title: Distinct involvement of the Gab1 and Grb2 adaptor proteins in signal transduction by the related receptor tyrosine kinases RON and MET.
abstract: Although the signal transduction mechanisms of the receptor tyrosine kinase MET are well defined, less is known about its close relative RON. MET initiates intracellular signaling by autophosphorylation on specific cytoplasmic tyrosines that form docking sites for the adaptor proteins Grb2 and Gab1. Grb2 binds directly and is essential for all of the biological activities of MET. Gab1 docks either directly or indirectly via Grb2 and controls only a subset of MET functions. Because MET and RON possess similar adaptor binding sites, it was anticipated that their adaptor interactions would be conserved. Here we show that in contrast to MET, RON relies primarily on Gab1 for signal transmission. Surprisingly, disruption of the Grb2 docking site of RON or Grb2 depletion augments activity, whereas enhancement of Grb2 binding attenuates Gab1 recruitment and signaling. Hence, RON and MET differ in their adaptor interactions; furthermore, Grb2 performs a novel antagonistic role in the context of RON signaling.
authors.affiliation: Department of Molecular Oncology, Genentech, Inc, South San Francisco, California 94080, USA. amitabha@gene.com
authors.forename: Amitabha
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Xie
authors.forename: Becky
authors.initials: B
authors.lastname: Yang
authors.forename: Kaushiki
authors.initials: K
authors.lastname: Mahapatra
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.forename: Sweta
authors.initials: S
authors.lastname: Bodepudi
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C490897:Gab1 protein, mouse; C495949:Grb2 protein, mouse; D010750:Phosphoproteins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases