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FLASH GENE
Symbol NUMB contributors: mct/pgu - updated : 24-04-2016
HGNC name numb homolog (Drosophila)
HGNC id 8060
Location 14q24.3      Physical location : 73.741.917 - 73.925.286
Synonym name protein S171
Synonym symbol(s) S171, NUMB3
DNA
TYPE functioning gene
STRUCTURE 183.37 kb     13 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status provisional
Map see PSEN1
regionally located locus AD3
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
13 splicing 3647 70.6 651 - 2009 19138666
  • bind to the plasma membrane by default
  • isoform 1
  • 12 splicing 3503 65.7 603 bind to the plasma membrane by default 2009 19138666
  • isoform 2
  • 12 splicing 3614 69.3 640 mostly found in the cytoplasm 2009 19138666
  • responsible for the selective endocytosis of P-selectin
  • binds P-selectin by its PTB domain
  • isoform 3
  • 11 splicing 3470 64.4 592 in the cytoplasm 2009 19138666
  • isoform 4
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouth   highly
    Lymphoid/Immunethymus   highly
    Nervousbrain    
    Reproductivefemale systembreastmammary gland highly Homo sapiens
    Respiratoryrespiratory tracttrachea  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    Nervousoligodendrocyte
    Reproductiveepithelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo
    Text oligodendrocyte progenitor cells
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal phosphotyrosine-binding (PTB) domain required for integrin beta1/beta3 endocytosis , with one region (amino acids 113148) mediating binding to both regions of MDM2
  • NPF (asparagine-proline-phenylalanine) motif
  • a PID domain
  • a proline-rich region (PRR) functionning as an SH3-binding domain
  • conjugated ubiquitinated
    HOMOLOGY
    interspecies homolog to Drosophila numb
    homolog to C.elegans NUMB
    homolog to yeast signal transducer Eps15
    homolog to murine Numb
    Homologene
    FAMILY
    CATEGORY adaptor , signaling
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endosome
    text
  • redistributed by AAK1 to perinuclear endosomes when overexpressed, while kinase depletion causes NUMB to accumulate at the plasma membrane)
  • mainly localized to the cytoplasmic membrane
  • basic FUNCTION
  • playing a role in generating asymetric cell division during neurogenesis
  • in enabling neural progenitor cells to balance self-renewal and neuron production by segregating asymmetrically to the progenitor daughter cells to specify their fates
  • NUMB signaling seems to play two contradictory roles: namely, it promotes progenitor over neuronal fates but is also required for neuronal differentiation
  • playing a crucial role in the maintenance of radial glia adherens junctions and, consequently, the integrity of the neurogenic epithelium
  • required for the tissue architecture of neurogenic niches and the cerebral cortex
  • controlling TP53 tumour suppressor activity by preventing ubiquitination and degradation of TP53
  • major determinant of binary cell fates and required for the differentiation of cerebellar granule cell progenitors (GCPs) at a stage of development responsive to the morphogenic glycoprotein Hedehog
  • endocytic protein that is proposed to influence clathrin-coated pit assembly
  • mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast
  • endocytic receptor for P-selectin that may be responsible for the rapid internalization of P-selectin when endothelial activation ends
  • depletes chronic myelogenious leukemia stem cells
  • regulates cell-cell adhesion and polarity in response to tyrosine kinase signalling
  • sensor of HGF signalling or Src activity during epithelial-mesenchymal transition
  • NUMB phosphorylation may act as an important regulatory process in the NOTCH1 pathway
  • important cell fate determinant that is asymmetrically inherited during mitosis and controls the fate of sibling cells by inhibiting the Notch signaling pathway in neural tissue
  • modulates intestinal epithelial cells towards the goblet cell phenotype by inhibiting the Notch signaling pathway
  • NUMB and NUMBL have evolved to acquire at least partially distinct functions
  • regulates steady-state levels of TP53 in cells by disrupting TP53-MDM2 acidic domain interactions
  • is an endocytic adaptor protein that regulates the endocytosis and trafficking of transmembrane receptors including NOTCH1, CDH1, and integrins
  • RBFOX3-dependent NUMB alternative splicing plays an important role in the progression of neuronal differentiation during vertebrate development
  • NUMB inhibits NOTCH1 signaling by promoting the degradation of the NOTCH1 intracellular domain in cardiomyocytes
  • novel role of NUMB that lies at the heart of TCR signaling initiation and termination
  • importance of NUMB and NUMBL in the control of myoepithelial cell fate determination, epithelial identity, and lactogenesis
  • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS development
    text
  • neuronal development/neurogenesis
  • depending of the isoform
  • PATHWAY
    metabolism
    signaling
    apparent role of the Musashi-NUMB pathway in regulating the formation of aggressive myeloid leukemia, and thus provide a potential molecular mechanism for the transition of chronic phase CML to the deadly blast crisis
    a component forming a trimeric complex with MDM2 and TP53 and has been shown to play a role in the stabilization of TP53 in cells
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • EPS15
  • interacts with the active intracellular domain of NOTCH1 (NICD) promoting degradation of NOTCH1, preventing its localization to the nucleus and its activity as a transcription factor
  • interacting with ACBD3
  • interacting with LNX1
  • binding to AAK1
  • bind to the alpha-adaptin of AP2 in clathrin-coated pits by its C-terminus
  • interacts with E-cadherin and regulates its localization to the lateral domain of epithelial cell-cell junction
  • endocytic protein that acts as a NOTCH1 inhibitor via binding to AP2 in coated pits
  • MDM2 acid domain binds NUMB and is critical for NUMB ubiquitination
  • potential novel roles of NUMB/NUMBL in regulating heart trabeculation and compaction by inhibiting NOTCH2 and BMP10 signalling
  • developmental regulator OFCC1 enables polarized integrin localization by modulating NUMB/NUMBL, thus directing the basal constriction that shapes the vertebrate retina epithelium
  • interactions with REPS1, BMP2K, and BCR
  • NUMB interacts with TRPV6 through charged residues and inhibits its activity via the regulation of protein expression
  • NUMB premRNA encoding a signaling adaptor protein is a target of RBFOX3 action, and RBFOX3 repressed the inclusion of an alternative exon via binding to the conserved UGCAUG element in the upstream intron
  • NUMB, NUMBL counteract VEGF receptor degradation and promote VEGFR2 recycling back to the plasma membrane
  • CD3E recruits NUMB to promote TCR degradation
  • MSI2 promotes the development and progression of pancreatic cancer by down-regulating NUMB protein
  • interaction of MSI2-NUMB plays a significant role in the development and progression of Pancreatic cancer
  • endocytic adaptor proteins NUMB and NUMBL were required for downregulation of ERBB2 signaling in maturing trabeculae
  • NUMB and NUMBL interacted with small GTPase RAB7A to transition ERBB2 from early to late endosome for degradation
  • cell & other
    REGULATION
    Phosphorylated by PRKCI (phosphorylates NUMB to prevent its binding to CTNND1 and AP2A1, thereby attenuating CDH1 endocytosis to maintain apicobasal polarity)
    Other is increased in the absence of SMO activity
    phosphorylated by adaptor-associated kinase 1 (AAK1), a key endocytic kinase
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral        
    frequent loss of NUMB expression in breast cancers causing expression of the receptor NOTCH5, resulting in an agressive tumour phenotype and a poor prognosis
    Susceptibility Alzheimer disease
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    Musashi-NUMB pathway may provide target for future therapies that are desperately needed for aggressive forms of myeloid leukemia
    ANIMAL & CELL MODELS
    nestin-CreER transgenic mice where Numb/Numbl are removed have severe damage to brain lateral ventricle integrity