CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation.
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.
Abou-Rjaily
George A
GA
Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo, Ohio 43614, USA.
Lee
Sang Jun
SJ
May
Denisa
D
Al-Share
Qusai Y
QY
Deangelis
Anthony M
AM
Ruch
Randall J
RJ
Neumaier
Michael
M
Kalthoff
Holger
H
Lin
Sue-Hwa
SH
Najjar
Sonia M
SM
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D007328:Insulin; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors