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Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B

Abstract

GLYCOGEN synthase kinase-3 (GSK3)1 is implicated in the regulation of several physiological processes, including the control of glycogen2 and protein3 synthesis by insulin, modulation of the transcription factors AP-1 and CREB4–6, the specification of cell fate in Drosophila7 and dorsoventral patterning in Xenopus embryos8. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors3,9–11 and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k)12,13. Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.

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References

  1. Embi, N., Rylatt, D. B. & Cohen P. Eur. J. Biochem. 107, 519–527 (1980).

    CAS  Article  PubMed  Google Scholar 

  2. Parker, P. J. J., Caudwell, F. B. & Cohen, P. Eur. J. Biochem. 130, 227–234 (1983).

    CAS  Article  PubMed  Google Scholar 

  3. Welsh, G. I. & Proud, C. G. Biochem. J. 294, 625–629 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Nikolakaki, E., Coffer, P., Hemelsoet, R., Woodgett, J. & Defize, L. Oncogene 8, 833–840 (1993).

    CAS  PubMed  Google Scholar 

  5. de Groot, R., Auwerx, J., Bourouis, M. & Sassone-Corsi, P. Oncogene 8, 841–847 (1993).

    CAS  PubMed  Google Scholar 

  6. Fiol, C. et al. J. biol. Chem. 269, 32187–32193 (1994).

    CAS  PubMed  Google Scholar 

  7. Siegfried, E., Chou, T.-B. & Perrimon, N. Cell 71, 1167–1179 (1992).

    CAS  Article  PubMed  Google Scholar 

  8. He, X., Saint-Jeannet, J.-P., Woodgett, J. R., Varmus, H. E. & Dawid, I. B. Nature 374, 617–622 (1995).

    ADS  CAS  Article  PubMed  Google Scholar 

  9. Hughes, K., Ramakrishna, S., Benjamin, W. B. & Woodgett, J. R. Biochem. J. 288, 309–314 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Cross, D. A. E. et al. Biochem. J. 303, 21–26 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Saito, Y., Vandenheede, J. R. & Cohen, P. Biochem. J. 303, 27–31 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Sutherland, C., Leighton, I. A. & Cohen, P. Biochem. J. 296, 15–19 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Sutherland, C. & Cohen, P. FEBS Lett. 338, 37–12 (1994).

    CAS  Article  PubMed  Google Scholar 

  14. Welsh, G. I., Foulstone, E. J., Young, S. W., Tavare, J. M. & Proud. C. G. Biochem. J. 303, 15–20 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. & Saltiel, A. L. J. biol. Chem. 270, 27489–27494 (1995).

    CAS  Article  PubMed  Google Scholar 

  16. Kuo, C. J. et al. Nature 358, 70–73 (1992).

    ADS  CAS  Article  PubMed  Google Scholar 

  17. Stambolic, V. & Woodgett, J. R. Biochem. J. 303, 701–704 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Eldar-Finkelman, H., Seger, R., Vandenheede, J. R. & Krebs, E. G. J. biol. Chem. 270, 987–990 (1995).

    CAS  Article  PubMed  Google Scholar 

  19. Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. J. biol. Chem. 269, 5241–5248 (1994).

    CAS  PubMed  Google Scholar 

  20. Coffer, P. J. & Woodgett, J. R. Eur. J. Biochem. 201, 475–481 (1991).

    CAS  Article  PubMed  Google Scholar 

  21. Jones, P. F., Jakubowicz, T., Pitossi, F. J., Maurer, F. & Hemmings, B. A. Proc. natn. Acad. Sci. U.S.A. 88, 4171–4175 (1991).

    ADS  CAS  Article  Google Scholar 

  22. Ahmed, N. N. et al. Molec. cell. Biol. 15, 2304–2310 (1995).

    Article  Google Scholar 

  23. Cheng, J. Q. et al. Proc. natn. Acad. Sci. U.S.A. 89, 9267–9271 (1992).

    ADS  CAS  Article  Google Scholar 

  24. Franke, T. F. et al. Cell 81, 727–736 (1995).

    CAS  Article  PubMed  Google Scholar 

  25. Burgering, B. M. Th. & Coffer, P. J. Nature 376, 599–602 (1995).

    ADS  CAS  Article  PubMed  Google Scholar 

  26. Palmer, R. H. et al. J. biol. Chem. 270, 22412–22416 (1995).

    CAS  Article  PubMed  Google Scholar 

  27. Goode, N., Hughes, K., Woodgett, J. R. & Parker, P. J. J. J. biol. Chem. 267, 16878–16882 (1992).

    CAS  PubMed  Google Scholar 

  28. Dent, P. et al. Nature 348, 302–308 (1990).

    ADS  CAS  Article  PubMed  Google Scholar 

  29. Lazar, D. F. et al. J. biol. Chem. 270, 20801–20807 (1995).

    CAS  Article  PubMed  Google Scholar 

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Cross, D., Alessi, D., Cohen, P. et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995). https://doi.org/10.1038/378785a0

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