The N-terminal region of the guanine nucleotide exchange factor Vav1 plays a distinguished role in T cell receptor mediated calcium signaling (P1158)

Abstract

Abstract Vav1 is a guanine nucleotide exchange factor specifically expressed in hematopoietic cells. It consists of multiple structural domains and plays important roles in T cell activation. The other highly conserved isoforms of Vav family, Vav2 and Vav3, are ubiquitously expressed in human tissues including lymphocytes. All the three Vav proteins activate Rho family small GTPases, which are involved in a variety of biological processes during T cell activation. Intensive studies have demonstrated that Vav1 is indispensable for T cell receptor mediated signal transduction. T cells lacking Vav1 exhibited severe defect in TCR-mediated calcium elevation, indicating that the co-existing Vav2 and Vav3 did not compensate Vav1 in calcium signaling. What is the functional particularity of Vav1 in lymphocytes? In this study, we identified the N-terminal region of Vav1 in calponin homology domain to be essential for its interaction with Calmodulin, that leads to TCR-induced calcium mobilization. Substitution of the region of Vav1 with the homologous region of Vav2 or Vav3 abolished the association with CaM, and the N-terminal mutations of Vav1 failed to potentiate normal TCR-induced calcium mobilization, that in turn, suspended nuclear factor of activated T cells activation and IL-2 production. This study highlights the importance of the N-terminal region of Vav1 for calmodulin binding, and that attributes irreplaceable role of Vav1 in T cell activation and signal transduction.