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Knockout of PKC Enhances Insulin Signaling Through PI3K

Max-Planck Institute for Experimental Endocrinology (M.L.), 30625 Hannover, Germany; Institute for Biochemistry II (M.P.), Medical Faculty, University of Cologne, D-50931 Cologne, Germany; and James A. Haley Hospital (M.L.S., G.B., M.P.S., Y.K., R.V.F.), University of South Florida College of Medicine, Tampa, Florida 33612

Address all correspondence and requests for reprints to: Dr. Robert Farese, J. A. Haley Veterans Hospital, University of South Florida College of Medicine, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: rfarese{at}com1 med.usf.edu.

Insulin stimulates glucose transport and certain other metabolic processes by activating atypical PKC isoforms (, , ) and protein kinase B (PKB) through increases in D3-polyphosphoinositides derived from the action of PI3K. The role of diacylglycerol-sensitive PKC isoforms is less clear as they have been suggested to be both activated by insulin and yet inhibit insulin signaling to PI3K. Presently, we found that insulin signaling to insulin receptor substrate 1-dependent PI3K, PKB, and PKC, and downstream processes, glucose transport and activation of ERK, were enhanced in skeletal muscles and adipocytes of mice in which the ubiquitous conventional diacylglycerol-sensitive PKC isoform, PKC, was knocked out by homologous recombination. On the other hand, insulin provoked wortmannin-insensitive increases in immunoprecipitable PKC activity in adipocytes and skeletal muscles of wild-type mice and rats. We conclude that 1) PKC is not required for insulin-stimulated glucose transport, and 2) PKC is activated by insulin at least partly independently of PI3K, and largely serves as a physiological feedback inhibitor of insulin signaling to the insulin receptor substrate 1/PI3K/PKB/PKC// complex and dependent metabolic processes.

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