CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation

Abstract

Phosphorylation of the cell adhesion protein CEACAM1 increases insulin sensitivity and decreases insulindependent 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.Nonstandard abbreviations used: Ad Cc1, adenovirus vector containing cDNA encoding CEACAM1-4L; Ad Cont, adenovirus control; -CC1, polyclonal -rat CEACAM1-4L; CEA, carcinoembryonic antigen; CEACAM1, CEA-related cell adhesion molecule; GST, glutathione-S-transferase; HB-EGF, heparin-binding EGF-like growth factor; IGF-1R, IGF-1 receptor; L-SACC1, liver-specific overexpression of the phosphorylation-defective S503A CEACAM1-4L mutant; -mCC1,