Mitogen-inducible gene-6 is a negative regulator of epidermal growth factor receptor signaling in hepatocytes and human hepatocellular carcinoma.
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.


CONCLUSIONS
Our data implicate mig-6 as a regulator of EGFR activity in hepatocytes and as a suppressor of EGFR signaling in human liver cancer.
Reschke
Markus
M
Max-Planck Institute of Biochemistry, Department of Molecular Biology, Martinsried, Germany.
Ferby
Ingvar
I
Stepniak
Ewa
E
Seitzer
Nina
N
Horst
David
D
Wagner
Erwin F
EF
Ullrich
Axel
A
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases