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Cbl-mediated ubiquitinylation and negative regulation of Vav.

The Cbl ubiquitin ligase has emerged as a negative regulator of receptor and non-receptor tyrosine kinases. Cbl is known to associate with the proto-oncogene product Vav, a hematopoietic-restricted Rac guanine nucleotide exchange factor, but the consequences of this interaction remain to be elucidated. Using immortalized T cell lines from Cbl(+/+) and Cbl(-/-) mice, and transfection analyses in 293T cells, we demonstrate that Vav undergoes Cbl-dependent ubiquitinylation under conditions that promote Cbl and Vav phosphorylation. Interaction with Cbl also induced the loss of phosphorylated Vav. In addition, we show that an activated Vav mutant (Vav-Y174F) is more sensitive to Cbl-dependent ubiquitinylation. We demonstrate that the Cbl-dependent ubiquitinylation of Vav requires Cbl/Vav association through phosphorylated Tyr-700 on Cbl, and also requires an intact Cbl RING finger domain. Finally, using transfection analyses in the Jurkat T cell line, we show that Cbl, but not its ubiquitin ligase mutant, can inhibit Vav-dependent signaling. Thus, our findings strongly support the role of Cbl, via its ubiquitin ligase activity, as a negative regulator of activated Vav.

Pubmed ID: 12881521 RIS Download

Mesh terms: Animals | Cell Line | Electrophoresis, Polyacrylamide Gel | Gene Expression Regulation | Humans | Immunoblotting | Jurkat Cells | Luciferases | Mice | Mice, Transgenic | Models, Genetic | Mutation | Oncogene Protein v-cbl | Oncogene Proteins | Phosphorylation | Plasmids | Precipitin Tests | Protein Binding | Protein Structure, Tertiary | Proto-Oncogene Proteins c-vav | Retroviridae Proteins, Oncogenic | Signal Transduction | Time Factors | Transfection | Tyrosine | Ubiquitin | Vanadates

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Associated grants

  • Agency: NCI NIH HHS, Id: CA70195
  • Agency: NCI NIH HHS, Id: CA75075
  • Agency: NCI NIH HHS, Id: CA76118
  • Agency: NCI NIH HHS, Id: CA81076
  • Agency: NCI NIH HHS, Id: CA87986
  • Agency: NCI NIH HHS, Id: CA99163
  • Agency: NCI NIH HHS, Id: CA99900

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