CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation.
CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation.
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DOI：
10.1172/jci21786
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发表时间：
2004
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影响因子：
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通讯作者：
G. Abou-Rjaily;S. J. Lee;D. May;Qusai Y. Al-Share;A. DeAngelis;R. Ruch;M. Neumaier;H. Kalthoff;Sue-Hwa Lin;S. Najjar
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作者：
G. Abou-Rjaily;S. J. Lee;D. May;Qusai Y. Al-Share;A. DeAngelis;R. Ruch;M. Neumaier;H. Kalthoff;Sue-Hwa Lin;S. Najjar
细胞粘附蛋白CEACAM 1的磷酸化增加胰岛素敏感性并降低体内胰岛素依赖性有丝分裂。在这里，我们表明CEACAM 1是EGFR的底物，并且在被磷酸化后，CEACAM 1减少了EGFR介导的转染的Cos-7和MCF-7细胞对EGF的反应。使用转基因小鼠过度表达磷酸化缺陷CEACAM 1突变体在肝脏（L-SACC 1），我们表明，CEACAM 1对EGF依赖性细胞增殖的影响是通过其结合和隔离Shc的能力介导的，从而解偶联EGFR信号从ras/MAPK通路。在L-SACC 1小鼠中，我们还发现CEACAM 1磷酸化受损导致EGFR介导的细胞增殖的配体非依赖性增加。这似乎是继发于内脏肥胖和代谢综合征，从小鼠的脂肪组织的游离脂肪酸和肝素结合EGF样生长因子的输出水平增加。因此，L-SACC 1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模型。
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.