Mitogen-Inducible Gene-6 is a Negative Regulator of Epidermal Growth Factor Receptor Signaling in Hepatocytes and Human Hepatocellular Carcinoma

作者：Reschke Markus; Ferby Ingvar; Stepniak Ewa; Seitzer Nina; Horst David; Wagner Erwin F; Ullrich Axel^*

来源：Hepatology, 2010, 51(4): 1383-1390.

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. Conclusion: Our data implicate mig-6 as a regulator of EGFR activity in hepatocytes and as a suppressor of EGFR signaling in human liver cancer. (HEPATOLOGY 2010;51: 1383-1390.)

• 出版日期2010-4