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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


  • Miura-Shimura Y
  • Duan L
  • Rao NL
  • Reddi AL
  • Shimura H
  • Rottapel R
  • Druker BJ
  • Tsygankov A
  • Band V
  • Band H


The Journal of biological chemistry

Publication Data

October 3, 2003

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

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