VAV IS A REGULATOR OF CYTOSKELETAL REORGANIZATION MEDIATED BY THE T-CELL RECEPTOR

Background: Vav is a guanine-nucleotide exchange factor for the Rho-li ke small GTPases RhoA, Rac1 and Cdc42, which regulate cytoskeletal reo rganization and activation of stress-activated protein kinases (SAPK/J NKs). Vav is expressed in hematopoietic cells and is phosphorylated in T and B cells following activation of various growth factor or antige n receptors. Vav interacts with several signaling molecules in T cells , but the functional relevance of these interactions is established on ly for Slp76: they cooperate to induce activity of the transcription f actor NF-AT and interleukin-2 expression. We have investigated the rol e of Vav in T cells by generating vav(-/-)mice. Results: Mice deficien t for vav were viable and healthy, but had impaired T-cell development . In vav(-/-) T cells, in response to activation of the T-cell recepto r (TCR), cell cycle progression, induction of NF-ATc1 activity, downre gulation of the cell-cycle inhibitor p27(Kip1) interleukin-2 productio n, actin polymerization and the clustering of TCRs into patches and ca ps - a cytoskeletal reorganization process - were defective. TCR-media ted activation of mitogen-activated protein kinase and SAPK/JNK was un affected. Ca2+ mobilization was impaired in vav(-/-) thymocytes and T cells. In wild-type cells, Vav constitutively associated with the cyto skeletal membrane anchors talin and vinculin. In the absence of Vav, p hosphorylation of Slp76, Slp76-talin interactions, and recruitment of the actin cytoskeleton to the CD3 xi 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-e production and cell cycl e progression. (C) Current Biology Ltd ISSN 0960-9822.