Max-Planck Institute of Biochemistry, Department of Molecular Biology, Martinsried, Germany.
Hepatology. 2010 Apr;51(4):1383-90. doi: 10.1002/hep.23428.
The mitogen-inducible gene-6 (mig-6) is a multi-adaptor protein implicated in the regulation of the HER family of receptor tyrosine kinases. We have reported recently that mig-6 is a negative regulator of epidermal growth factor receptor (EGFR)-dependent skin morphogenesis and tumor formation in vivo. In the liver, ablation of mig-6 leads to an increase in EGFR protein levels, suggesting that mig-6 is a negative regulator of EGFR function. In line with this observation, primary hepatocytes isolated from mig-6 knockout and wild-type control mice display sustained mitogenic signaling in response to EGF. In order to explore the role of mig-6 in the liver in vivo, we analyzed liver regeneration in mig-6 knockout and wild-type control mice. Interestingly, mig-6 knockout mice display enhanced hepatocyte proliferation in the initial phases after partial hepatectomy. This phenotype correlates with activation of endogenous EGFR signaling, predominantly through the protein kinase B pathway. In addition, mig-6 is an endogenous inhibitor of EGFR signaling and EGF-induced tumor cell migration in human liver cancer cell lines. Moreover, mig-6 is down-regulated in human hepatocellular carcinoma and this correlates with increased EGFR expression.
Our data implicate mig-6 as a regulator of EGFR activity in hepatocytes and as a suppressor of EGFR signaling in human liver cancer.
有丝分裂原诱导基因 6（mig-6）是一种多接头蛋白，参与调节表皮生长因子受体（HER）家族的受体酪氨酸激酶。我们最近报道 mig-6 是表皮生长因子受体（EGFR）依赖性皮肤形态发生和体内肿瘤形成的负调节剂。在肝脏中，mig-6 的缺失会导致 EGFR 蛋白水平增加，这表明 mig-6 是 EGFR 功能的负调节剂。与这一观察结果一致，从 mig-6 敲除和野生型对照小鼠分离的原代肝细胞对 EGF 的反应显示持续的有丝分裂信号。为了探讨 mig-6 在体内肝脏中的作用，我们分析了 mig-6 敲除和野生型对照小鼠的肝再生。有趣的是，mig-6 敲除小鼠在部分肝切除后的初始阶段显示出增强的肝细胞增殖。这种表型与内源性 EGFR 信号的激活相关，主要通过蛋白激酶 B 途径。此外，mig-6 是人类肝癌细胞系中 EGFR 信号和 EGF 诱导的肿瘤细胞迁移的内源性抑制剂。此外，mig-6 在人肝癌中下调，这与 EGFR 表达增加相关。
我们的数据表明 mig-6 是肝细胞中 EGFR 活性的调节剂，也是人肝癌中 EGFR 信号的抑制剂。
