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. we have investigated the role of vav in t cells by generating vav-/- mice.
Results:
Mice deficient for vav were viable and healthy, but had impaired t-cell development. in vav-/- t cells, in response to activation of the t-cell receptor (tcr), cell cycle progression, induction of nf-atc1 activity, downregulation of the cell-cycle inhibitor p27kip1, interleukin-2 production, actin polymerization and the clustering of tcrs into patches and caps--a cytoskeletal reorganization process--were defective. tcr-mediated activation of mitogen-activated protein kinase and sapk/jnk was unaffected. ca2+ mobilization was impaired in vav-/- thymocytes and t cells. in wild-type cells, vav constitutively associated with the cytoskeletal membrane anchors talin and vinculin. in the absence of vav, phosphorylation of slp76, slp76-talin interactions, and recruitment of the actin cytoskeleton to the cd3 zeta chain of the tcr co-receptor were impaired.
Conclusions:
Vav is a crucial regulator of tcr-mediated ca2+ flux, cytoskeletal reorganization and tcr clustering, and these are required for t-cell maturation, interleukin-2 production and cell cycle progression.