The multisubstrate docking site of the MET receptor is dispensable for MET-mediated RAS signaling and cell scattering

The scatter factor/hepatocyte growth factor regulates scattering and morpho genesis of epithelial cells through activation of the MET tyrosine kinase r eceptor. In particular, the noncatalytic C-terminal tail of MET contains tw o autophosphorylation tyrosine residues, which form a multisubstrate-bindin g site for several cytoplasmic effectors and are thought to be essential fo r signal transduction. We show here that a MET receptor mutated on the four C-terminal tyrosine residues, Y1311F, Y1347F, Y1354F, and Y1363F, can indu ce efficiently a transcriptional response and cell scattering, whereas it c annot induce cell morphogenesis. Although the mutated receptor had lost its ability to recruit and/or activate known signaling molecules, such as GRB2 , SHC, GAB1, and PI3K, by using a sensitive association-kinase assay we fou nd that the mutated receptor can still associate and phosphorylate a simila r to 250-kDa protein. By further examining signal transduction mediated by the mutated MET receptor, we established that it can transmit efficient RAS signaling and that cell scattering by the mutated MET receptor could be in hibited by a pharmacological inhibitor of the MEK-ERK (MAP kinase kinase-ex tracellular signal-regulated kinase) pathway. We propose that signal transd uction by autophosphorylation of the C-terminal tyrosine residues is not th e sole mechanism by which the activated MET receptor can transmit RAS signa ling and cell scattering.