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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
204,58 € per year
only 4,01 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Embi, N., Rylatt, D. B. & Cohen P. Eur. J. Biochem. 107, 519–527 (1980).
Parker, P. J. J., Caudwell, F. B. & Cohen, P. Eur. J. Biochem. 130, 227–234 (1983).
Welsh, G. I. & Proud, C. G. Biochem. J. 294, 625–629 (1993).
Nikolakaki, E., Coffer, P., Hemelsoet, R., Woodgett, J. & Defize, L. Oncogene 8, 833–840 (1993).
de Groot, R., Auwerx, J., Bourouis, M. & Sassone-Corsi, P. Oncogene 8, 841–847 (1993).
Fiol, C. et al. J. biol. Chem. 269, 32187–32193 (1994).
Siegfried, E., Chou, T.-B. & Perrimon, N. Cell 71, 1167–1179 (1992).
He, X., Saint-Jeannet, J.-P., Woodgett, J. R., Varmus, H. E. & Dawid, I. B. Nature 374, 617–622 (1995).
Hughes, K., Ramakrishna, S., Benjamin, W. B. & Woodgett, J. R. Biochem. J. 288, 309–314 (1992).
Cross, D. A. E. et al. Biochem. J. 303, 21–26 (1994).
Saito, Y., Vandenheede, J. R. & Cohen, P. Biochem. J. 303, 27–31 (1994).
Sutherland, C., Leighton, I. A. & Cohen, P. Biochem. J. 296, 15–19 (1993).
Sutherland, C. & Cohen, P. FEBS Lett. 338, 37–12 (1994).
Welsh, G. I., Foulstone, E. J., Young, S. W., Tavare, J. M. & Proud. C. G. Biochem. J. 303, 15–20 (1994).
Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. & Saltiel, A. L. J. biol. Chem. 270, 27489–27494 (1995).
Kuo, C. J. et al. Nature 358, 70–73 (1992).
Stambolic, V. & Woodgett, J. R. Biochem. J. 303, 701–704 (1994).
Eldar-Finkelman, H., Seger, R., Vandenheede, J. R. & Krebs, E. G. J. biol. Chem. 270, 987–990 (1995).
Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. J. biol. Chem. 269, 5241–5248 (1994).
Coffer, P. J. & Woodgett, J. R. Eur. J. Biochem. 201, 475–481 (1991).
Jones, P. F., Jakubowicz, T., Pitossi, F. J., Maurer, F. & Hemmings, B. A. Proc. natn. Acad. Sci. U.S.A. 88, 4171–4175 (1991).
Ahmed, N. N. et al. Molec. cell. Biol. 15, 2304–2310 (1995).
Cheng, J. Q. et al. Proc. natn. Acad. Sci. U.S.A. 89, 9267–9271 (1992).
Franke, T. F. et al. Cell 81, 727–736 (1995).
Burgering, B. M. Th. & Coffer, P. J. Nature 376, 599–602 (1995).
Palmer, R. H. et al. J. biol. Chem. 270, 22412–22416 (1995).
Goode, N., Hughes, K., Woodgett, J. R. & Parker, P. J. J. J. biol. Chem. 267, 16878–16882 (1992).
Dent, P. et al. Nature 348, 302–308 (1990).
Lazar, D. F. et al. J. biol. Chem. 270, 20801–20807 (1995).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/378785a0
