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FLASH GENE
Symbol IRS2 contributors: mct/npt/pgu - updated : 12-06-2015
HGNC name insulin receptor substrate 2
HGNC id 6126
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • pleckstrin-homology (PH) domain
  • phosphotyrosine-binding (PTB) domain
  • many potential tyrosine and serine/threonine phosphorylation sites
  • a kinase regulatory-loop binding (KRLB) region
    • mono polymer complex
    HOMOLOGY
    interspecies homolog to rattus Irs2 (87.4 pc)
    homolog to murine Irs2 (87.1 pc)
    intraspecies homolog to IRS1
    Homologene
    FAMILY
  • IRS family
    • CATEGORY protooncogene , signaling hormone growth factor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic,microsome
    basic FUNCTION
  • pleiotropic mediator of insulin coordinating Igf-1 receptor-mediated beta cell development
  • playing a role in insulin and cytokine signaling
  • mediating the control of various cellular processes by insulin
  • multisite docking protein positioned immediately downstream from the type I IGF and insulin receptors
  • involved in the migratory response of breast cancer cells to IGFs
  • with IRS1, control the migratory response of breast cancer cells to IGF1 and may, therefore, be key molecules in determining breast cancer spread
  • acts as a negative regulator on memory formation by restricting dendritic spine generation
  • novel roles for IRS2 and FOXO3 in the regulation of kidney epithelial cells by CDH1
  • IRS2 signaling can modulate Huntington disease progression
  • is essential for hearing
  • IRS2 signalling is required for the proper development of spinal sensory neurons involved in the perception of pain
  • expressed in the kidney epithelium and may play a role in the downstream protective events triggered by BMP7 in the kidney
  • plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development
  • IRS1/2 promotes EMT and cell proliferation through stabilizing DVL2
  • IRS2 phosphorylation is cell cycle-regulated and PLK1 phosphorylation of IRS2 prevents premature mitotic exit via AKT1 inactivation
    • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS development
    text
  • positive control of cell proliferation
  • brain development
    • PATHWAY
    metabolism carbohydrate
    signaling signal transduction
  • glucose metabolism/IGF1 signaling cascade
    • a component
  • forming a complex with 14-3-3 protein (YWHA) in a baculovirus system
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • insulin receptor
  • PTPRN2 is involved in beta-cell growth via regulating stability of IRS2 protein by the molecular interaction with insulin receptor
  • interacting with FOXO1 (reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling)
  • alternative binding of ZNF1489 or SP1 to the described region in the IRS2 promoter regulates neuronal IRS2 expression in a PI3K-dependent manner
  • EIF2AK2 regulates IRS2, in the liver, at the transcriptional rather than the posttranslational level, and this effect is mediated by the transcription factor, FOXO1
  • TGFB1 signals via IRS2 in kidney epithelial cells
  • MAPK10 protects beta-cells from apoptosis and dysfunction mainly through maintenance of a normal IRS2 to AKT2 signaling pathway
  • CAMK4 regulates beta-cell proliferation and apoptosis in a CREB1-dependent manner and CAMK4-induced IRS2 expression is important in these processes
  • IRS2 signalling is important for maintaining the activity of liver GCK
  • APPL1 is a critical molecule that promotes IRS1/2-INSR interaction
  • PLK1 is the responsible kinase for phosphorylation of IRS2 on two serine residues
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) NIDDM3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in macrophages enhanced their accumulation in the vascular wall accompanied by increased expression of proinflammatory mediators in macrophages
    constitutional     --over  
    in the kidney tubules of diabetic nephropathy
    constitutional     --low  
    in Type 2 diabetics as well as in Alzheimer patients (
    Susceptibility
  • polycystic ovary syndrome in non diabetic African-American women with th G/G genotype (G1057D) polymorphism
  • morbid obesity with glucose intolerance
    • Variant & Polymorphism
    Candidate gene
    Marker
  • marker and/or mediator of diabetic nephropathy progression
    • Therapy target
    SystemTypeDisorderPubmed
    cancer  
    new models to develop inhibitors against IRSs for anticancer therapy
    neurologyneurodegenerativehuntington chorea
    decreasing IRS2 signaling could be part of a therapeutic approach to slow the progression of HD
    diabetemetabolic syndrom 
    reduced IRS2-mediated insulin signal in macrophages is a potentially important therapeutic target to prevent the progression of atherosclerosis in patients with type 2 diabetes
    ANIMAL & CELL MODELS
  • irs2-/- mice
  • chico-/-drosophila
  • chronic hyperinsulinemia downregulates the mRNA for IRS2 in ob/ob mice
  • female infertility caused by deletion of IRS2
  • less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice
  • Irs2-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function
  • liver content of GCK was reduced in Irs2(-/-) mice as compared with controls, although GCKR levels were similar
  • Irs2 (-/-) mice also exhibited reduced testicular size, suggesting that impairments in this model occur during development
  • complete disruption of Irs2 in mice impairs long-term potentiation (LTP) of synaptic transmission in the hippocampus