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J. Biol. Chem., Vol. 280, Issue 38, 32693-32699, September 23, 2005

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Shp2 Is Required for Protein Kinase C-dependent Phosphorylation of Serine 307 in Insulin Receptor Substrate-1^*

From the Division of Endocrinology, Metabolism, and Pathobiochemistry, Department of Internal Medicine, University Hospital of Tübingen, Tübingen 72076, Germany

The function of insulin receptor substrate-1 (IRS-1), a key molecule of insulin signaling, is modulated by phosphorylation at multiple serine/threonine residues. Phorbolester stimulation of cells induces phosphorylation of two inhibitory serine residues in IRS-1, i.e. Ser-307 and Ser-318, suggesting that both sites may be targets of protein kinase C (PKC) isoforms. However, in an in vitro system using a broad spectrum of PKC isoforms (, 1, 2, , , , µ), we detected only Ser-318, but not Ser-307 phosphorylation, suggesting that phorbol ester-induced phosphorylation of this site in intact cells requires additional signaling elements and serine kinases that link PKC activation to Ser-307 phosphorylation. As we have observed recently that the tyrosine phosphatase Shp2, a negative regulator of insulin signaling, is a substrate of PKC, we studied the role of Shp2 in this context. We found that phorbol ester-induced Ser-307 phosphorylationis reduced markedly in Shp2-deficient mouse embryonic fibroblasts (Shp2^–/–) whereas Ser-318 phosphorylation is unaltered. The Ser-307 phosphorylation was rescued by transfection of mouse embryonic fibroblasts with wild-type Shp2 or with a phosphatase-inactive Shp2 mutant, respectively. In this cell model, tumor necrosis factor--induced Ser-307 phosphorylation as well depended on the presence of Shp2. Furthermore, Shp2-dependent phorbol ester effects on Ser-307 were blocked by wortmannin, rapamycin, and the c-Jun NH₂-terminal kinase (JNK) inhibitor SP600125. This suggests an involvement of the phosphatidylinositol 3-kinase/mammalian target of rapamycin cascade and of JNK in this signaling pathway resulting in IRS-1 Ser-307 phosphorylation. Because the activation of these kinases does not depend on Shp2, it is concluded that the function of Shp2 is to direct these activated kinases to IRS-1.

Received for publication, June 16, 2005 , and in revised form, July 27, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant KE 553/7-1. 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: Innere Medizin IV, Medizinische Universitätsklinik Tübingen, Otfried-Müller-Strasse 10, Tübingen 72076, Germany. Tel.: 49-0-7071-29-83670; Fax: 49-0-7071-29-2784; E-mail: Hans-Ulrich.Haering{at}med.uni-tuebingen.de.

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