c-Cbl is involved in Met signaling in B cells and mediates hepatocyte growth factor-induced receptor ubiquitination.
Hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase Met are key regulators of epithelial motility and morphogenesis. Recent studies indicate that the HGF/Met pathway also plays a role in B cell differentiation, whereas uncontrolled Met signaling may lead to B cell neoplasia. These observations prompted us to explore HGF/Met signaling in B cells. In this study, we demonstrate that HGF induces strong tyrosine phosphorylation of the proto-oncogene product c-Cbl in B cells and increases Cbl association with the Src family tyrosine kinases Fyn and Lyn, as well as with phosphatidylinositol-3 kinase and CrkL. In addition, we demonstrate that c-Cbl mediates HGF-induced ubiquitination of Met. This requires the juxtamembrane tyrosine Y1001 (Y2) of Met, but not the multifunctional docking site (Y14/15) or any additional C-terminal tyrosine residues (Y13-16). In contrast to wild-type c-Cbl, the transforming mutants v-Cbl and 70Z/3 Cbl, which lack the ubiquitin ligase RING finger domain, suppress Met ubiquitination. Our findings identify c-Cbl as a negative regulator of HGF/Met signaling in B cells, mediating ubiquitination and, consequently, proteosomal degradation of Met, and suggest a role for Cbl in Met-mediated tumorigenesis.
Pubmed ID: 12244174 RIS Download
Adaptor Proteins, Signal Transducing | Animals | B-Lymphocytes | COS Cells | Cell Membrane | Hepatocyte Growth Factor | Humans | Ligases | Nuclear Proteins | Phosphatidylinositol 3-Kinases | Phosphorylation | Phosphotyrosine | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-cbl | Proto-Oncogene Proteins c-fyn | Proto-Oncogene Proteins c-met | Signal Transduction | Substrate Specificity | Tumor Cells, Cultured | Ubiquitin-Protein Ligases | Ubiquitins | src-Family Kinases