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[Cancer Research 62, 2064-2071, April 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Hepatocyte Growth Factor Induces Wnt-independent Nuclear Translocation of ß-Catenin after Met-ß-Catenin Dissociation in Hepatocytes1

Satdarshan P. S. Monga, Wendy M. Mars, Peter Pediaditakis, Aaron Bell, Karen Mulé, William C. Bowen, Xue Wang, Reza Zarnegar and George K. Michalopoulos2

Division of Cellular and Molecular Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261

Hepatocyte growth factor (HGF) and Wnt signaling pathways have been shown to be important in embryogenesis and carcinogenesis. The aim of this study was to elucidate the mechanism of functional similarities observed in the two pathways. We used normal rat liver, primary hepatocyte cultures and a dominant-negative Met expression system to study the effect of HGF on Wnt pathway components. We demonstrate novel association of ß-catenin and Met, a tyrosine kinase receptor of HGF, at the inner surface of the hepatocyte membrane. HGF induces dose-dependent nuclear translocation of ß-catenin in primary hepatocyte cultures that is Wnt independent. The source of ß-catenin for translocation in hepatocytes is the Met-ß-catenin complex, which appears to be independent of the E-cadherin-ß-catenin complex. To test the functionality of this association, we used a dominant-negative Met expression system that expresses only the extracellular and transmembrane regions of the ß-subunit of Met. A loss of Met-ß-catenin association resulted in abrogation of nuclear translocation of ß-catenin upon HGF stimulation. This event is tyrosine phosphorylation dependent, and the association of Met and ß-catenin is crucial for this event. We conclude that the HGF causes similar redistribution of ß-catenin as Wnt-1 in the hepatocytes and that this effect is attributable to subcellular association of Met and ß-catenin. The intracellular kinase domain of Met is essential for tyrosine phosphorylation and nuclear translocation of ß-catenin. Part of the multifunctionality of HGF might be attributable to nuclear ß-catenin and the resulting target gene expression.




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