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Insulin Induces Specific Interaction between Insulin Receptor and Protein Kinase C in Primary Cultured Skeletal Muscle

Faculty of Life Sciences (L.B., A.A., A.B., T.T., S.R.S.) Gonda-Goldschmied Center Bar-Ilan University Ramat-Gan 52900, Israel
Institute of Molecular Oncology (T.K.) and Department of Microbiology (M.O.) Showa University Tokyo 142-8555, Japan

Certain protein kinase C (PKC) isoforms, in particular PKCs ßII, , and , are activated by insulin stimulation. In primary cultures of skeletal muscle, PKCs ßII and , but not PKC, are activated via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. The purpose of this study was to investigate the possibility that PKC may be activated upstream of PI3K by direct interaction with insulin receptor (IR). Experiments were done on primary cultures of newborn rat skeletal muscle, age 5–6 days in vitro. The time course of insulin-induced activation of PKC closely paralleled that of IR. Insulin stimulation caused a selective coprecipitation of PKC with IR, and these IR immunoprecipitates from insulin-stimulated cells displayed a striking induction of PKC activity due specifically to PKC. To examine the involvement of PKC in the IR signaling cascade, we used recombinant adenovirus constructs of wild-type (W.T.) or dominant negative (D.N.) PKC. Overexpression of W.T.PKC induced PKC activity and coassociation of PKC and IR without addition of insulin. Overexpression of D.N.PKC abrogated insulin- induced coassociation of PKC and IR. Insulin-induced tyrosine phosphorylation of IR was greatly attenuated in cells overexpressing W.T.PKC, whereas in myotubes overexpressing D.N.PKC, tyrosine phosphorylation occurred without addition of insulin and was sustained longer than that in control myotubes. In control myotubes IR displayed a low level of serine phosphorylation, which was increased by insulin stimulation. In cells overexpressing W.T.PKC, serine phosphorylation was strikingly high under basal conditions and did not increase after insulin stimulation. In contrast, in cells overexpressing D.N.PKC, the level of serine phosphorylation was lower than that in nonoverexpressing cells and did not change notably after addition of insulin. Overexpression of W.T.PKC caused IR to localize mainly in the internal membrane fractions, and blockade of PKC abrogated insulin-induced IR internalization. We conclude that PKC is involved in regulation of IR activity and routing, and this regulation may be important in subsequent steps in the IR signaling cascade.

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