title: Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation.
abstract: The Met receptor tyrosine kinase (RTK) regulates epithelial remodeling, dispersal, and invasion and is deregulated in many human cancers. It is now accepted that impaired down-regulation, as well as sustained activation, of RTKs could contribute to their deregulation. Down-regulation of the Met receptor involves ligand-induced internalization, ubiquitination by Cbl ubiquitin ligases, and lysosomal degradation. Here we report that a ubiquitination-deficient Met receptor mutant (Y1003F) is tumorigenic in vivo. The Met Y1003F mutant is internalized, and undergoes endosomal trafficking with kinetics similar to the wild-type Met receptor, yet is inefficiently targeted for degradation. This results in sustained activation of Met Y1003F and downstream signals involving the Ras-mitogen-activated protein kinase pathway, cell transformation, and tumorigenesis. Although Met Y1003F undergoes endosomal trafficking and localizes with the cargo-sorting protein Hrs, it is unable to induce phosphorylation of Hrs. Fusion of monoubiquitin to Met Y1003F is sufficient to decrease Met receptor stability and prevent sustained MEK1/2 activation. In addition, this rescues Hrs tyrosine phosphorylation and decreases transformation in a focus-forming assay. These results demonstrate that Cbl-dependent ubiquitination is dispensable for Met internalization but is critical to target the Met receptor to components of the lysosomal sorting machinery and to suppress its inherent transforming activity.
authors.affiliation: Molecular Oncology Group H5.21, Department of Biochemistry, McGill University Health Centre, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1.
authors.forename: Jasmine V
authors.initials: JV
authors.lastname: Abella
authors.forename: Pascal
authors.initials: P
authors.lastname: Peschard
authors.forename: Monica A
authors.initials: MA
authors.lastname: Naujokas
authors.forename: Tong
authors.initials: T
authors.lastname: Lin
authors.forename: Caroline
authors.initials: C
authors.lastname: Saucier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Urbé
authors.forename: Morag
authors.initials: M
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004285:Dogs; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000502:physiology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D018631:ras Proteins / Q000502:physiology
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D025801:Ubiquitin; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D050721:Proto-Oncogene Proteins c-cbl; D019859:Proto-Oncogene Proteins c-met; D048730:MAP Kinase Kinase Kinase 2; D048369:MAP Kinase Kinase 1; D018631:ras Proteins