Negative regulation of cold-induced thermogenesis Source: YuBioLab
Negative regulation of endothelial cell chemotaxis Source: UniProtKB
Negative regulation of extracellular matrix constituent secretion Source: BHF-UCL
Negative regulation of gene expression Source: UniProtKB
Negative regulation of glial cell proliferation Source: UniProtKB
Negative regulation of growth rate Source: UniProtKB
Negative regulation of inner ear auditory receptor cell differentiation Source: Ensembl
Negative regulation of myoblast differentiation Source: UniProtKB
Negative regulation of myotube differentiation Source: UniProtKB
Negative regulation of neurogenesis Source: UniProtKB
Negative regulation of oligodendrocyte differentiation Source: UniProtKB
Negative regulation of ossification Source: BHF-UCL
Negative regulation of osteoblast differentiation Source: BHF-UCL
Negative regulation of photoreceptor cell differentiation Source: Ensembl
Negative regulation of pro-B cell differentiation Source: UniProtKB
Negative regulation of stem cell differentiation Source: UniProtKB
Negative regulation of transcription, DNA-templated Source: BHF-UCL
Negative regulation of transcription by RNA polymerase II Source: ARUK-UCL
Neural tube development Source: Ensembl
Neuronal stem cell population maintenance Source: UniProtKB
Notch signaling involved in heart development Source: BHF-UCL
Notch signaling pathway Source: UniProtKB
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation Source: Ensembl
Oligodendrocyte differentiation Source: Ensembl
Outflow tract morphogenesis Source: BHF-UCL
Pericardium morphogenesis Source: BHF-UCL
Positive regulation of aorta morphogenesis Source: Ensembl
Positive regulation of apoptotic process involved in morphogenesis Source: BHF-UCL
Positive regulation of astrocyte differentiation Source: UniProtKB
Positive regulation of BMP signaling pathway Source: UniProtKB
Positive regulation of cardiac epithelial to mesenchymal transition Source: BHF-UCL
Positive regulation of cardiac muscle cell proliferation Source: BHF-UCL
Positive regulation of cell migration Source: BHF-UCL
Positive regulation of cell population proliferation Source: UniProtKB
Positive regulation of endothelial cell differentiation Source: Ensembl
Positive regulation of epithelial cell proliferation Source: Ensembl
Positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
Positive regulation of gene expression Source: BHF-UCL
Positive regulation of keratinocyte differentiation Source: Ensembl
Positive regulation of neuroblast proliferation Source: Ensembl
Positive regulation of Notch signaling pathway Source: Reactome
Positive regulation of Ras protein signal transduction Source: UniProtKB
Positive regulation of receptor signaling pathway via JAK-STAT Source: UniProtKB
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Positive regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: UniProtKB
Positive regulation of transcription of Notch receptor target Source: BHF-UCL
Positive regulation of viral genome replication Source: Ensembl
Prostate gland epithelium morphogenesis Source: Ensembl
Pulmonary valve morphogenesis Source: BHF-UCL
Regulation of epithelial cell proliferation involved in prostate gland development Source: Ensembl
Regulation of extracellular matrix assembly Source: BHF-UCL
Regulation of somitogenesis Source: Ensembl
Regulation of transcription, DNA-templated Source: UniProtKB
Regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation Source: BHF-UCL
Response to corticosteroid Source: Ensembl
Response to lipopolysaccharide Source: Ensembl
Response to muramyl dipeptide Source: Ensembl
Secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development Source: Ensembl
Skeletal muscle cell differentiation Source: Ensembl
Somatic stem cell division Source: Ensembl
Spermatogenesis Source: Ensembl
Sprouting angiogenesis Source: Ensembl
Tissue regeneration Source: Ensembl
Transcription initiation from RNA polymerase II promoter Source: Reactome
Tube formation Source: UniProtKB
Vasculogenesis involved in coronary vascular morphogenesis Source: BHF-UCL
Venous endothelial cell differentiation Source: BHF-UCL
Ventricular septum morphogenesis Source: BHF-UCL
Ventricular trabecula myocardium morphogenesis Source: BHF-UCL

Cell membrane
Notch 1 intracellular domain: Nucleus. Following proteolytical processing NICD is translocated to the nucleus. Nuclear location may require MEGF10.

Aortic valve disease 1 (AOVD1):
A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome.
Adams-Oliver syndrome 5 (AOS5):
A form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins.

Extracellular: 19-1735
Helical: 1736-1756
Cytoplasmic: 1757-2555

Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).
Phosphorylated.
O-glycosylated on the EGF-like domains (PubMed:24226769). O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).
Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).
Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).