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J. Biol. Chem., Vol. 280, Issue 15, 14536-14544, April 15, 2005

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Insulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport^*

Marianna Sadagurski, Galina Weingarten, Christopher J. Rhodes, Morris F. White¶, and Efrat Wertheimer||

From the Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, the Pacific Northwest Research Institute, Seattle, Washington, and the ^¶Division of Endocrinology, Howard Hughes Medical Institute Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates. In the present study, we investigated the role of IRS-2 in skin epidermal keratinocytes and dermal fibroblasts. Although skin is not a classical insulin target tissue, we have previously demonstrated that insulin, via the insulin receptor, is essential for normal skin cell physiology. To identify the role of IRS-2 in skin cells, we studied cells isolated from IRS-2 knock-out (KO) mice. Whereas proliferation and differentiation were not affected in the IRS-2 KO cells, a striking effect was observed on glucose transport. In IRS-2 KO keratinocytes, the lack of IRS-2 resulted in a dramatic increase in basal and insulin-stimulated glucose transport. The increase in glucose transport was associated with an increase in total phosphatidylinositol (PI) 3-kinase and Akt activation. In contrast, fibroblasts lacking IRS-2 exhibited a significant decrease in basal and insulin-induced glucose transport. We identified the point of divergence, leading to these differences between keratinocytes and fibroblasts, at the IRS-PI 3-kinase association step. In epidermal keratinocytes, PI 3-kinase is associated with and activated by only the IRS-1 protein. On the other hand, in dermal fibroblasts, PI 3-kinase is exclusively associated with and activated by the IRS-2 protein. These observations suggest that IRS-2 functions as a negative or positive regulator of glucose transport in a cell-specific manner. Our results also show that IRS-2 function depends on its cell-specific association with PI 3-kinase.

Received for publication, September 7, 2004 , and in revised form, January 27, 2005.

^* 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.

^|| To whom correspondence should be addressed: Dept. of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: 972-3-640-6111; Fax: 972-3-640-9141; E-mail: effy{at}patholog.tau.ac.il.

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