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J. Biol. Chem., Vol. 280, Issue 45, 37393-37399, November 11, 2005

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The Phosphorylation of Ser³¹⁸ of Insulin Receptor Substrate 1 Is Not per se Inhibitory in Skeletal Muscle Cells but Is Necessary to Trigger the Attenuation of the Insulin-stimulated Signal^*

From the Department of Internal Medicine IV, Endocrinology, Metabolism, Pathobiochemistry, and Clinical Chemistry, University Hospital Tuebingen, D-72076 Tuebingen, Germany

The Ser/Thr phosphorylation of insulin receptor substrate 1 (IRS) is one key mechanism to stimulate and/or attenuate insulin signal transduction. Using a phospho-specific polyclonal antibody directed against phosphorylated Ser³¹⁸ of IRS-1, we found a rapid and transient insulin-stimulated phosphorylation of Ser³¹⁸ in human and rodent skeletal muscle cell models and in muscle tissue of insulin-treated mice. None of the investigated insulin resistance-associated factors (e.g. high glucose, tumor necrosis factor-, adrenaline) stimulated the phosphorylation of Ser³¹⁸. Studying the function of this phosphorylation, we found that replacing Ser³¹⁸ by alanine completely prevented both the attenuation of insulin-stimulated Akt/protein kinase B Ser⁴⁷³ phosphorylation and glucose uptake after 60 min of insulin stimulation. Unexpectedly, after acute insulin stimulation, we observed that phosphorylation of Ser³¹⁸ is not inhibitory but rather enhances insulin signal transduction because introduction of Ala³¹⁸ led to a reduction of the insulin-stimulated Akt/protein kinase B phosphorylation. Furthermore, replacing Ser³¹⁸ by glutamate, i.e. mimicking phosphorylation, improved glucose uptake after acute insulin stimulation. These data suggest that phosphorylation of Ser³¹⁸ is not per se inhibitory but is necessary to trigger the attenuation of the insulin-stimulated signal in skeletal muscle cells. Investigating the molecular mechanism of insulin-stimulated Ser³¹⁸ phosphorylation, we found that phosphatidylinositol 3-kinase-mediated activation of atypical protein kinase C- and recruitment of protein kinase C- to IRS-1 was responsible for this phosphorylation. We conclude that Ser³¹⁸ phosphorylation of IRS-1 is an early physiological event in insulin-stimulated signal transduction, which attenuates the continuing action of insulin.

Received for publication, June 6, 2005 , and in revised form, August 10, 2005.

^* This work was supported by a grant from the German Diabetes Society (DDG) and German Research Council Grant KFO-114. 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 IV, Endocrinology, Metabolism, Pathobiochemistry, and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. Tel.: 49-0-70-71/29-83193; Fax: 49-0-70-71/29-53-48; E-mail: rainer.lehmann{at}med.uni-tuebingen.de.

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