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- Title
CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation.
- Authors
Abou-Rjaily, George A.; Lee, Sang Jun; May, Denisa; Al-Share, Qusai V.; Deangelis, Anthony M.; Ruch, Randall J.; Neumaier, Michael; Kalthoff, Holger; Lin, Sue-Hwa; Najjar, Sonia M.; Al-Share, Qusai Y
- 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.
- Subjects
CELL adhesion molecules; PHOSPHORYLATION; CELL proliferation; INSULIN; ADIPOSE tissues; METABOLISM; ANIMAL experimentation; ANTIGENS; CELL division; CELL lines; CELLULAR signal transduction; COMPARATIVE studies; EPIDERMAL growth factor; LIVER; RESEARCH methodology; MEDICAL cooperation; MICE; OBESITY; RATS; RECOMBINANT proteins; RESEARCH; RESEARCH funding; TUMOR antigens; EVALUATION research
- Publication
Journal of Clinical Investigation, 2004, Vol 114, Issue 7, p944
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI200421786