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

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Abstract

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 Sip76: 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 p27(Kip1), 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 Vav1 phosphorylation of Slp76, Slp76-talin interactions, and recruitment of the actin cytoskeleton to the CD3ζ 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.

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Fischer, K. D., Kong, Y. Y., Nishina, H., Tedford, K., Marengère, L. E. M., Kozieradzki, I., … Penninger, J. M. (1998). Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Current Biology, 8(10), 554–562. https://doi.org/10.1016/s0960-9822(98)70224-6

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