Grb2-independent Recruitment of Gab1 Requires the C-terminal Lobe and Structural Integrity of the Met Receptor Kinase Domain
Copyright policy )Grb2-independent Recruitment of Gab1 Requires the C-terminal Lobe and Structural Integrity of the Met Receptor Kinase Domain
The Gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of Gab1 occurs indirectly, via the adapter protein Grb2. In addition, Gab1 interacts with the Met/hepatocyte growth factor receptor in a Grb2-independent manner. This interaction requires a Met binding domain (MBD) in Gab1 and is essential for Met-mediated epithelial morphogenesis. The Gab1 MBD has been proposed to act as a phosphotyrosine binding domain that binds Tyr-1349 in the Met receptor. We show that a 16-amino acid motif within the Gab1 MBD is sufficient for interaction with the Met receptor, suggesting that it is unlikely that the Gab1 MBD forms a structured domain. Alternatively, the structural integrity of the Met receptor, and residues upstream of Tyr-1349 located in the C-terminal lobe of the kinase domain, are required for Grb2-independent interaction with the Gab1 MBD. Moreover, the substitution of Tyr-1349 with an acidic residue allows for the recruitment of the Gab1 MBD and for phosphorylation of Gab1. We propose that Gab1 and the Met receptor interact in a novel manner, such that the activated kinase domain of Met and the negative charge of phosphotyrosine 1349 engage the Gab1 MBD as an extended peptide ligand.
- University of Toronto Canada
- McGill University Health Centre Canada
Models, Molecular, Binding Sites, Amino Acid Motifs, Blotting, Western, Molecular Sequence Data, Ligands, Phosphoproteins, Models, Biological, Precipitin Tests, Cell Line, Microscopy, Fluorescence, Humans, Amino Acid Sequence, Phosphorylation, Peptides, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, Glutathione Transferase, Plasmids, Protein Binding
Models, Molecular, Binding Sites, Amino Acid Motifs, Blotting, Western, Molecular Sequence Data, Ligands, Phosphoproteins, Models, Biological, Precipitin Tests, Cell Line, Microscopy, Fluorescence, Humans, Amino Acid Sequence, Phosphorylation, Peptides, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, Glutathione Transferase, Plasmids, Protein Binding
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