MUTATION OF JUXTAMEMBRANE TYROSINE RESIDUE-1001 SUPPRESSES LOSS-OF-FUNCTION MUTATIONS OF THE MET RECEPTOR IN EPITHELIAL-CELLS

Signals transduced by the met tyrosine kinase, which is the receptor f or scatter factor/hepatocyte growth factor, are of major importance fo r the regulation of epithelial cell motility, morphogenesis, and proli feration. We report here that different sets of tyrosine residues in t he cytoplasmic domain of the met receptor affect signal transduction i n epithelial cells in a positive or negative fashion: mutation of the C-terminal tyrosine residues 13-16 (Y1311, Y1347, Y1354, and Y1363) re duced or abolished ligand-induced cell motility and branching morphoge nesis. In contrast, mutation of the juxtamembrane tyrosine residue 2 ( Y1001) produced constitutively mobile, fibroblastoid cells, Furthermor e, the gain of-function mutation of tyrosine residue 2 suppressed the loss-of-function mutations of tyrosine residue 15 or 16. The opposite roles of the juxtamembrane and C-terminal tyrosine residues may explai n the suggested dual function of the met receptor in both epithelial-m esenchymal interactions and tumor progression.