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| - Insulin Stimulates Increased Catalytic Activity of Phosphoinositide-DependentKinase-1 by a Phosphorylation-Dependent Mechanism
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| - Phosphoinositide-dependent kinase-1 (PDK-1) is a serine−threonine kinase downstream fromPI 3-kinase that phosphorylates and activates other important kinases such as Akt that are essential forcell survival and metabolism. Previous reports have suggested that PDK-1 has constitutive catalytic activitythat is not regulated by stimulation of cells with growth factors. We now show that insulin stimulation ofNIH-3T3IR cells or rat adipose cells may significantly increase the intrinsic catalytic activity of PDK-1.Insulin treatment of NIH-3T3IR fibroblasts overexpressing PDK-1 increased both phosphorylation ofrecombinant PDK-1 in intact cells and PDK-1 kinase activity in an immune-complex kinase assay. Insulinstimulation of rat adipose cells also increased catalytic activity of endogenous PDK-1 immunoprecipitatedfrom the cells. Both insulin-stimulated phosphorylation and activity of PDK-1 were inhibited by wortmanninand reversed by treatment with the phosphatase PP-2A. A mutant PDK-1 with a disrupted PH domain(W538L) did not undergo phosphorylation or demonstrate increased kinase activity in response to insulinstimulation. Similarly, a PDK-1 phosphorylation site point mutant (S244A) had no increase in kinaseactivity in response to insulin stimulation. Thus, the insulin-stimulated increase in PDK-1 catalytic activitymay involve PI 3-kinase- and phosphorylation-dependent mechanisms. We conclude that the basalconstitutive catalytic activity of PDK-1 in NIH-3T3IR cells and rat adipose cells can be significantlyincreased upon insulin stimulation.
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