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FLASH GENE
Symbol NOTCH1 contributors: shn - updated : 06-10-2015
HGNC name notch 1
HGNC id 7881
Corresponding disease
AOS5 Adams-Oliver syndrome 5
FAVD1 familial aortic valve disease 1
TAN1 T-cell acute lymphocytic leukemia
Location 9q34.3      Physical location : 139.388.896 - 139.440.238
Synonym name
  • Notch homolog 1, translocation-associated (Drosophila)
  • Notch (Drosophila) homolog 1 (translocation-associated)
  • translocation-associated NOTCH homolog 1
  • neurogenic locus notch homolog protein 1
  • Synonym symbol(s) hN1, TAN1
    DNA
    TYPE functioning gene
    STRUCTURE 51.34 kb     34 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status confirmed
    Map cen - D9S1826 - D9S158 - NOTCH1 - D9S905 - D9S1838 - qter
    Physical map
    GBDR1 9q34.1-q34.3 TNF receptor-associated factor 2 BTBD14A 9q34.3 BTB (POZ) domain containing 14A LOC392400 9 similar to F4N2.10 LOC389806 9 hypothetical gene supported by BC009060 LOC389807 9 LOC389807 LOC389808 9 LOC389808 LOC389809 9 LOC389809 LHX3 9q34.3 LIM homeobox protein 3 QSCN6L1 9q34.3 quiescin Q6-like 1 AGS3 9q34.3 activator of G-protein signaling 3 LOC389810 9 LOC389810 CARD9 9q34.3 caspase recruitment domain family, member 9 SNAPC4 9q34.2-q34.3 small nuclear RNA activating complex, polypeptide 4, 190kDa SDCCAG3 9q34.3 serologically defined colon cancer antigen 3 PMPCA 9q34.3 peptidase (mitochondrial processing) alpha INPP5E 9q34.3 inositol polyphosphate-5-phosphatase, 72kDa KIAA0310 9q34.1 inositol polyphosphate-5-phosphatase, 72kDa FLJ36779 9q34.3 hypothetical protein FLJ36779 NOTCH1 9q34.3 Notch homolog 1, translocation-associated (Drosophila) LOC389811 9 similar to HSPC324 EGFL7 9q34.3 EGF-like-domain, multiple 7 AGPAT2 9q34.3 1-acylglycerol-3-phosphate O-acyltransferase 2 (lysophosphatidic acid acyltransferase, beta) MGC20262 9q34.3 hypothetical protein MGC20262 MGC16037 9q34.3 hypothetical protein MGC16037 LCN6 9q34.3 lipocalin 6 LOC138307 LOC389812 LOC392401 9 similar to vacuolar H(+)-ATPase subunit; V-ATPase subunit; M16 MGC14141 9q34.3 hypothetical protein MGC14141 MGC15438 9q34.3 hypothetical protein MGC15438 FLJ10101 9q34.3 FLJ10101 protein LOC389813 9 similar to ENSANGP00000006371 PHP14 9q34.3 phosphohistidine phosphatase AEGP 9q34.3 apical early endosomal glycoprotein precursor EDF1 9q34.3 endothelial differentiation-related factor 1 TRAF2 9q34 TNF receptor-associated factor 2
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    34 - 9309 - 2555 - 2010 19725072
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestivecholedoque   lowly
     esophagus   highly
     pancreas exocrine   lowly
    Endocrinepancreas   moderately
    Nervousnervecranial nerve  highly
    Visualeyeanterior segmentcornea highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    Epithelialbarrier/liningendometrium  
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveacinar
    Nervousoligodendrocyte
    Visualepithelial cell
    cell lineage CD34+ hematopoietic cells (see TAN1), bone marrow CD34 positive cells
    cell lines
    fluid/secretion blood
    at STAGE
    physiological period embryo, fetal, pregnancy
    Text in the developing cochlear duct, spleen, brainstem, lung, kidney, heart (epicardium), aorta, in proliferative oligodendrocytes progenitor cells (OPCs)
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a nuclear localization signal (NLS)
  • thirty six extracellular EGF repeats in the extracellular region
  • an intracellular domain (ICD) with three cysteine-rich lin/notch repeats, HDn and HDc domains, implicated in SIRT1 binding
  • six ankyrin/CDC10 repeats and a glutamine-rich domain
  • a RAM23 domain and PEST sequences
  • a transcriptional activation domain (TAD), playing essential role for in fetal development
  • C terminal PEST domain
  • conjugated PhosphoP
    mono polymer heteromer , dimer
    isoforms Precursor
    HOMOLOGY
    interspecies ortholog to LOC493574, Rattus norvegicus
