Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor.

Background: Vav is a guanine-nucleotide exchange factor for the Rho-like small GTPases RhoA, Rac1 and Cdc42, which regulate cytoskeletal reorganization and activation of stress-activated protein kinases (SAPK/JNKs). Vav is expressed in hematopoietic cells and is phosphorylated in T and B cells following activation of various growth factor or antigen receptors. Vav interacts with several signaling molecules in T cells, but the functional relevance of these interactions is established only for Slp76: they cooperate to induce activity of the transcription factor NF-AT and interleukin-2 expression.

Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum.

In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin. We report here that mice bearing a disruption in the NF-ATc gene fail to develop normal cardiac valves and septa and die of circulatory failure before day 14.5 of development.

The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production.

NF-ATc1 is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In activated T cells, nuclear NF-AT binds to the promoter regions of multiple cytokine genes and induces their transcription. The role of NF-ATc1 was investigated in recombination activating gene-1 (RAG-1)-deficient blastocyst complementation assays using homozygous NF-ATc1-/- mutant ES cell lines.

The SH3 domain of Itk/Emt binds to proline-rich sequences in the cytoplasmic domain of the T cell costimulatory receptor CD28.

Engagement of the transmembrane receptor CD28 potentiates T cell survival, proliferation, and activation. The biochemical basis by which CD28 controls these outcomes is unclear, although early events following cross-linking of the receptor are characterized by tyrosine phosphorylation of CD28 and other cellular substrates. We demonstrate that following CD28 ligation, a CD28-associated tyrosine kinase activity is increased in parallel to activation of the T cell-specific tyrosine kinase Itk (Itk/Emt), while Lck and Fyn kinase activities are not increased.

Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells.

The molecular adapter c-Cbl is rapidly tyrosine phosphorylated following stimulation through the TCR and associates with Src homology domain-2 (SH2)/SH3 domain-containing adapters such as Grb2, Crk, and Crk-L, which interact with guanine nucleotide exchange factors specific for the Ras family. This suggests that c-Cbl may link TCR activation to molecules that regulate GTP binding proteins. The SH2/SH3-containing protein Vav also contains a guanine nucleotide exchange factor domain, and Vav has a crucial role in thymocyte development and activation of peripheral T cells following stimulation through the TCR.