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Symbol IRS2 contributors: mct/npt/pgu - updated : 12-06-2015
HGNC name insulin receptor substrate 2
HGNC id 6126
Corresponding disease
NIDDM3 diabetes mellitus, non insulin-dependent, 3
Location 13q34      Physical location : 110.406.185 - 110.438.914
Synonym symbol(s) EVI86, IRS-2
TYPE functioning gene
STRUCTURE 32.73 kb     2 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
2 - 7014 - 1338 - -
Type widely
   expressed in (based on citations)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveliver   highly Homo sapiens
Endocrineadrenal gland   moderately
 neuroendocrinepituitary  highly
 pancreas   highly Homo sapiens
Nervousnervecranial nerve  highly
Reproductivefemale systemovary  highly
Urinarykidney   predominantly Homo sapiensAdult
 kidney   predominantly Homo sapiensFetal
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Connectiveadipose    Homo sapiens
Muscularstriatumskeletal   Homo sapiensAdult
SystemCellPubmedSpeciesStageRna symbol
Lymphoid/Immunelymphocyte Homo sapiensAdult
Lymphoid/Immunemacrophage Homo sapiensAdult
Urinaryepithelial cell Homo sapiensAdult
Urinaryepithelial cell Homo sapiensFetal
cell lineage
cell lines
  • 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
    interspecies homolog to rattus Irs2 (87.4 pc)
    homolog to murine Irs2 (87.1 pc)
    intraspecies homolog to IRS1
  • IRS family
  • CATEGORY protooncogene , signaling hormone growth factor
    SUBCELLULAR LOCALIZATION     plasma membrane
    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
  • positive control of cell proliferation
  • brain development
    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
    small molecule
  • 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
    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 (
  • 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 and/or mediator of diabetic nephropathy progression
  • Therapy target
    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
  • 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