Mitogen-inducible gene-6 is a negative regulator of epidermal growth factor receptor signaling in hepatocytes and human hepatocellular carcinoma
| Autor: | Ewa Stepniak, Markus Reschke, Ingvar Ferby, Erwin F. Wagner, David Horst, Nina Seitzer, Axel Ullrich |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Carcinoma Hepatocellular Regulator Receptor tyrosine kinase Mice Cell Movement Cell Line Tumor Internal medicine medicine Animals Humans ERBB3 Epidermal growth factor receptor Extracellular Signal-Regulated MAP Kinases Protein kinase B Adaptor Proteins Signal Transducing Cell Proliferation Hepatology biology Tumor Suppressor Proteins Liver Neoplasms Intracellular Signaling Peptides and Proteins Liver regeneration ErbB Receptors Mice Inbred C57BL Endocrinology Hepatocytes biology.protein Cancer research Cyclin-dependent kinase 8 Skin morphogenesis Signal Transduction |
| Zdroj: | Hepatology. 51:1383-1390 |
| ISSN: | 0270-9139 |
| Popis: | 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 2009.) |
| Databáze: | OpenAIRE |
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