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

Nature. 1994 Nov 10;372(6502):186-90. doi: 10.1038/372186a0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Blood Glucose
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Phosphotyrosine
  • Tyrosine
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)