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

Nature volume 372, pages 186–190 (1994)Cite this article

An Erratum to this article was published on 15 December 1994

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-l/pplSS)1–7. After tyrosine phosphorylation at several sites, IRS-1 binds to and activates phosphatidylinositol-3′-OH kinase (PI(3)K)8–11 and several other proteins containing SH2 (Src-homology 2) domains12–14. 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-indepen-dent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.

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Author notes

  1. Eiichi Araki

    Present address: Department of Metabolic Medicine, Kumamoto University Medical School, 860, Kumamoto, Japan

  2. C. Ronald Kahn: To whom correspondence should be addressed.

Authors and Affiliations

  1. Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02215, USA

    Eiichi Araki, Myra A. Lipes, Mary-Elizabeth Patti, Jens Claus Brüning, Burritt Haag III, Randall S. Johnson & C. Ronald Kahn

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  1. Eiichi Araki
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Araki, E., Lipes, M., Patti, ME. et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190 (1994). https://doi.org/10.1038/372186a0

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