Abou-Rjaily George A, Lee Sang Jun, May Denisa, Al-Share Qusai Y, Deangelis Anthony M, Ruch Randall J, Neumaier Michael, Kalthoff Holger, Lin Sue-Hwa, Najjar Sonia M
Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo, Ohio 43614, USA.
J Clin Invest. 2004 Oct;114(7):944-52. doi: 10.1172/JCI21786.
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.
细胞黏附蛋白CEACAM1的磷酸化可提高胰岛素敏感性，并在体内降低胰岛素依赖性有丝分裂。我们在此表明，CEACAM1是表皮生长因子受体（EGFR）的底物，磷酸化后的CEACAM1可响应表皮生长因子（EGF），减少EGFR介导的转染Cos-7和MCF-7细胞的生长。利用在肝脏中过表达磷酸化缺陷型CEACAM1突变体的转基因小鼠（L-SACC1），我们发现CEACAM1对EGF依赖性细胞增殖的影响是通过其与Shc结合并隔离Shc的能力介导的，从而使EGFR信号与ras/丝裂原活化蛋白激酶（MAPK）途径解偶联。在L-SACC1小鼠中，我们还表明，CEACAM1磷酸化受损会导致EGFR介导的细胞增殖在不依赖配体的情况下增加。这似乎继发于内脏肥胖和代谢综合征，小鼠脂肪组织中游离脂肪酸和肝素结合表皮生长因子样生长因子的输出水平增加。因此，L-SACC1小鼠为代谢受损状态下细胞增殖增加与内脏肥胖之间的机制联系提供了一个模型。
