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Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein


SINCE the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the α subunit of the insulin receptor which activates the tyrosine kinase in the β subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown1,2. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates3. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues4–10; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling6,11. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite Mocking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains12–14. Thus IRS–1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.

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  1. Kahn, C. R. & White, M. F. J. clin. Invest. 82, 1151–1156 (1988).

    Article  CAS  Google Scholar 

  2. Rosen, O. M. Science 237, 1452–1458 (1987).

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Gibbs, E. M., Allard, W. J. & Leinhard, G. E. J. biol. Chem. 261, 16597–16603 (1986).

    CAS  Google Scholar 

  5. Maegawa, H. et al. J. biol. Chem. 263, 12629–12637 (1988).

    CAS  PubMed  Google Scholar 

  6. White, M. F., Stegmann, E. W., Dull, Y. J., Ullrich, A. & Kahn, C. R. J. biol. Chem. 262, 9769–9777 (1987).

    CAS  PubMed  Google Scholar 

  7. Kadowaki, T. et al. J. biol. Chem. 262, 7342–7350 (1987).

    CAS  PubMed  Google Scholar 

  8. Shemer, J. et al. J. biol. Chem. 262, 15476–15482 (1987).

    CAS  PubMed  Google Scholar 

  9. Momomura, K., Tobe, K., Seyama, Y., Takaku, F. & Kasuga, M. Biochem. biophys. Res. Commun. 155, 1181–1186 (1988).

    Article  CAS  Google Scholar 

  10. Tobe, K. et al. Diabetes 39, 528–533 (1990).

    Article  CAS  Google Scholar 

  11. Wilden, P. A. et al. Proc. natn. Acad. Sci. U.S.A. 87, 3358–3362 (1990).

    Article  ADS  CAS  Google Scholar 

  12. Cantley, L. C. et al. Cell 64, 281–302 (1991).

    Article  CAS  Google Scholar 

  13. Escobedo, J. A. et al. Cell 65, (1991).

  14. Anderson, D. et al. Nature 250, 979–982 (1990).

    CAS  Google Scholar 

  15. Rothenberg, P. L. et al. J. biol. Chem. 266, 8302–8311 (1991).

    CAS  PubMed  Google Scholar 

  16. Lathe, R. J. molec. Biol. 83, 1 (1985).

    Article  Google Scholar 

  17. Hanks, S. K., Quinn, A. M. & Hunter, T. Science 241, 42–52 (1990).

    Article  ADS  Google Scholar 

  18. Pines, J. & Hunter, T. The New Biologist 2, 389–401 (1990).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Backer, J. M. et al. Biochemistry (in the press).

  21. Escobedo, J. A., Kaplan, D. R., Kavanaugh, W. M., Turck, C. W. & Williams, L. T. Molec. cell. Biol. 11, 1125–1132 (1991).

    Article  CAS  Google Scholar 

  22. 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 

  23. Endemann, G., Yonezawa, K. & Roth, R. A. J. biol. Chem. 265, 396–400 (1990).

    CAS  PubMed  Google Scholar 

  24. Hjollund, E., Richelsen, B. & Pedersen, O. Acta endrocrinol. (Copenh.) 118, 59–67 (1988).

    CAS  Google Scholar 

  25. Morgan, S. J., Smith, A. D. & Parker, P. J. Eur. J. Biochem. 191, 761–767 (1990).

    Article  CAS  Google Scholar 

  26. Carpenter, C. L. et al. J. biol. Chem. 265, 19704–19711 (1990).

    CAS  PubMed  Google Scholar 

  27. Kaplan, D. R. et al. Cell 50, 1021–1029 (1987).

    Article  CAS  Google Scholar 

  28. Hartman, S. C. & Mulligan, R. C. Proc. natn. Acad. Sci. U.S.A. 85, 8047–8051 (1988).

    Article  ADS  CAS  Google Scholar 

  29. Haring, H.-U., Kasuga, M., White, M. F., Crettaz, M. & Kahn, C. R. Biochemistry 23, 3298–3306 (1984).

    Article  CAS  Google Scholar 

  30. Perlman, R., Bottaro, D., White, M. F. & Kahn, C. R. J. biol. Chem. 264, 8946–8950 (1989).

    CAS  PubMed  Google Scholar 

  31. Brindle, N. P. J., Tavare, J. M., Dickens, M., Whittaker, J. & Siddle, K. Biochem. J. 268, 615–620 (1990).

    Article  CAS  Google Scholar 

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Sun, X., Rothenberg, P., Kahn, C. et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73–77 (1991).

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