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FLASH GENE
Symbol NOTCH4 contributors: mct - updated : 28-05-2020
HGNC name Notch homolog 4 (Drosophila)
HGNC id 7884
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a putative signal peptide
  • 29 EGF-like repeats
  • a transmembrane segment (1TM)
  • three notch/lin-12 (LNR) repeats
  • a RAM23 domain
  • six cdc10/ankyrin (ANK) repeats
  • the C terminal PEST conserved region
    • mono polymer heteromer , dimer
    isoforms Precursor
    HOMOLOGY
    interspecies homolog to rattus Notch4 (81.24 pc)
    homolog to murine Notch4 (82.04 pc)
    intraspecies homolog to MMTV integration site int-3
    Homologene
    FAMILY
  • NOTCH family
    • CATEGORY regulatory , structural protein , receptor membrane
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    basic FUNCTION
  • receptor for membrane-bound ligands Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4
  • mediating cell-cell interactions that specify cell fate during development, and the changes of the endometrium during menstrual cycle and development of endometrial cancers
  • involved in endothelial-pericyte interactions
  • possible contribution of Notch4 signalling to the development of brain arteriovenous malformations (AVMs)
  • role of NOTCH4 in the vasculature, and in fine-tuning the forming vascular plexus
  • negative regulatory role for the PI3K-AKT pathway in NOTCH4 nuclear signaling
  • NOTCH1 and NOTCH4 signaling pathways regulate endothelial cell homeostasis
  • role of NOTCH4 signaling in promoting human megakaryopoiesis
    • CELLULAR PROCESS cell life, differentiation
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling signal transduction
    AP-1-Notch4 pathway, may be crucial for transducing angiogenic signals and deregulated upon aberrant signal transduction in cancer
    a component
  • protein constituent of transmembrane
    • INTERACTION
    DNA
    RNA
    small molecule other,
  • Ca
    • protein
  • ligands
  • interacting with TACC3
  • antagonistic relationship between NOTCH4 and TP53, which is controlled by the MDM2-dependent ubiquitylation and degradation of the NOTCH receptor
  • functional interaction of NOTCH4(ICD) and ELOC provides novel insight into regulation of NOTCH1 signaling in epithelial cell biology and disease
  • IL1B regulates NOTCH1 and NOTCH4 activity in opposite directions, consistent with a selective targeting of NOTCH1 in inflamed endothelium
  • NOTCH4, not NOTCH1, is the specific receptor for the DLL4/NOTCH-EFNB2 cascade
  • NOTCH4 signaling controls EFNB2-induced endothelial progenitor cell dysfunction in preeclampsia
  • NOTCH4 expression was negatively controlled by RUNX1 via a novel regulatory DNA element within the locus, and we examined its involvement in Megakaryocytes (MKs) generation
    • cell & other
    REGULATION
    activated by delta (DLK1) jagged (JAG*)
    induced by MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH4
    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
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in endometrial cancer
    constitutional     --over  
    in proliferating hemangiomas
    tumoral     --low  
    in colorectal cancer (CRC), which could determine tumor proliferation, relapse, and prognosis
    Susceptibility
  • schizophrenia (minor locus)
  • alopecia areata(ALPCA)
  • to rheumatoid arthritis
  • to variation of characteristics of migraine
    • Variant & Polymorphism SNP
  • A>G 5 utr,(CTG)10 alleles (exon 1)
  • variants in the NOTCH4 Gene influence the clinical features of migraine
    • Candidate gene
    Marker
  • NOTCH4 mRNA level could be an independent prognostic factor for both disease-free and overall survival of colorectal cancer (CRC) patients
    • Therapy target
    ANIMAL & CELL MODELS
  • Notch4 null mice exhibited slightly delayed vessel growth in the retina