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Volume 272, Number 14, Issue of April 4, 1997 pp. 9581-9586
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional Importance of Shc Tyrosine 317 on Insulin Signaling in Rat1 Fibroblasts Expressing Insulin Receptors

(Received for publication, September 13, 1996, and in revised form, December 5, 1996)

Hajime Ishihara , Toshiyasu Sasaoka , Manabu Ishiki , Yasumitsu Takata , Takeshi Imamura , Isao Usui , W. John Langlois § , Tasuku Sawa and Masashi Kobayashi

From the First Department of Medicine, Toyama Medical & Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan and the § Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada

Shc is phosphorylated on Tyr-317, which serves as a docking site for Grb2. To investigate the specific role of Shc phosphorylation and Shc·Grb2 coupling on insulin signaling, we generated expression vectors for wild-type (WT-Shc) and a mutant Shc with a Tyr-317 right-arrow Phe substitution (317Y/F-Shc) and stably transfected them into Rat1 fibroblasts expressing insulin receptors (HIRc). From different clonal cell lines, cells expressing 10 times greater amounts of WT-Shc or 317Y/F-Shc compared with endogenous Shc were chosen for analysis of insulin signaling. Insulin-induced Shc phosphorylation and subsequent association with Grb2 was enhanced in WT-Shc cells. Because of competition between Shc and IRS-1 for interaction with the insulin receptor, insulin-stimulated tyrosine phosphorylation of IRS-1 was decreased in WT-Shc cells compared with that in HIRc cells. Likewise, reduction of endogenous Shc expression by antisense Shc mRNA resulted in increased insulin stimulation of IRS-1 phosphorylation. Although 317Y/F-Shc was also able to interact with insulin receptor, decreased amounts of Shc phosphorylation and Shc association with Grb2 were observed in 317Y/F-Shc cells, indicating that 317Y/F-Shc functions as a dominant-negative mutant. The kinetics of mitogen-activated protein (MAP) kinase activation closely paralleled the kinetics of Shc phosphorylation. Thus, insulin stimulation of MAP kinase activation occurred more rapidly and was prolonged in WT-Shc cells, while the activation was delayed and transient in 317Y/F-Shc cells compared with that in HIRc cells. Importantly, WT-Shc cells displayed enhanced sensitivity to insulin stimulation of thymidine and bromodeoxyuridine incorporation, whereas the sensitivity was decreased in 317Y/F-Shc cells. These results indicate that Shc Tyr-317 phosphorylation plays an important role, via coupling with Grb2 and competition with IRS-1, in signal transduction to MAP kinase by insulin, ultimately leading to mitogenesis in Rat1 fibroblasts.


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