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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Figure 1

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EGF induces CEACAM1-4L phosphorylation by EGFR in intact HT29p human col...
EGF induces CEACAM1-4L phosphorylation by EGFR in intact HT29p human colon cancer cells. Serum-starved HT29p cells were treated with buffer alone (_) or with the EGFR inhibitor PD168393 (Inhi; +) for 1 hour prior to treatment with EGF (100 nM) for 0_10 minutes. Equal amounts (100 μg) of cell lysates were immunoprecipitated (IP) with α-EGFR (A) or α-C1N3 (B) prior to analysis by SDS-PAGE and immunoblotting (IB) with α-pTyr for detection of tyrosine-phosphorylated proteins (pEGFR and pCC1) and re-immunoprobing (ReIB) with α-EGFR and α-C1N3 to account for the amount of these proteins in the immunoprecipitates. For examination of the CEACAM1-4L/EGFR association, 100 μg of cell lysates were immunoprecipitated with α-EGFR and immunoblotted with α-C1N3 (C, lanes 2_4). To account for nonspecific binding of proteins to agarose, equal amounts of proteins were incubated without the addition of antibody (C, lane 1). The results obtained were consistent in at least three experiments.