INHIBITION OF GLYCOGEN-SYNTHASE KINASE-3 BY INSULIN-MEDIATED BY PROTEIN-KINASE-B

GLYCOGEN synthase kinase-3 (GSK3)(1) is implicated in the regulation o f several physiological processes, including the control of glycogen(2 ) and protein(3) synthesis by insulin, modulation of the transcription factors AP-1 and CREB(4-6), the specification of cell fate in Drosoph ila(7) and dorsoventral patterning in Xenopus embryos(8). GSK3 is inhi bited by serine phosphorylation in response to insulin or growth facto rs and in vitro by either MAP kinase-activated protein (MAPKAP) kinase -1 (also known as p90(rsk)) or p70 ribosomal S6 kinase (p70(S6k))(12,1 3). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70(S6k) by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated pr otein kinase inactivates GSK3 under these conditions, and Ne demonstra te 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), th e activation of PKB is prevented by inhibitors of phosphatidylinositol (PT) 3-kinase.