Vav is a GTP͞GDP exchange factor (GEF) for members of the Rho-family of GTPases that is rapidly tyrosine-phosphorylated after engagement of the T cell receptor (

The Rac1 guanosine triphosphatase (GTPase) has been implicated in multiple cellular functions, including actin dynamics, proliferation, apoptosis, adhesion, and migration resulting from signaling by multiple receptors, including the B cell antigen receptor (BCR). We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage. In the absence of both Rac1 and the highly related Rac2, B cell development was almost completely blocked. Both GTPases were required to transduce BCR signals leading to proliferation, survival and up-regulation of BAFF-R, a receptor for BAFF, a key survival molecule required for B cell development and maintenance.

Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4+CD8+ double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-γ1 (PLCγ1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCγ1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCγ1 and the adaptor molecule Src homology 2 domain–containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.

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.