title: Degradation of the GAB1 adaptor by the ubiquitin-proteasome pathway hampers HGF/SF-MET signaling.
abstract: The GRB2 associated binder 1 (GAB1) is an essential docking/adaptor protein for transmitting intracellular signals of the MET tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). We found that in response to hours of HGF/SF treatment, the GAB1 protein level is degraded by a mechanism involving MET activity and the proteasomal machinery. We also showed that GAB1 is both multi- and poly-ubiquitinated in a CBL-dependent manner. A long term exposure to HGF/SF caused a more sustained down-regulation of GAB1 than of MET, associated with a loss of reactivation of the ERK MAP kinases to subsequent acute ligand treatment. These data demonstrate that GAB1 is ubiquitinated by CBL and degraded by the proteasome, and plays a role in negative-feedback regulation of HGF/SF-MET signaling.
authors.affiliation: CNRS UMR, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, France.
authors.forename: Gautier
authors.initials: G
authors.lastname: Goormachtigh
authors.forename: Zongling
authors.initials: Z
authors.lastname: Ji
authors.forename: Arnaud
authors.initials: A
authors.lastname: Le Goff
authors.forename: Véronique
authors.initials: V
authors.lastname: Fafeur
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; C066855:HGF protein, human; D017978:Receptors, Growth Factor; D025801:Ubiquitin; D017228:Hepatocyte Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D046988:Proteasome Endopeptidase Complex; C067419:CBL protein, human