c-Cbl Is Involved in Met Signaling in B Cells and Mediates Hepatocyte Growth Factor-Induced Receptor Ubiquitination
| Autor: | Marcel Spaargaren, Steven T. Pals, Esther A. Beuling, Jannie Borst, Esther P. M. Tjin, T. E. I. Taher |
|---|---|
| Přispěvatelé: | Dermatology, Pathology |
| Rok vydání: | 2002 |
| Předmět: |
Ubiquitin-Protein Ligases
Immunology SRC Family Tyrosine Kinase Proto-Oncogene Proteins c-fyn Proto-Oncogene Mas environment and public health Receptor tyrosine kinase Substrate Specificity Ligases Phosphatidylinositol 3-Kinases chemistry.chemical_compound FYN LYN Proto-Oncogene Proteins hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Humans Immunology and Allergy Proto-Oncogene Proteins c-cbl Phosphorylation Phosphotyrosine Ubiquitins Adaptor Proteins Signal Transducing B-Lymphocytes biology Hepatocyte Growth Factor Cell Membrane Nuclear Proteins Tyrosine phosphorylation Proto-Oncogene Proteins c-met enzymes and coenzymes (carbohydrates) src-Family Kinases chemistry Acetylation COS Cells biology.protein Cancer research Hepatocyte growth factor biological phenomena cell phenomena and immunity Signal Transduction medicine.drug |
| Zdroj: | Journal of immunology (Baltimore, Md., 169(7), 3793-3800. American Association of Immunologists |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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