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Originally published In Press as doi:10.1074/jbc.M009443200 on January 25, 2001

J. Biol. Chem., Vol. 276, Issue 16, 12805-12812, April 20, 2001
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Insulin Signals to Prenyltransferases via the Shc Branch of Intracellular Signaling*

Marc L. GoalstoneDagger §, J. Wayne LeitnerDagger , Paulos Berhanu§, Prem M. Sharma||, Jerrold M. Olefsky||**Dagger Dagger , and Boris DrazninDagger §§§

From the Dagger  Veterans Affairs Medical Center Research Service and the § Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80220, the ** Veterans Affairs Medical Center Research Service, La Jolla, California 92161, and the || Department of Medicine, University of California at San Diego, and the Dagger Dagger  Whittier Diabetes Institute, La Jolla, California 92093

We assessed the roles of insulin receptor substrate-1 (IRS-1) and Shc in insulin action on farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) using Chinese hamster ovary (CHO) cells that overexpress wild-type human insulin receptors (CHO-hIR-WT) or mutant insulin receptors lacking the NPEY domain (CHO-Delta NPEY) or 3T3-L1 fibroblasts transfected with adenoviruses that express the PTB or SAIN domain of IRS-1 and Shc, the pleckstrin homology (PH) domain of IRS-1, or the Src homology 2 (SH2) domain of Shc. Insulin promoted phosphorylation of the alpha -subunit of FTase and GGTase I in CHO-hIR-WT cells, but was without effect in CHO-Delta NPEY cells. Insulin increased FTase and GGTase I activities and the amounts of prenylated Ras and RhoA proteins in CHO-hIR-WT (but not CHO-Delta NPEY) cells. Overexpression of the PTB or SAIN domain of IRS-1 (which blocked both IRS-1 and Shc signaling) prevented insulin-stimulated phosphorylation of the FTase and GGTase I alpha -subunit activation of FTase and GGTase I and subsequent increases in prenylated Ras and RhoA proteins. In contrast, overexpression of the IRS-1 PH domain, which impairs IRS-1 (but not Shc) signaling, did not alter insulin action on the prenyltransferases, but completely inhibited the insulin effect on the phosphorylation of IRS-1 and on the activation of phosphatidylinositol 3-kinase and Akt. Finally, overexpression of the Shc SH2 domain completely blocked the insulin effect on FTase and GGTase I activities without interfering with insulin signaling to MAPK. These data suggest that insulin signaling from its receptor to the prenyltransferases FTase and GGTase I is mediated by the Shc pathway, but not the IRS-1/phosphatidylinositol 3-kinase pathway. Shc-mediated insulin signaling to MAPK may be necessary (but not sufficient) for activation of prenyltransferase activity. An additional pathway involving the Shc SH2 domain may be necessary to mediate the insulin effect on FTase and GGTase I.

* This work was supported in part by the Medical Research Service of the Department of Veterans Affairs, National Institutes of Health Grant DK 54475 (to P. B.), the Foundation for Biomedical Education and Research, the Denver Research Institute, the HealthONE Foundation, the Diabetes and Endocrine Research Fund, and the American Diabetes Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a fellowship from the American Heart Association and recipient of a Veterans Affairs Research Service career development award.

§§ To whom correspondence should be addressed: VA Medical Center (151), 1055 Clermont St., Denver, CO 80220. Tel.: 303-393-4619; Fax: 303-377-5686; E-mail: Boris.Draznin@med.va.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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