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Papers In Press, published online ahead of print January 25, 2001
Endocrinology 111-H, VAMC, Denver, Colorado 80220-3808
Corresponding Author: Boris.Draznin{at}med.va.gov
We assessed the roles of IRS-1 and Shc in insulin action on farnesyltransferase (FTase) and geranygeranyltransferase I (GGTase I), using CHO cells that overexpressed wild type insulin receptors (CHO-hIR-WT) or mutant insulin receptors lacking the NPEY domain (CHO-
J. Biol. Chem, 10.1074/jbc.M009443200
Submitted on October 16, 2000
Revised on January 25, 2001
Accepted on January 25, 2001
Insulin signals to prenyltransferases via the Shc branch of the intracellular signaling
NPEY), or 3T3-L1 fibroblasts transfected with adenoviruses that expressed the PTB or SAIN domains of IRS-1 and Shc, the PH domain of IRS-1, or the Shc-SH2 domain. Insulin promoted the phosphorylation of the 
-subunit of FTase and GGTase I in CHO-hIR-WT, but was without effect in CHO-NPEY cells. In concert, insulin increased FTase and GGTase I activity and the amounts of prenylated Ras and Rho-A protein in CHO-hIR-WT, but not in CHO-NPEY cells. Overexpression of the PTB or SAIN domain of IRS-1 (that blocked both IRS-1 and Shc signaling) prevented insulin-stimulated phosphorylation of the FTase and GGTase I -subunit, and blocked activation of FTase and GGTase I and subsequent increases in prenylated Ras and Rho-A proteins. In contrast, overexpression of the IRS-1-PH domain (that impairs IRS-1 but not Shc signaling) did not alter insulin action on the prenyl transferases even though it completely inhibited insulin effect on the phosphorylation of IRS-1 and on activation of PI 3-kinase and Akt. Finally, overexpression of Shc-SH2 domain completely blocked insulin effect on FTase and GGTase I activities without interfering with the insulin signaling to MAP kinase. Taken together, these data suggest that insulin signaling from its receptor to the prenyl transferases FTase and GGTase I is mediated by Shc and not IRS-1/PI 3-kinase pathways. Shc-mediated insulin signaling to MAP kinase may be necessary but not sufficient for activation of prenyl transferase activity. An additional pathway involving the Shc-SH2 domain may be necessary to mediated insulin effect on FTase and GGTase I.
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