    ortholog to NOTCH1, pan troglodytes
    ortholog to Notch1, Mus musculus
    ortholog to zgc:154151, Danio rerio
    Homologene
    FAMILY
  • NOTCH family
  • CATEGORY regulatory , receptor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,lysosome
    intracellular,cytoplasm,cytosolic,vesicle
    text
  • located on the cell surface
  • co-localization of DLL3 and NOTCH1 occurs only in cytoplasmic vesicles that are likely to be late endosomes and lysosomes
  • basic FUNCTION
  • functions as a receptor for membrane bound ligands and plays a role in a variety of developmental processes by controlling cell fate decisions during hematopoiesis
  • Notch signals regulate development and differentiation of adult self-renewing cells
  • receptor for membrane-bound ligands Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4
  • controlling binary cell fate decisions during developement
  • inducing delay of hematopoietic differentiation and alteration of cell cycle kinetics
  • mediating cell-cell interactions that specify cell fate during development, and the changes of the endometrium during menstrual cycle and development of endometrial cancers
  • regulating T-cell development
  • playing a fundamental role during the establishment of cell fates in the central nervous system (CNS) by regulating neural cell differentiation
  • provides a CNTF-independent instructive signal of astroglia differentiation in central nervous system multipotent progenitor cells
  • role in early embryonic development like the establishment of the rostro-caudal polarity of somites
  • play a role in neuronal development by regulating the capacity of neurons to extend and elaborate neurites
  • involved in human keratinocyte tumor suppression
  • NOTCH1 signaling pathway is a critical controller of cell fate decisions and is a key regulator of cell growth and metabolism during T-cell development and transformation
  • NOTCH1 pathway is crucial in podocyte development
  • acting as a net inhibitor of bone resorption, exerting its effect both directly in osteoclast precursors and indirectly via osteoblast lineage cells
  • Notch signaling is involved in endothelial–mesenchymal transformation in the ventricular chamber, atrioventricular valves and vasculature
  • may have critical implications in the control of heart homeostasis and its adaptation to pathologic states
  • with RELN necessary to induce the expression of brain lipid binding protein (FABP7) and to promote the process extension and the maturation of the neuronal progenitors, the radial glial cells
  • acts in aged muscle regeneration and bone homeostasis by regulating both osteoclastogenesis and osteoblastic proliferation and by maintaining a pool of mesenchymal progenitors in bone mrarrow
  • Notch1 functions as a tumor suppressor gene in mammalian skin
  • as other Notch family members and ligands, expressed in the human corneal epithelium and appear to play pivotal roles in corneal epithelial cell differentiation
  • new signaling pathway involved in holoprosencephaly
  • NOTCH1 signalling is necessary for the initial phases of myogenesis of dorsomedial lip cells
  • role for NOTCH signalling during early haematopoietic stem cell differentiation, suggesting that the NOTCH pathway can play both tumour-promoting and -suppressive roles within the same tissue
  • may function as a tumor suppressor gene rather than an oncogene in Head and neck squamous cell carcinoma
  • regulates gene expression by associating with the DNA-binding factor RBPJ and is oncogenic in T-cell progenitors
  • during early pancreatic development, NOTCH1 signaling represses differentiation of endocrine cells and promotes proliferation of multipotent progenitor cells (MPCs)
  • activation of the NOTCH1 pathway is a novel mechanism in the human Treg-cell induction mediated by MSCs
  • NOTCH1 signaling not only preserves stem cell characteristics, but that it can confer stem cell characteristics upon a subset of progenitor cells
