Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes.
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 beta-catenin and Met, a tyrosine kinase receptor of HGF, at the inner surface of the hepatocyte membrane. HGF induces dose-dependent nuclear translocation of beta-catenin in primary hepatocyte cultures that is Wnt independent. The source of beta-catenin for translocation in hepatocytes is the Met-beta-catenin complex, which appears to be independent of the E-cadherin-beta-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 beta-subunit of Met. A loss of Met-beta-catenin association resulted in abrogation of nuclear translocation of beta-catenin upon HGF stimulation. This event is tyrosine phosphorylation dependent, and the association of Met and beta-catenin is crucial for this event. We conclude that the HGF causes similar redistribution of beta-catenin as Wnt-1 in the hepatocytes and that this effect is attributable to subcellular association of Met and beta-catenin. The intracellular kinase domain of Met is essential for tyrosine phosphorylation and nuclear translocation of beta-catenin. Part of the multifunctionality of HGF might be attributable to nuclear beta-catenin and the resulting target gene expression.
Monga
Satdarshan P S
SP
Division of Cellular and Molecular Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Mars
Wendy M
WM
Pediaditakis
Peter
P
Bell
Aaron
A
Mulé
Karen
K
Bowen
William C
WC
Wang
Xue
X
Zarnegar
Reza
R
Michalopoulos
George K
GK
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000502:physiology; D008297:Male; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013912:Threonine / Q000378:metabolism; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495245:Wnt1 protein, rat; D029961:Zebrafish Proteins; D051176:beta Catenin; D013912:Threonine; D012694:Serine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met