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Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene.

The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). After tyrosine phosphorylation at several sites, IRS-1 binds to and activates phosphatidylinositol-3'-OH kinase (PI(3)K) and several other proteins containing SH2 (Src-homology 2) domains. To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. These mice had no IRS-1 and showed no evidence of IRS-1 phosphorylation or IRS-1-associated PI(3)K activity. They also had a 50 per cent reduction in intrauterine growth, impaired glucose tolerance, and a decrease in insulin/IGF-1-stimulated glucose uptake in vivo and in vitro. The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.

Pubmed ID: 7526222


  • Araki E
  • Lipes MA
  • Patti ME
  • BrĂ¼ning JC
  • Haag B
  • Johnson RS
  • Kahn CR



Publication Data

November 10, 1994

Associated Grants


Mesh Terms

  • Animals
  • Blood Glucose
  • Female
  • Growth
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance
  • Insulin-Like Growth Factor I
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases
  • Phosphoproteins
  • Phosphotransferases (Alcohol Group Acceptor)
  • Phosphotyrosine
  • Signal Transduction
  • Tyrosine