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Endocrinology Vol. 138, No. 6 2474-2480
Copyright © 1997 by The Endocrine Society

ARTICLES

Insulin Stimulates the Phosphorylation of the 66- and 52-Kilodalton Shc Isoforms by Distinct Pathways1

Aimee W. Kao, Steven B. Waters2, Shuichi Okada and Jeffrey E. Pessin

Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Jeffrey E. Pessin, The Department of Physiology and Biophysics, The University of Iowa, Iowa City, Iowa 52242-1109. E-mail: Jeffrey-Pessin{at}UIOWA.EDU

In contrast to the 52-kDa Shc isoform, insulin stimulation caused a quantitative, time-dependent decrease in the SDS-PAGE mobility of 66-kDa Shc in both Chinese hamster ovary/IR cells and 3T3L1 adipocytes. Alkaline phosphatase treatment and direct phosphoamino acid analysis demonstrated that insulin stimulated an increase in serine phosphorylation of the 66-kDa isoform but not 52-kDa Shc, although the latter displayed a marked increase in tyrosine phosphorylation. To identify the responsible kinase pathway, we compared the effects on 66-kDa Shc serine phosphorylation by insulin, anisomycin, and osmotic shock, agents that specifically activate the ERK, JNK, or both pathways, respectively. Insulin and osmotic shock both stimulated a decrease in 66-kDa Shc mobility, whereas anisomycin had no effect. Furthermore, expression of a dominant-interfering Ras mutant (N17Ras) prevented the insulin-stimulated, but not the osmotic shock-induced serine phosphorylation of 66-kDa Shc. Consistent with a MEK-dependent pathway mediating 66-kDa Shc serine phosphorylation, the specific MEK inhibitor (PD98059) and expression of a dominant-interfering MEK mutant partially inhibited both the insulin and osmotic shock-induced reduction in 66-kDa Shc mobility. In contrast, expression of the MAP kinase phosphatase (MKP-1) completely prevented ERK activation but did not inhibit the serine phosphorylation of 66-kDa Shc. These data demonstrate that insulin stimulates the serine phosphorylation of the 66-kDa Shc isoform through a MEK-dependent mechanism.




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