GAB1 COUPLING TO THE HGF MET RECEPTOR MULTIFUNCTIONAL DOCKING SITE REQUIRES BINDING OF GRB2 AND CORRELATES WITH THE TRANSFORMING POTENTIAL/

Activation of the HGF receptor, encoded by the c-MET protooncogene (Me t receptor), triggers motility, matrix-invasion and branching morphoge nesis in epithelial cells. It has recently been shown that the Met rec eptor interacts with Gab-1, an IRS-like adaptor protein, via the docki ng site (Y(1349)VHVNATY(1356)VNV) known to bind Grb2 and multiple SH2- containing signal transducers. Here we show that Gab1 is the major pho sphorylation-substrate of the Met receptor and of its oncogenic varian t Tpr-Met. A series of point mutations in the docking site established a direct correlation between the ability to recruit and phosphorylate Gab1 and the transforming potential, Interestingly. the mutations of either Y-1356 or N-1358 abolished the binding of both Grb2 and Gab1 in intact cells, Furthermore, peptides designed to block either the SH2 or the SH3 domains of Grb2 interfered,vith the receptor-Gab1 interacti on, These data indicate that Gab1 coupling to the Met receptor require s binding of Grb2 and correlates with the transforming potential of Tp r-Met.