Vav1: a key signal transducer downstream of the TCR

Abstract

Vav1 is a 95-kDa protein expressed in all hemopoietic cells that becomes rapidly tyrosine phosphorylated following T cell antigen receptor (TCR) stimulation. Vav1 contains multiple domains characteristic of signal transducing proteins, including a Dbl homology domain, a hallmark of a guanine nucleotide exchange factor (GEF) for Rho-family GTPases. Indeed Vav1 is a GEF for Rac1, Rac2 and RhoG, and it is activated following tyrosine phosphorylation. Generation of mice deficient in Vav1 has shown that it plays an important role in selection events within the thymus, including both positive and negative selection, consistent with Vav1 transducing TCR signals required to drive these processes. Furthermore, Vav1-deficient T cells are defective in TCR-induced proliferation and cytokine synthesis. Analysis of TCR signaling pathways in Vav1-deficient T cells and thymocytes has shown that Vav1 is required to transduce signals to the activation of a calcium flux, extracellular signal-regulated kinase (ERK) and the nuclear factor kappaB (NF-kappaB) transcription factor. Vav1 has also been shown to control the activation of phospholipase Cgamma1 (PLCgamma1) via both phosphoinositide-3-kinase (PI3K)-dependent and -independent pathways. Finally, Vav1 has been shown to transduce TCR signals to some but not all cytoskeleton-dependent pathways. In particular, Vav1 is required for efficient TCR-induced conjugate formation with antigen presenting cells (APCs), activation of the integrin leukocyte function-associated antigen-1 (LFA-1) and cell polarization.

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4+T cells

“…Intriguingly, Vav2, a GEF for the Rho family of Ras-related GTPases, was down-regulated after chronic TNF treatment. Vav is important in T cell activation (23), is required for synapse formation, and is necessary for Ca 2ϩ flux and activation of extracellular signal-regulated kinase (ERK) (23)(24)(25)(26)(27). Holsinger et al (28) showed that vavϪ/Ϫ T cells were deficient in IL-2 production and proliferation, and the peak of Ca 2ϩ mobilization was reduced, although of normal duration.…”

Alterations in Lipid Raft Composition and Dynamics Contribute to Abnormal T Cell Responses in Systemic Lupus Erythematosus

“…Although the precise mechanisms mediating increased calcium responses in SLE are not known, there are important leads in this direction. There is growing support for a connection between Vav1 and PLC␥1 in inducing calcium flux (54). Previous studies in Vav1 knockout mice have revealed that Vav1 is important for maintaining sustained calcium levels following T cell activation (63).…”

“…Therefore, we explored the possibility that Vav1 may be involved in mediating rapid kinetics of actin polymerization in SLE. Phosphorylation of tyrosine residues is essential for the activation of Vav1 (52,53), and Vav1 induces actin polymerization primarily by its association with actin-binding proteins such as Rac-1, Rac-2, and Rho G proteins (49,50,54). Thus, we compared the amounts of phosphorylated Vav1 that associates with actin-bound proteins in normal and SLE T cells following treatment of 1% Triton X-100-insoluble fractions with cytochalasin B, which is known to release proteins from the cytoskeletal network (28).…”

Vav1 Promotes T Cell Cycle Progression by Linking TCR/CD28 Costimulation to FOXO1 and p27kip1 Expression

“…The critical role of the Vav family of guanine exchange factors (GEFs) 5 for Rho GTPases in T cell development, activation, and proliferation is well established (1,2). This family consists of three mammalian members, Vav1, -2, and -3, which display different expression profiles, Vav1 expression being restricted to the hemopoietic lineage (1).…”