Distinct recruitment and function of Gab1 and Gab2 in Met receptor-mediated epithelial morphogenesis.
The Gab family of docking proteins (Gab1 and Gab2) are phosphorylated in response to various cytokines and growth factors. Gab1 acts to diversify the signal downstream from the Met receptor tyrosine kinase through the recruitment of multiple signaling proteins, and is essential for epithelial morphogenesis. To determine whether Gab1 and Gab2 are functionally redundant, we have examined the role of Gab2 in epithelial cells. Both Gab1 and Gab2 are expressed in epithelial cells and localize to cell-cell junctions. However, whereas overexpression of Gab1 promotes a morphogenic response, the overexpression of Gab2 fails to induce this response. We show that Gab2 recruitment to the Met receptor is dependent on the Grb2 adapter protein. In contrast, Gab1 recruitment to Met is both Grb2 dependent and Grb2 independent. The latter requires a novel amino acid sequence present in the Met-binding domain of Gab1 but not Gab2. Mutation of these residues in Gab1 impairs both association with the Met receptor and the ability of Gab1 to promote a morphogenic response, whereas their insertion into Gab2 increases Gab2 association with Met, but does not confer on Gab2 the ability to promote epithelial morphogenesis. We propose that the Grb2-independent recruitment of Gab proteins to Met is necessary but not sufficient to promote epithelial morphogenesis.
Lock
Lisa S
LS
Department of Biochemistry, Molecular Oncology Group, McGill University Health Centre, Montreal, Quebec, Canada H3A 1A1.
Maroun
Christiane R
CR
Naujokas
Monica A
MA
Park
Morag
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004285:Dogs; D004847:Epithelial Cells / Q000502:physiology*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C098587:GAB1 protein, human; C490895:GAB2 protein, human; C490897:Gab1 protein, mouse; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D019859:Proto-Oncogene Proteins c-met