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J. Biol. Chem., Vol. 282, Issue 25, 18018-18027, June 22, 2007

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Common Inhibitory Serine Sites Phosphorylated by IRS-1 Kinases, Triggered by Insulin and Inducers of Insulin Resistance^*

Avia Herschkovitz, Yan-Fang Liu, Erez Ilan, Denise Ronen, Sigalit Boura-Halfon, and Yehiel Zick¹

From the Department of Molecular Cell Biology, The Weizmann Institute of Science, and the Institute of Biochemistry, Food Science, and Nutrition, Faculty of Agricultural, Food, and Environmental Quality, The Hebrew University of Jerusalem, P. O. Box 12, Rehovot 76100, Israel

The Insulin Receptor Substrate (IRS) proteins are key players in insulin signal transduction and are the best studied targets of the insulin receptor. Ser/Thr phosphorylation of IRS proteins negatively modulates insulin signaling; therefore, the identification of IRS kinases and their target Ser phosphorylation sites is of physiological importance. Here we show that in Fao rat hepatoma cells, the IB kinase (IKK) is an IRS-1 kinase activated by selected inducers of insulin resistance, including sphingomyelinase, ceramide, and free fatty acids. Moreover, IKK shares a repertoire of seven potential target sites on IRS-1 with protein kinase C (PKC), an IRS-1 kinase activated both by insulin and by inducers of insulin resistance. We further show that mutation of these seven sites (Ser-265, Ser-302, Ser-325, Ser-336, Ser-358, Ser-407, and Ser-408) confers protection from the action of IKK and PKC when they are overexpressed in Fao cells or primary hepatocytes. This enables the mutated IRS proteins to better propagate insulin signaling. These findings suggest that insulin-stimulated IRS kinases such as PKC overlap with IRS kinases triggered by inducers of insulin resistance, such as IKK, to phosphorylate IRS-1 on common Ser sites.

Received for publication, November 28, 2006 , and in revised form, April 16, 2007.

^* This work was supported by research grants from The Juvenile Diabetes Foundation International, The European Foundation for the Study of Diabetes, The U.S.-Israel Binational Fund, The Israel Science Foundation (founded by the Israel Academy of Sciences and Humanities), The Russell Berrie Foundation and D Cure, Diabetes Care in Israel, The Mitchel Kaplan Fund for Diabetes Research, and the MINERVA Foundation. 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 Incumbent of the Marte R. Gomez Professorial Chair. To whom correspondence should be addressed. Tel.: 972-8-9342-380; Fax: 972-8-9344-125; E-mail: yehiel.zick{at}weizmann.ac.il.

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