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Degree

Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo Health Science Campus, Graduate School, 2005.

Abstract

CEACAM1 is a substrate of the insulin receptor in the liver, a major site of insulin clearance. Upon its phosphorylation, CEACAM1 takes part of the insulin endocytosis complex to promote its receptor-mediated uptake and degradation. Overexpressing the S503A phosphorylation-dependent CEACAM1 isoform in the liver of L-SACC1 transgenic mice impairs insulin clearance and leads to visceral obesity and altered fat metabolism, including increased plasma free fatty acids (FFAs) and triglycerides levels. Altered fat metabolism also includes reduced ability of insulin to acutely decrease fatty acid synthase activity. We herein demonstrate that CEACAM1 is also a substrate of the epidermal growth factor receptor (EGFR) and that upon its phosphorylation, it reduces EGFRmediated growth of transfected Cos-7 and MCF-7 cells in response to EGF. Using the LSACC1 mouse, we show that the CEACAM1 effect on EGF-dependent cell proliferation is mediated by its ability to bind to and sequester Shc, thus uncoupling EGFR signaling from the Ras/MAP kinase 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 FFAs 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.

Subject Headings

Health Sciences, Pharmacology

Keywords

CEACAM1; EGFR; Insulin; FAS; Phosphorylation; L-SACC1; kinase

Advisor

Sonia Najjar, Ph.D

Pages

186p.

Document number: mco1107352295
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=mco1107352295

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