Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the β-catenin pathway

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