  • NOTCH1 signaling leads to activation of parallel survival and apoptotic pathways in endothelial cells
  • importance of NOTCH1 signaling regulation in male germ cells for their survival and differentiation
  • plays essential roles in cell fate specification during embryonic development and in adult tissue maintenance
  • oncogenic role for NOTCH1 in chronic myeloid leukaemia (CML) and BCR-ABL disruption of NOTCH1–NOV signalling contributes potentially to the pathogenesis of CML
  • NOTCH1 signaling is required for the formation of mesangial cells from a stromal mesenchyme precursor during kidney development
  • critical role of NOTCH signaling in RPE cells
  • NOTCH1 and NOTCH2 expression in osteoblast precursors regulates cancellous bone volume and microarchitecture
  • required to generate the earliest embryonic hematopoietic stem cells (HSCs)
  • important cell-autonomous functions for Notch1 signaling in fetal HSC homeostasis
  • endothelial NOTCH1 activity promotes angiogenesis and osteogenesis in bone
  • SLBP and NOTCH1 signaling are required for retinal progenitor cell proliferation and subsequent neurogenesis
  • NOTCH1 is the primary receptor regulating intestinal stem cell function and NOTCH1 and NOTCH2 together regulate epithelial cell proliferation, cell fate determination, and post-injury regeneration
  • NOTCH1 and NOTCH2 are the primary NOTCH receptors regulating epithelial cell homoeostasis in human stomach
  • CELLULAR PROCESS cell life, differentiation
    cell organization/biogenesis
    cell communication
    PHYSIOLOGICAL PROCESS development , immunity/defense , reproduction/sex
    text
  • spermatogenesis
  • hematopoiesis
  • PATHWAY
    metabolism
    signaling
  • NOTCH pathway plays a pivotal role in neuron-glia differentiation
  • Notch signaling pathway implicated in remyelinating lesions indicating that remyelination may occur in the presence of Notch signaling
  • Notch signalling pathway is repeatedly employed during embryonic development and adult homeostasis of a variety of tissues (Gering 2010)
  • autocrine signaling loop between NOTCH1 and NRG1 that controls melanoma growth
  • NOTCH1/RBPJ signaling regulates the generation and differentiation of arcuate nucleus (Arc) neurons, which contribute to homeostatic regulation of body size neurons
  • NOTCH1-ROCK1 pathway critical for cellular differentiation and loss of self-renewal capacity in a subset of immature cells
  • Notch signaling induces gene expression of the T cell lineage
  • NOTCH1/RBPJ signaling regulates dopamine responsiveness in the striatum, which may explain the mechanism whereby NOTCH1/RBPJ signaling affects an individual susceptibility to neuropsychiatric disease
  • a component
  • protein constituent of plasma smembrane
  • APBB1 facilitates stable association between NOTCH11 and E3 ligase ITCH through the formation of a trimeric complex
  • INTERACTION
    DNA
    RNA
    small molecule
  • Ca2+
  • protein
  • NUMB (negative regulator of NOTCH1 activity)
  • interacting with DTX1, DTX2, MAML1, MAMOL2, MAML3, DNER, RBPSUH
  • negative regulation of ROCK1/2 and MRCKalpha kinases
  • regulatory circuit linking NOTCH1 signaling with PTEN expression and PI3K-AKT activity may contribute to NOTCH1-induced transformation and could mediate, at least in part, the cellular response to NOTCH1 inhibitors in T-ALL
  • upregulating the genes encoding cyclin D, cyclin E and SP7 (osterix)
  • interacting with NKX2.5, a novel target gene of NOTCH1 (NKX2.5 is an early event in the growth of embryonic myocytes but its role in the postnatal heart remained unclear)
  • TP53 target with a role in tumor suppression through negative regulation of Rho effectors ROCK1/2 and CDC42BPA
  • F3/contactin acts as a functional ligand of Notch1
  • Delta like 4 (DLL4, Delta family of Notch ligands)
  • SEL-10 interacts with nuclear forms of Notch1 it requires a phosphorylation event
  • Glycogen synthase kinase 3 beta (GSK3beta)
