Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76

Céline Charvet, Ann Janette Canonigo, Daniel D. Billadeau, Amnon Altman

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The Vav family of guanine exchange factors plays a critical role in lymphocyte proliferation, cytoskeletal reorganization, and gene transcription upon immunoreceptor engagement. Although the role of Vav1 in T cells is well documented, the role of Vav3 is less clear. We investigated the subcellular localization of Vav3 during T cell activation. We report here that phosphorylation of Vav3 on tyrosine residue Tyr173 is not required for T cell receptor (TCR)-induced Vav3 membrane translocation or immunological synapse (IS) recruitment, but mutation of this residue enhanced TCR-induced nuclear factor of activated T cells (NFAT) activation. However, Vav3 mutants either containing an Src homology 2 (SH2)-disabled point mutation (R697L) or lacking its SH3-SH2-SH3 domains were unable to bind SLP-76 did not translocate to the membrane or to the IS and furthermore failed to activate NFAT. Importantly, the membrane translocation of Vav3 was abrogated in Lck, ZAP-70, LAT, and SLP-76-deficient T cells, where Vav3 binding to SLP-76 was disrupted. Finally, we confirmed and underlined the critical role of Vav3 in NFAT activation by knocking down Vav3 expression in Vav1-deficient T cells. Altogether, our data show that TCR-induced association of Vav3 with SLP-76 is required for its membrane/IS localization and function.

Original languageEnglish (US)
Pages (from-to)15289-15299
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number15
DOIs
StatePublished - Apr 15 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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