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Papers In Press, published online ahead of print November 1, 2001
Department of Pharmacology, Medical College of Ohio, Toledo, Oh 43614
Corresponding Author: snajjar{at}mco.edu
CEACAM1, a tumor suppressor, is a plasma membrane protein that undergoes phosphorylation on Tyr488 in its cytoplasmic tail by the insulin receptor tyrosine kinase. Co-expression of CEACAM1 with insulin receptors decreased cell growth in response to insulin. Co-immunoprecipitation experiments in intact NIH 3T3 cells and GST pull-down assays revealed that phophorylated Tyr488 in CEACAM1 binds to the SH2 domain of Shc, another substrate of the insulin receptor. Overexpressing Shc SH2 domain relieved endogenous Shc from binding to CEACAM1 and restored MAP kinase activity, growth of cells in response to insulin and their colonization in soft agar. Thus, by binding to Shc, CEACAM1 sequesters this major coupler of Grb2 to the insulin receptor and downregulates the Ras/MAP kinase mitogenesis pathway. Additionally, CEACAM1 binding to Shc enhances its ability to compete with IRS-1 for phosphorylation by the insulin receptor. This leads to a decrease in IRS-1 binding to PI-3 kinase and to the downregulation of the PI-3 kinase/Akt pathway that mediates cell proliferation and survival. Thus, binding to Shc appears to constitute a major mechanism for the downregulatory effect of CEACAM1 on cell proliferation.
J. Biol. Chem, 10.1074/jbc.M108415200
Submitted on August 30, 2001
Revised on October 31, 2001
Accepted on November 1, 2001
Shc and CEACAM1 interact to regulate the mitogenic action of insulin
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