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J. Biol. Chem., Vol. 278, Issue 10, 8460-8467, March 7, 2003

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Grb10 Inhibits Insulin-stimulated Insulin Receptor Substrate (IRS)-Phosphatidylinositol 3-Kinase/Akt Signaling Pathway by Disrupting the Association of IRS-1/IRS-2 with the Insulin Receptor^*

KeriLyn R. Wick^§, Eric D. Werner^¶, Paul Langlais, Fresnida J. Ramos, Lily Q. Dong^**, Steven E. Shoelson^¶, and Feng Liu

From the Departments of  Pharmacology,  Biochemistry, and ^** Cellular & Structural Biology, The University of Texas Health Science Center, San Antonio, Texas 78229 and the ^¶ Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

Grb10 has been proposed to inhibit or activate insulin signaling, depending on cellular context. We have investigated the mechanism by which full-length hGrb10 inhibits signaling through the insulin receptor substrate (IRS) proteins. Overexpression of hGrb10 in CHO/IR cells and in differentiated adipocytes significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2. Inhibition occurred rapidly and was sustained for 60 min during insulin stimulation. In agreement with inhibited signaling through the IRS/PI 3-kinase pathway, we found hGrb10 to both delay and reduce phosphorylation of Akt at Thr³⁰⁸ and Ser⁴⁷³ in response to insulin stimulation. Decreased phosphorylation of IRS-1/2 may arise from impaired catalytic activity of the receptor, since hGrb10 directly associates with the IR kinase regulatory loop. However, yeast tri-hybrid studies indicated that full-length Grb10 blocks association between IRS proteins and IR, and that this requires the SH2 domain of Grb10. In cells, hGrb10 inhibited insulin-stimulated IRS-1 tyrosine phosphorylation in a dose-dependent manner, but did not affect IR catalytic activity toward Tyr⁹⁷² in the juxtamembrane region and Tyr^{1158/1162/1163} in the regulatory domain. We conclude that binding of hGrb10 to IR decreases signaling through the IRS/PI 3-kinase/AKT pathway by physically blocking IRS access to IR.

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