TY - JOUR
T1 - CEACAM1 modulates epidermal growth factor receptor-mediated cell proliferation
AU - Abou-Rjaily, George A.
AU - Sang, Jun Lee
AU - May, Denisa
AU - Al-Share, Qusai Y.
AU - DeAngelis, Anthony M.
AU - Ruch, Randall J.
AU - Neumaier, Michael
AU - Kalthoff, Holger
AU - Lin, Sue Hwa
AU - Najjar, Sonia M.
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=9644270398&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=9644270398&partnerID=8YFLogxK
U2 - 10.1172/JCI200421786
DO - 10.1172/JCI200421786
M3 - Article
C2 - 15467833
AN - SCOPUS:9644270398
SN - 0021-9738
VL - 114
SP - 944
EP - 952
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -