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Molecular and Cellular Biology, September 2006, p. 6372-6380, Vol. 26, No. 17
0270-7306/06/$08.00+0 doi:10.1128/MCB.00509-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
The R-Ras GTPase Mediates Cross Talk between Estrogen and Insulin Signaling in Breast Cancer Cells
Yi Yu, Yansheng Hao, and Larry A. Feig*Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111
Received 17 March 2005/ Returned for modification 2 May 2005/ Accepted 16 June 2006
The signaling cascades activated by insulin and IGF-1 contribute to the control of multiple cellular functions, including glucose metabolism and cell proliferation. In most cases these effects are mediated, at least in part, by insulin receptor substrates (IRS), one of which is insulin receptor substrate 1 (IRS-1). R-Ras is a member of the Ras family of GTPases and is involved in a variety of biological processes, including integrin activation, cell migration, and control of cell proliferation. Here we demonstrate that both R-Ras and BCAR3, a regulator of R-Ras activity that has been implicated in breast cancer, regulate the level of IRS-1 protein in estrogen-dependent MCF-7 and ZR75 breast cancer cells. In particular, expression of a constitutively activated R-Ras mutant, R-Ras38V, or of BCAR3 accelerates the degradation of IRS-1, leading to the impairment of signaling through insulin but not epidermal growth factor receptors. Moreover, knockdown of endogenous R-Ras levels in MCF-7 cells inhibits IRS-1 degradation induced by estrogen signaling blockade but not by long-term insulin treatment. Consistent with these results, both R-Ras38V expression and estrogen signaling blockade lead to the degradation of IRS-1, at least in part, through calpain activity. These findings show that R-Ras activity mediates inhibition of insulin signaling associated with suppression of estrogen action, implicating this GTPase in a growth-inhibitory mechanism associated with antiestrogen treatment of breast cancer.
* Corresponding author. Mailing address: Tufts University School of Medicine, Biochemistry Department, Jaharis 613, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-6956. Fax: (617) 636-2409. E-mail: larry.feig{at}tufts.edu.
Molecular and Cellular Biology, September 2006, p. 6372-6380, Vol. 26, No. 17
0270-7306/06/$08.00+0 doi:10.1128/MCB.00509-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
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