title: The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor alpha.
abstract: The Cbl protooncogene product has emerged as a negative regulator of receptor and nonreceptor tyrosine kinases. We recently demonstrated that oncogenic Cbl mutants upregulate the endogenous tyrosine kinase signaling machinery when expressed in the NIH 3T3 cells, and identified the platelet-derived growth factor receptor-alpha (PDGFRalpha) as one of the tyrosine kinases targeted by these oncogenes. These findings suggested a role for the normal Cbl protein in negative regulation of the PDGFRalpha. However, the mechanism of such negative regulation remained to be determined. Here we show that overexpression of the wild-type Cbl enhances the ligand-induced ubiquitination of the PDGFRalpha. Concomitantly, the PDGFRalpha in Cbl-overexpressing cells undergoes a faster ligand-induced degradation compared with that in the control cells. These results identify a role for Cbl in the regulation of ligand-induced ubiquitination and degradation of receptor tyrosine kinases and suggest one potential mechanism for evolutionarily conserved negative regulatory influence of Cbl on tyrosine kinases.
authors.affiliation: Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: S
authors.initials: S
authors.lastname: Miyake
authors.forename: M L
authors.initials: ML
authors.lastname: Lupher
authors.forename: B
authors.initials: B
authors.lastname: Druker
authors.forename: H
authors.initials: H
authors.lastname: Band
mesh_terms: D016475:3T3 Cells; D000818:Animals; D051379:Mice; D050722:Oncogene Protein v-cbl; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D050722:Oncogene Protein v-cbl; D015682:Retroviridae Proteins, Oncogenic; D014452:Ubiquitins; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor