Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the β-Catenin Pathway

Abstract

β-Catenin is an oncogenic protein involved in regulation of cell-cell adhesion and gene expression. Accumulation of cellular β-catenin occurs in many types of human cancers. Four mechanisms are known to cause increases in β-catenin: mutations of β-catenin, adenomatous polyposis coli, or axin genes and activation of Wnt signaling. We report a new cause of β-catenin accumulation involving oncogenic mutants of RON and MET receptor tyrosine kinases (RTKs). Cells transfected with oncogenic RON or MET were characterized by β-catenin tyrosine phosphorylation and accumulation; constitutive activation of a Tcf transcriptional factor; and increased levels of β-catenin/Tcf target oncogene proteins c-mycand cyclin D1. Interference with the β-catenin pathway reduced the transforming potential of mutated RON and MET. Activation of β-catenin by oncogenic RON and MET constitutes a new pathway, which might lead to cell transformation by these and other mutant growth factor RTKs.

ACKNOWLEDGMENTS

We thank B. Vogelstein (Johns Hopkins University, Oncology Center, Baltimore, Md.) for β-Gal- and DN Tcf-4-containing adenoviral constructs, R. Breathnach (INSERM U211, Nantes, France) for human RON WT cDNA, F.A. Montero-Julian (Immunotech, Nantes, France) for mouse monoclonal anti-RON antibodies, and P. Dashner (Carcinogenesis and Cellular Defense Section, Basic Research Laboratory, SAIC, Frederick, Md.) for his help in luciferase assays.