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

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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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References

  1. White, M. F., Maron, R. & Kahn, C. R. Nature 318, 183–186 (1985).

    Article  ADS  CAS  PubMed  Google Scholar 

  2. White, M. F. & Kahn, C. R. J. biol. Chem. 269, 1–5 (1994).

    CAS  PubMed  Google Scholar 

  3. Keller, S. R., Kitagawa, K., Aebersold, R., Lienhard, G. E. & Garner, C. W. J. biol. Chem. 266, 12817–12820 (1991).

    CAS  PubMed  Google Scholar 

  4. Sun, X. J. et al. Nature 352, 73–77 (1991).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Araki, E., Haag, B. L. & Kahn, C. R. Biochim. biophys. Acta 1221, 353–356 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Araki, E. et al. Diabetes 42, 1041–1054 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Beguinot, F., Kahn, C. R., Moses, A. C., White, M. F. & Smith, R. J. Endocrinology 125, 1599–1605 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Ruderman, N., Kapeller, R., White, M. F. & Cantley, L. C. Proc. natn. Acad. Sci. U.S.A. 87, 1411–1415 (1990).

    Article  ADS  CAS  Google Scholar 

  9. Sun, X. J. et al. J. biol. Chem. 267, 22662–22672 (1992).

    CAS  PubMed  Google Scholar 

  10. Giorgetti, S., Ballotti, R., Kowalski-Chauvel, A., Tartare, S. & Van Obberghen, E. J. biol. Chem. 268, 7358–7364 (1993).

    CAS  PubMed  Google Scholar 

  11. Folli, F., Saad, M. J. A., Backer, J. M. & Kahn, C. R. J. biol. Chem. 267, 22171–22177 (1992).

    CAS  PubMed  Google Scholar 

  12. Skolnik, E. Y. et al. Science 260, 1953–1955 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Chuang, L. M. et al. Molec. cell. Biol. 13, 6653–6660 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kuhne, M. R., Pawson, T., Lienhard, G. E. & Feng, G.-S. J. biol. Chem. 268, 11479–11481 (1993).

    CAS  PubMed  Google Scholar 

  15. Saad, M. J. A. et al. J. clin. Invest. 90, 1839–1849 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sung, C. K., Sanchez-Margalet, V. & Goldfine, I. D. J. biol. Chem. 269, 12503–12507 (1994).

    CAS  PubMed  Google Scholar 

  17. Kovacina, K. S. & Roth, R. A. Biochem. biophys. Res. Commun. 192, 1303–1311 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Van Horn, D. J., Myers, M. G. Jr & Backer, J. M. J. Biochem. 269, 29–32 (1994).

    CAS  Google Scholar 

  19. Waters, S. B., Yamauchi, K. & Pessin, J. E. J. biol. Chem. 268, 22231–22234 (1993).

    CAS  PubMed  Google Scholar 

  20. Myers, M. G. Jr. et al. Endocrinology 132, 1421–1430 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. White, M. F. et al. Cell 54, 641–649 (1988).

    Article  CAS  PubMed  Google Scholar 

  22. Rose, D. W., Saltiel, A. R., Majumdar, M., Decker, S. J. & Olefsky, J. M. Proc. natn. Acad. Sci. U.S.A. 91, 797–801 (1994).

    Article  ADS  CAS  Google Scholar 

  23. Tamemoto, H. et al. Nature 372, 182–186 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Liu, J. P., Baker, J., Perkins, J. A., Robertson, E. J. & Efstratiadis, A. Cell 75, 59–72 (1993).

    CAS  PubMed  Google Scholar 

  25. Miralpeix, M. et al. Biochemistry 31, 9031–9039 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Wang, L.-M. et al. Proc. natn. Acad. Sci. U.S.A. 90, 4032–4036 (1993).

    Article  ADS  CAS  Google Scholar 

  27. Keegan, A. D. et al. Cell 76, 811–820 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Wang, L. M. et al. Science 261, 1591–1594 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Papaioannou, V. & Johnson, R. in Gene Targeting: A Practical Approach (ed. Joyner, A.) Oxford University Press. Oxford, 1993).

    Google Scholar 

  30. Lipes, M. A. et al. Science 259, 1165–1169 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  31. Shepherd, P. R. et al. J. biol. Chem. 269, 22232–22248 (1993).

    Google Scholar 

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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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  2. Myra A. Lipes
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  6. Randall S. Johnson
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  7. C. Ronald Kahn
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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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  • DOI: https://doi.org/10.1038/372186a0

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