  • Numb protein promotes the ubiquitination of membrane-bound Notch1 receptor and its intracellular domain degradation following activation
  • Delta1, Jagged1, and Jagged2
  • histone acetyltransferases PCAF and GCN5
  • tyrosine kinase p56(lck) and phosphatidylinositol 3-kinase (PI3K)
  • recombination signal binding protein Jkappa (RBP-Jkappa) and Mastermind like 1 (MAML1)
  • interacts with nuclear factor-kappa B proteins in T cells
  • Nephroblastoma overexpressed gene (NOV/ccn3)
  • m-Numb, transcription factor RBP-J kappa/Su(H)
  • Smad3, transcription factor Ying Yang 1 (YY1)
  • Transcriptional coactivator RBP, WDR12, presenilin-1 (PS1)
  • Ski-interacting protein (SKIP)
  • interaction with HUWE1 (ubiquitin ligase HUWE1 operates upstream of the MYCN-DLL3-NOTCH1 pathway to control neural stem cell activity and promote neurogenesis)
  • Crbp1 (RBP1)a direct Notch1 target within the corneal epithelium
  • peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1)
  • NOTCH1 in concert with NOTCH2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBPJ-dependent manner
  • TLX1 and NOTCH synergistically regulate transcription in T-ALL, at least in part via the sharing of a TLE corepressor and by augmenting expression of MYC
  • AKT1 and FOXM1 are downstream targets of NOTCH1 signaling
  • SGK1 inhibits the NOTCH1 signaling pathway via phosphorylation of FBXW7
  • DLL3 interacts with the unprocessed full-length form of NOTCH1 (NOTCH1 inhibition by DLL3 implicated in abnormal vertebral segmentation in spondylocostal dysostosis)
  • NOTCH1 activation induces RUNX3 expression in human endothelial cells
  • neuronal NOTCH1 signaling is positively regulated by ARC, an activity-induced gene required for synaptic plasticity
  • JARID2 is a potential regulator of NOTCH1 signaling
  • SIRT1 associates with ICD and functions as a ICD deacetylase, which opposes the acetylation-induced ICD stabilization
  • binds preferentially to promoters, to RBPJ binding sites, and near imputed ZNF143, ETS, and RUNX sites
  • APBB1 attenuates NOTCH1 signaling via the accelerated degradation of the membrane-tethered NOTCH1 in the cytoplasm
  • NOTCH1 directly regulates the transcription of NRG1 by binding to its promoter region
  • EIF6 is one of the downstream effectors of NOTCH1 in the pathway that controls cell motility and invasiveness
  • both NOTCH1 and KDR modulate FLT4 protein and activation levels independently and in opposite directions
  • NOTCH1-FURIN interaction is regulated by the non-receptor tyrosine kinase, SRC
  • USP12 directly targets NOTCH1 and directs it to lysosomal degradation
  • CAMK2A is crucial for the regulation between NOTCH1 and WNT5A signaling
  • NOTCH1 intracellular domain increases cytoplasmic EZH2 levels during early megakaryopoiesis
  • CAMK4 remarkably increased NOTCH1-intracellular domain stability, and the kinase activity of CAMK4 was essential for facilitating NOTCH1 signaling
  • endothelial cell-derived NO is a regulator of NOTCH1 signaling in aortic valve interstitial cells (AVICs) in the development of the aortic valve and adult aortic valve disease
  • mosaic expression of FOXN4 and proneural factors may serve as the trigger to initiate asymmetric DLL4-NOTCH1 and subsequent BMP/TGFB1 signaling events required for neuronal diversity in the V2 interneurons domain
  • NOV is a non-canonical NOTCH1 ligand
  • SNAI1-DLL4/NOTCH1 axis controls embryonic vascular development
  • FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH1 or inhibition of NOTCH1 signal transduction
  • ACVRL1 synergises with NOTCH1 in stalk cells to induce expression of the NOTCH1 targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting
  • inhibits chondrogenic differentiation of mesenchymal progenitor cells by targeting TWIST1
  • LOXL2 is a direct repressor of NOTCH1, and represses NOTCH1 expression in the skin to promote squamous cell carcinoma progression
  • activated NOTCH1 leads to pronounced accumulation of SMO within primary cilia and elevated levels of full-length GLI3
