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.
Taher
Taher E I
TE
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Tjin
Esther P M
EP
Beuling
Esther A
EA
Borst
Jannie
J
Spaargaren
Marcel
M
Pals
Steven T
ST
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D008025:Ligases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D051076:Proto-Oncogene Proteins c-fyn; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017228:Hepatocyte Growth Factor; D008025:Ligases; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D019000:Phosphotyrosine; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D051076:Proto-Oncogene Proteins c-fyn; D019859:Proto-Oncogene Proteins c-met; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins; D019061:src-Family Kinases; C082869:CRKL protein; C000715470:MAS1 protein, human; C494957:FYN protein, human; C060902:lyn protein-tyrosine kinase; C067419:CBL protein, human