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Dependence of Insulin-Stimulated Glucose Transporter 4 Translocation on 3-Phosphoinositide-Dependent Protein Kinase-1 and Its Target Threonine-410 in the Activation Loop of Protein Kinase C-

J.A. Haley Veterans’ Hospital Research Service and Department of Internal Medicine (G.B., M.L.S., M.P.S., R.V.F.) University of South Florida College of Medicine Tampa, Florida 33612
Department of Radiation Oncology (L.M.K.) Mayo Foundation Rochester, Minnesota 55905
Hypertension-Endocrine Branch (L.C., M.J.Q.) National Heart, Lung and Blood Institute National Institutes of Health Bethesda, Maryland, 20892

Previous studies have suggested that 1) atypical protein kinase C (PKC) isoforms are required for insulin stimulation of glucose transport, and 2) 3-phosphoinositide-dependent protein kinase-1 (PDK-1) is required for activation of atypical PKCs. Presently, we evaluated the role of PDK-1, both in the activation of PKC-, and the translocation of epitope-tagged glucose transporter 4 (GLUT4) to the plasma membrane, during insulin action in transiently transfected rat adipocytes. Overexpression of wild-type PDK-1 provoked increases in the activity of cotransfected hemagglutinin (HA)-tagged PKC- and concomitantly enhanced HA-tagged GLUT4 translocation. Expression of both kinase-inactive PDK-1 and an activation-resistant form of PKC- that is mutated at Thr-410, the immediate target of PDK-1 in the activation loop of PKC-, inhibited insulin-induced increases in both HA-PKC- activity and HA-GLUT4 translocation to the same extent as kinase-inactive PKC-. Moreover, the inhibitory effects of kinase-inactive PDK-1 were fully reversed by cotransfection of wild-type PDK-1 and partly reversed by wild-type PKC-, but not by wild-type PKB. In contrast to the T410A PKC- mutant, an analogous double mutant of PKB (T308A/S473A) that is resistant to PDK-1 activation had only a small effect on insulin-stimulated HA-GLUT4 translocation and did not inhibit HA-GLUT4 translocation induced by overexpression of wild-type PDK-1. Our findings suggest that both PDK-1 and its downstream target, Thr-410 in the activation loop of PKC-, are required for insulin-stimulated glucose transport.

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