  • CTF1 activates NOTCH1 signaling through the up-regulation of ADAM10, a rate-limiting factor of NOTCH1 signaling activation
  • KRT8 regulates NOTCH1 signalling activity and differentiation in the epithelium of the large intestine
  • cell & other
    REGULATION
    activated by delta (DLK1) jagged (JAG1, JAG2)
    activation of WNT signaling in hematopoietic stem cells induced increases expression of NOTCH1
    repressed by Mesp2
    Phosphorylated by CAMK4 and phosphorylated NOTCH1-IC by CAMK4 increases NOTCH1-IC stability, which enhances osteoclast differentiation
    Other undergoing a first proteolytic cleavage by furin (PACE1) in the Golgi during trafficking of Notch to the cell surface, undergoing further cleavage by gamma secretase (see PSEN1) releasing an intracellular domain (NICD) which translocates to the nucleus and modulates transcription of target genes
    modulated by FRINGE (LFNG, MFNG, RFNG) through elongation of linked fucose residues on side chains on some EGF repeats
    regulated by TP53
    Deltex-1 (DTX1) regulates NOTCH1 transcription
    enhanced by PIN1 through its prolyl-isomerase activity
    cleaved by ADAM10 or ADAM17
    conserved regulation of NOTCH1 signaling by the ubiquitin system
    ASSOCIATED DISORDERS
    corresponding disease(s) TAN1 , FAVD1 , AOS5
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    adult Down syndrome cortex
    tumoral       gain of function
    in T-cell lymphoblastic leukemias and lymphomas
    constitutional     --over  
    inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling
    constitutional germinal mutation      
    heart valve disease such as bicuspid aortic valve, hypoplastic left heart syndrome,aortic stenosis and other serious valvular anomalies with calcifications in many cases
    tumoral       gain of function
    activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease
    constitutional       gain of function
    causes severe osteosclerosis owing to increased proliferation of immature osteoblasts
    constitutional     --low  
    promotes osteoclastogenesis indirectly by enhancing the ability of osteoblast lineage cells to stimulate osteoclastogenesis
    tumoral     --low  
    in keratinocyte cancer cell lines and tumors
    constitutional     --over  
    in immune thrombocytopenic purpura
    tumoral   deletion    
    T cell-specific deletion of floxed NOTCH1 promoter/exon 1 sequences significantly accelerates leukemogenesis
    Susceptibility to left ventricular outflow tract abnormalities
    Variant & Polymorphism other mutations in left ventricular outflow tract malformations reduce ligand-induced signaling
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductiveprostate
    down-regulation of Notch-1 by novel agents could become a newer approach for the prevention of tumor progression and/or treatment of prostate carcinoma
    miscelleaneousurinary 
    Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target
    osteoarticularboneostéoporosis
    therapeutic inhibition of NOTCH signaling may adversely accelerate bone loss and osteoporosis (potential complication of therapeutic inhibition of NOTCH activity)
    bloodcoagulation 
    blockage of Notch1 pathway is likely a promising therapeutic concept in immune thrombocytopenic purpura
    cancerhemopathy 
    reversible activation of the Notch pathway may represent an attractive future therapy, targeting specifically the progression and relapse of granulocytic and monocytic neoplasms
    ANIMAL & CELL MODELS
  • Notch1 mutant and Notch1/Notch4 double mutant mouse embryos displayed severe defects in angiogenic vascular remodeling
  • ablation of Notch1 in mouse skin resulted in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis
  • doubly mouse embryos mutant for Notch1 and Notch2 exhibited multiple defects in left-right asymmetry
  • Notch1 -/- corneal progenitor mouse cells lost the ability to repair mechanically wounded corneal epithelium