CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation
George A. Abou-Rjaily, … , Sue-Hwa Lin, Sonia M. Najjar
George A. Abou-Rjaily, … , Sue-Hwa Lin, Sonia M. Najjar
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):944-952. https://doi.org/10.1172/JCI21786.
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Article Oncology

CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation

Abstract

Phosphorylation of the cell adhesion protein CEACAM1 increases insulin sensitivity and decreases insulin-dependent mitogenesis in vivo. Here we show that CEACAM1 is a substrate of the EGFR and that upon being phosphorylated, CEACAM1 reduces EGFR-mediated growth of transfected Cos-7 and MCF-7 cells in response to EGF. Using transgenic mice overexpressing a phosphorylation-defective CEACAM1 mutant in liver (L-SACC1), we show that the effect of CEACAM1 on EGF-dependent cell proliferation is mediated by its ability to bind to and sequester Shc, thus uncoupling EGFR signaling from the ras/MAPK pathway. In L-SACC1 mice, we also show that impaired CEACAM1 phosphorylation leads to ligand-independent increase of EGFR-mediated cell proliferation. This appears to be secondary to visceral obesity and the metabolic syndrome, with increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from the adipose tissue of the mice. Thus, L-SACC1 mice provide a model for the mechanistic link between increased cell proliferation in states of impaired metabolism and visceral obesity.

Authors

George A. Abou-Rjaily, Sang Jun Lee, Denisa May, Qusai Y. Al-Share, Anthony M. DeAngelis, Randall J. Ruch, Michael Neumaier, Holger Kalthoff, Sue-Hwa Lin, Sonia M. Najjar

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Increased activation of EGFR-mediated mitogenesis pathways in L-SACC1 he...
Increased activation of EGFR-mediated mitogenesis pathways in L-SACC1 hepatocytes. (A_C) Livers were removed from 3 age-matched male mice and lysed and equal amounts of proteins were subjected to phosphorylation for 5 minutes in the presence of 50 μM ATP and EGF. Proteins were immunoprecipitated with α-EGFR (A), α-mCC1 (B), or α-Shc (C) prior to immunoblotting with α-pTyr for examination of tyrosine phosphorylation (upper gel of each panel). pShc, phosphorylated Shc. To account for these proteins in the immunoprecipitates, each of these gels was reprobed with the antibody that was used in immunoprecipitation (middle gel). For examination of the association between EGFR and Shc, CEACAM1-4L and EGFR, and Shc and CEACAM1-4L, α-EGFR immunoprecipitates were reprobed with α-Shc (A, lower gel); the α-CEACAM1-4L immunoprecipitates, with α-EGFR (B, lower gel); and the α-Shc immunoprecipitates, with α-CEACAM1-4L (C, lower gel). (D) For assay of MAPK activity, proteins were immunoblotted with α-pMAPK for assessment of phosphorylation of MAPK (p44 and p42; upper gel) and were reprobed with α-MAPK to account for the amount of this protein in the lysates (lower gel). Bars in graphs at right correspond to lanes in gels at left. *P < 0.05 versus (_) of both WT and L-SACC1; P < 0.05 versus (_) WT.