THE 10TH DATTA-LECTURE - PDK1, ONE OF THE MISSING LINKS IN INSULIN SIGNAL-TRANSDUCTION

The initial steps in insulin signal transduction occur at the plasma m embrane and lead to the activation of phosphatidylinositide (PtdIns) 3 -kinase and the formation of PtdIns(3,4,5,)P-3 in the inner leaflet of the plasma membrane which is then converted to PtdIns(3,4)P-2 by a sp ecific phosphatase, Inhibitors of PtdIns 3-kinase suppress nearly all the metabolic actions of insulin indicating that PtdIns(3,4,5)P-3 and/ or PtdIns(3,4)P-2 are key 'second messengers' for this hormone, A majo r effect of insulin is its ability to stimulate the synthesis of glyco gen in skeletal muscle, By 'working backwards' from glycogen synthesis , we have dissected an insulin-stimulated protein kinase cascade which is triggered by the activation of PtdIns 3-kinase. The first enzyme i n this cascade is termed 3-phosphoinositide-dependent protein kinase ( PDK1), because it is only active in the presence of PtdIns(3,4,5)P-3 o r PtdIns(3,4)P-2. PDK1 then activates protein kinase B (PKB) which, in turn, inactivates glycogen synthase kinase-3 (GSK3), leading to the d ephosphorylation and activation of glycogen synthase and hence to an a cceleration of glycogen synthesis. We review the evidence which indica tes that the phosphorylation of other proteins by PKB and GSK3 is like ly to mediate many of the intracellular actions of insulin. (C) 1997 F ederation of European Biochemical Societies.