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 (Met receptor), triggers motility, matrix-invasion and branching morphogenesis in epithelial cells. It has recently been shown that the Met receptor interacts with Gab-1, an IRS-like adaptor protein, via the docking site (Y1349VHVNATY1356VNV) known to bind Grb2 and multiple SH2-containing signal transducers. Here we show that Gab1 is the major phosphorylation-substrate of the Met receptor and of its oncogenic variant 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 Y1356 or N1358 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 with the receptor-Gab1 interaction. These data indicate that Gab1 coupling to the Met receptor requires binding of Grb2 and correlates with the transforming potential of Tpr-Met.
Bardelli
A
A
Institute for Cancer Research and Treatment (IRCC), University of Torino School of Medicine, Candiolo, Italy.
Longati
P
P
Gramaglia
D
D
Stella
M C
MC
Comoglio
P M
PM
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D051380:GRB2 Adaptor Protein; D006801:Humans; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014170:Transformation, Genetic; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010750:Phosphoproteins; D011506:Proteins; D019859:Proto-Oncogene Proteins c-met