Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists

Mutations in the genes encoding for Met, Ret and Kit receptor tyrosine kina ses invariably result in increased kinase activity and in the acquisition o f transforming potential. However, the requirement of receptor ligands for the transformation process is still unclear. We have investigated the role of hepatocyte growth factor (HGF), the high-affinity ligand for Met, in mut ant Met-mediated cell transformation. We provide evidence that the transfor ming potential displayed by mutant forms of Met found in human cancer is no t only sensitive but entirely dependent on the presence of HGF, by showing that mutant Met transforms NIH3T3 fibroblasts, which produce endogenous HGF , but is not able to transform epithelial cells, unless exogenous HGF is su pplied. Accordingly, mutant Met-induced transformation of NIH3T3 cells can be inhibited by HGF antagonists and increased by HGF stimulation, We also s how that an engineered Met receptor which contains an oncogenic mutation bu t is impaired in its ability to bind HGF completely loses its transforming activity, which can be rescued by causing receptor dimerization using a mon oclonal antibody. These results indicate that point mutations resulting in Met kinase activation are necessary but not sufficient to cause cell transf ormation, the latter being dependent on ligand-induced receptor dimerizatio n, They also suggest that mutant Met-driven tumour growth depends on the av ailability and tissue distribution of active HGF, and provide proof-of-conc ept for the treatment of mutant-Met related pathologies by HGF-antagonizing drugs.