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FLASH GENE
Symbol IRS1 contributors: mct - updated : 21-03-2017
HGNC name insulin receptor substrate 1
HGNC id 6125
Corresponding disease
NIDDM3 diabetes mellitus, non insulin-dependent, 3
Location 2q36.3      Physical location : 227.596.033 - 227.663.506
Synonym symbol(s) HIRS1, IRS-1
DNA
TYPE functioning gene
STRUCTURE 67.47 kb     2 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status provisional
Physical map
FACL3 2q34 fatty-acid-Coenzyme A ligase, long-chain 3 KCNE4 2q36.3 potassium voltage-gated channel, Isk-related family, member 4 SCG2 2q35-q36 secretogranin II (chromogranin C) LOC391487 2 similar to transcription factor-like protein 4 isoform beta; MAX-like bHLHZIP protein; MAX-like protein X; BigMax protein AP1S3 2q36.3 adaptor-related protein complex 1, sigma 3 subunit WDFY1 2q36.2 WD repeat and FYVE domain containing 1 MRPL44 2q36.3 mitochondrial ribosomal protein L44 SERPINE2 2q33-q35 serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 LOC391488 2 similar to Ubiquitin carboxyl-terminal hydrolase 21 (Ubiquitin thiolesterase 21) (Ubiquitin-specific processing protease 21) (Deubiquitinating enzyme 21) (NEDD8-specific protease) FLJ22746 2q36.3 hypothetical protein FLJ22746 CUL3 2q36.3 cullin 3 DOCK10 2q24.1-q36.3 dedicator of cytokinesis 10 KIAA1486 2q36.3 KIAA1486 protein IRS1 2q36 insulin receptor substrate 1 DKFZp547E052 2q36.3 hypothetical protein DKFZp547E052 COL4A4 2q35-q37.1 collagen, type IV, alpha 4 COL4A3 2q37.1 collagen, type IV, alpha 3 (Goodpasture antigen) LOC389077 2 LOC389077 GL004 2q37.1 LOC389077 FLJ22800 2q36.3 hypothetical protein FLJ22800 HRB 2q36 HIV-1 Rev binding protein DKFZp547H025 2q36.3 hypothetical protein DKFZp547H025 LOC389078 2 hypothetical gene supported by AK125767 SLC19A3 2q37 solute carrier family 19, member 3 CCL20 2q35-q36 chemokine (C-C motif) ligand 20 FLJ25955 2q36.3 hypothetical protein FLJ25955 SKIP 17p13 hypothetical protein FLJ25955 FLJ20701 2q37.1 hypothetical protein FLJ20701 DNER 2q37.1 delta-notch-like EGF repeat-containing transmembrane TRIP12 2q36.1 thyroid hormone receptor interactor 12 LOC130888 FLJ30794 SP110 2q37.1 SP110 nuclear body protein SP140 2q36.1 SP140 nuclear body protein LOC93349 2q37.1 hypothetical protein BC004921 SP100 2q37.1 nuclear antigen SP100 HMG1L3 2q35 high-mobility group (nonhistone chromosomal) protein 1-like 3 LOC389079 2 similar to tropomyosin 3 LOC391489 2 similar to LOC93349 protein MO25 2q37.1 MO25 protein
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
2 - 8743 - 1242 - 1995 7499194
EXPRESSION
Type widely
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Endocrineparathyroid   highly
 thyroid   highly
Nervousnerve   highly
Urinarybladder   highly
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Connectiveadipose  moderately
Muscularstriatumskeletal  
cells
SystemCellPubmedSpeciesStageRna symbol
 adipocyte
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • an N-terminal pleckstrin homology (PH) domain that can bind to the plasma membrane by interaction with phosphoinositides
  • a phosphotyrosine-binding (PTB) domain recognizing phosphotyrosine in the amino acid sequence NPXpY, which is present in the juxtamembrane region of the autophosphorylated insulin receptor,
  • several tyrosine phosphorylation sites in the C terminal region
  • HOMOLOGY
    interspecies homolog to rattus Irs1 (90.6 pc)
    homolog to murine Irs1 (90.5 pc)
    Homologene
    FAMILY
    CATEGORY signaling growth factor , receptor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic,microsome
    intracellular,nucleus
    text localization in proximity with the insulin receptor at the plasma membrane and caveolae has implications for insulin signaling in adipocytes
    basic FUNCTION
  • mediating the biological response to insulin stimulation by binding and activating various enzymes or adaptor molecules
  • may mediate the control of various cellular processes by insulin
  • activating phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit
  • critical mediator of the insulin/insulin-like growth factor 1 signaling, which is a proteolytic target of the CUL7 E3 ligase
  • multisite docking protein positioned immediately downstream from the type I IGF and insulin receptors
  • with IRS2, control the migratory response of breast cancer cells to IGF1 and may, therefore, be key molecules in determining breast cancer spread
