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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Elevated adipokines activate EGFR activation in L-SACC1 hepatocytes. Fiv...
Elevated adipokines activate EGFR activation in L-SACC1 hepatocytes. Five age-matched male mice were treated with KT6-207 (+; black bars) or vehicle alone (_; gray bars for L-SACC1 mice and white bars for WT mice). (A) At the end of the treatment, blood was removed for determination of plasma FFA levels. (B) Visceral adipose tissues were removed from the intra-abdominal cavity and lysed for sequential immunoblotting with α_HB-EGF followed by α-actin for determination of HB-EGF content. (C) Livers were removed from age-matched mice and lysed and equal amounts of proteins were subjected to immunoprecipitation with α-EGFR prior to sequential immunoblotting with α-pTyr for examination of EGFR phosphorylation and α-EGFR to account for the amount of this protein in the immunoprecipitates. (D) Equal amounts of proteins were analyzed by Western blotting with α-PCNA and were normalized by reprobing with α-actin for determination of cell proliferation. *P < 0.05 versus (_) WT.