CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation
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
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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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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CEACAM1-4L downregulates cell growth in response to EGF. (A) Cos-7 and M...
CEACAM1-4L downregulates cell growth in response to EGF. (A) Cos-7 and MCF-7 cells were stably transfected with vector alone (+ Vec) or with cDNA encoding rat CEACAM1-4L (+ CC1-4L), EGFR (+ EGFR), or both (+ EGFR/CC1-4L). Cells were also transfected with cDNA encoding EGFR and CEACAM1_4S (+ EGFR/CC1-4S). Numbers in parentheses (in key) denote the clone number. After being incubated for 24 hours in serum-containing complete medium (maximal growth) or in serum-free medium supplemented with 0.1% BSA either alone (basal growth) or with 100 nM EGF, cells were counted by the MTT method. EGF-induced cell growth was calculated as the percent maximal minus basal growth divided by the number of cells grown in complete medium. These experiments were performed in triplicate and were repeated at least three times per clone. Data represent the mean ± SD of repeated experiments. At least two stable clones were examined. *P < 0.05 versus Vec; P < 0.05 versus EGFR (clone 28). (B) For examination of EGFR phosphorylation, serum-starved cells were treated with EGF as described in Figure 1 and lysed and the EGFR immunoprecipitates were analyzed by SDS-PAGE, immunoblotting with α-pTyr for detection of tyrosine-phosphorylated EGFR, and re-immunoblotting with α-EGFR to account for the amount of EGFR in the immunoprecipitates. (C) For examination of CEACAM1-4L phosphorylation, cell lysates were lectin-purified prior to phosphorylation in the presence of EGF and [γ-32P]ATP, immunoprecipitation of CEACAM1-4L, and analysis of its phosphorylation by autoradiography (upper gel). To account for the amount of CEACAM1-4L in the immunoprecipitate, proteins were reprobed with α-CC1 (lower gel).