Vav1 oncogenic mutation inhibits T cell receptor-induced calcium mobilization through inhibition of phospholipase Cγ1 activation

Mira Knyazhitsky, Etay Moas, Ekaterina Shaginov, Anna Luria, Alex Braiman

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Robust elevation of the cytosolic calcium concentration is a crucial early step for T cell activation triggered by the T cell antigen receptor. Vav1 is a proto-oncogene expressed in hematopoietic cells that is indispensable for transducing the calciummobilizing signal. Following T cell receptor stimulation, Vav1 facilitates formation of signaling microclusters through multiple interactions with other proteins participating in the signaling cascade. Truncation of the N terminus of Vav1 produces its oncogenic version, which is unable to support normal calcium flux following T cell activation. We show here that truncation of the N-terminal region of Vav1 alters the fine structure of protein complexes in the signaling clusters, affecting the interaction of Vav1 with phospholipase Cγ1 (PLCγ1). This alteration is accompanied by a decrease in PLCγ1 phosphorylation and inhibition of inositol 1,4,5-trisphosphate production. We suggest that the structural integrity of the N-terminal region of Vav1 is important for the proper formation of the Vav1-associated signaling complexes. The oncogenic truncation of this region elicits conformational changes that interfere with the Vav1-mediated activation of PLCγ1 and that inhibit calcium mobilization.

Original languageEnglish
Pages (from-to)19725-19735
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number23
DOIs
StatePublished - 1 Jun 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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