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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


  • Taher TE
  • Tjin EP
  • Beuling EA
  • Borst J
  • Spaargaren M
  • Pals ST


Journal of immunology (Baltimore, Md. : 1950)

Publication Data

October 1, 2002

Associated Grants


Mesh Terms

  • 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