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J. Biol. Chem., Vol. 283, Issue 17, 11226-11233, April 25, 2008

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Phosphorylation of Ser³⁵⁷ of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C- on Insulin Action in Skeletal Muscle Cells^*

Rizwana Sanaullah Waraich, Cora Weigert¹, Hubert Kalbacher^¶, Anita M. Hennige^||, Stefan Z. Lutz^||, Hans-Ulrich Häring^||, Erwin D. Schleicher, Wolfgang Voelter, and Rainer Lehmann

From the Division of Clinical Chemistry and Pathobiochemistry, the Interfacultary Institute of Biochemistry, the ^¶Medical and Natural Sciences Research Centre, and the ^||Department of Internal Medicine 4, University of Tuebingen, 72076 Tuebingen, Germany

The activation of the protein kinase C (PKC) family of serine/threonine kinases contributes to the modulation of insulin signaling, and the PKC-dependent phosphorylation of insulin receptor substrate (IRS)-1 has been implicated in the development of insulin resistance. Here we demonstrate Ser³⁵⁷ of rat IRS-1 as a novel PKC--dependent phosphorylation site in skeletal muscle cells upon stimulation with insulin and phorbol ester using Ser(P)³⁵⁷ antibodies and active and kinase dead mutants of PKC-. Phosphorylation of this site was simulated using IRS-1 Glu³⁵⁷ and shown to reduce insulin-induced tyrosine phosphorylation of IRS-1, to decrease activation of Akt, and to subsequently diminish phosphorylation of glycogen synthase kinase-3. When the phosphorylation was prevented by mutation of Ser³⁵⁷ to alanine, these effects of insulin were enhanced. When the adjacent Ser³⁵⁸, present in mouse and rat IRS-1, was mutated to alanine, which is homologous to the human sequence, the insulin-induced phosphorylation of glycogen synthase kinase-3 or tyrosine phosphorylation of IRS-1 was not increased. Moreover, both active PKC- and phosphorylation of Ser³⁵⁷ were shown to be necessary for the attenuation of insulin-stimulated Akt phosphorylation. The phosphorylation of Ser³⁵⁷ could lead to increased association of PKC- to IRS-1 upon insulin stimulation, which was demonstrated with IRS-1 Glu³⁵⁷. Together, these data suggest that phosphorylation of Ser³⁵⁷ mediates at least in part the adverse effects of PKC- activation on insulin action.

Received for publication, October 16, 2007 , and in revised form, February 13, 2008.

^* This work was supported by grants from the Higher Education Commission of Pakistan and German Academic Exchange Service (to R. S. W.), from the Deutsche Forschungsgemeinschaft International Graduate School (to E. D. S.), and the Deutsche Diabetes Gesellschaft (to R. L.) and by Grant P-LS-Prot/29 from Landesstiftung Baden-Wuerttemberg (to R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, Division of Clinical Chemistry and Pathobiochemistry, University of Tuebingen, Otfried-Mueller-Strasse 10, 72076 Tuebingen, Germany. Tel.: 49-7071-29-85670; Fax: 49-7071-29-5348; E-mail: Cora.Weigert{at}med.uni-tuebingen.de.

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