Cbl-mediated ubiquitinylation and negative regulation of Vav

Yuko Miura-Shimura, Lei Duan, Navin L. Rao, Alagarsamy L. Reddi, Hideki Shimura, Rob Rottapel, Brain J. Druker, Alexander Tsygankov, Vimla Band, Hamid Band

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44 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)38495-38504
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
StatePublished - Oct 3 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Miura-Shimura, Y., Duan, L., Rao, N. L., Reddi, A. L., Shimura, H., Rottapel, R., Druker, B. J., Tsygankov, A., Band, V., & Band, H. (2003). Cbl-mediated ubiquitinylation and negative regulation of Vav. Journal of Biological Chemistry, 278(40), 38495-38504. https://doi.org/10.1074/jbc.M305656200