  • role for IRS1 in TGFB1-induced epithelial-mesenchymal transition in lung epithelial cells
  • regulation of IRS1 expression level is critical for determining the differentiating capacity of mesenchymal stem cells (MSCs) and OS cells, and derangement of IRS1 levels can be a critical step in osteosarcoma (OS) transformation
  • IRS1/2 promotes EMT and cell proliferation through stabilizing DVL2
  • functions as a molecular scaffold to coordinate IGF1/IGFBP2 signaling during osteoblast differentiation
  • new function of IRS1: that of maintaining cells in their normal, differentiated state
  • new role for IRS1 as an endocytic regulator of IGFIR that ensures sustained IGF bioactivity, independent of its classic role as an adaptor in IGFIR signaling
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism carbohydrate
    signaling signal transduction
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • several proteins containing SH2 domains, such as PIK3s, GRB2 and with TNF, PTEN
  • tyrosine phosphorylated in response to insulin stimulation
  • binding to ROCK1
  • is a critical mediator of the myogenic functions of raptor and RHEB
  • KHDRBS1 interacts with IRS1 in basal conditions, and insulin increases the affinity between these two partners
  • SQSTM1 participates in the insulin-signaling pathway through its interactions with IRS1
  • MEMO1 binds to IRS1, activates the downstream PI3K/AKT1 signaling pathway, leads to upregulation of SNAI1 and thereby triggers the epithelial-mesenchymal transition (EMT) program
  • CRTC2 can regulate insulin signaling at the level of insulin receptor substrate-1 (IRS1)
  • CRTC2 negatively feeds back to IRS1 via control of FBXW8 stability and localization
  • TNS2 is a novel protein tyrosine phosphatase (PTPase) of IRS1 that acts as a mediator to reduce IRS1 under a catabolic condition, resulting in muscle atrophy
  • in addition to persistent MTOR signalling, increased CRTC2 signals can promote insulin resistance due to CRTC2-mediated degradation of IRS1
  • TRIM72 is an ubiquitin E3 ligase that induces IRS1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H
  • APPL1 is a critical molecule that promotes IRS1/2-INSR interaction
  • IRS1 is recruited to interact with the INSRR-catalyzed phospho-tyrosine CAV2, which facilitates IRS1 association with and activation by INSR to initiate IRS1-mediated downstream signaling
  • PLIN2 inhibits insulin&
  • 8209;induced glucose uptake by activating NLRP3, CASP1 and IL1B, leading to a decreased IRS1 expression
  • LPIN1 enhances the tumour-promoting function of insulin receptor substrate 1 (IRS1) by controlling IRS1 stability
  • IRS1 modulates how long ligand-activated IGFIR remains at the cell surface before undergoing endocytosis in cell
  • cell & other
    REGULATION
    activated by EIF2AK2 that up-regulates the inhibitory phosphorylation of IRS1 at Ser312
    induced by PTEN (augments insulin promoted tyrosine phosphorylation of IRS1)
    repressed by TNF (impairs insulin promoted tyrosine phosphorylation of IRS1)
    ASSOCIATED DISORDERS
    corresponding disease(s) NIDDM3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral       loss of function
    enhances breast cancer metastasis and IRS1 has potentially metastasis suppressor functions for breast cancer
    constitutional     --low  
    in diabetes, IRS1 is down-regulated, and cells become resistant to insulin
    tumoral     --over  
    in breast cancer
    Susceptibility
  • to type 2 or type 1 diabetes
  • to polycystic ovary syndrome (PCOS)
  • to high body mass index
  • Variant & Polymorphism SNP , other
  • polymorphism associated to susceptibility to obesity with insulin resistance and to type 1 diabetes (variant G972R)
  • Gly972Arg polymorphism is associated with PCOS in the Japanese population
  • C allele of rs2943641 is associated
  • with increased T2D risk, fasting- and glucose-stimulated hyperinsulinemia and impaired insulin sensitivity
  • body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and increased body mass index
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    new models to develop inhibitors against IRSs for anticancer therapy
    neurologyacquired 
    IRS1 signaling is a therapeutic target for hypoxic brain injury in neonates
    ANIMAL & CELL MODELS