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Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways

Lucinda F. Reynolds¹, Lesley A. Smyth¹, Trisha Norton¹, Norman Freshney², Julian Downward², Dimitris Kioussis¹ and Victor L.J. Tybulewicz¹

¹ National Institute for Medical Research, London NW7 1AA, United Kingdom
² Cancer Research UK, London Research Institute, London WC2A 3PX, United Kingdom

Address correspondence to V.L.J. Tybulewicz, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. Phone: 4420-8913-8699; Fax: 4420-8906-4477; E-mail: vtybule{at}nimr.mrc.ac.uk

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-1 (PLC1) is defective. Furthermore, we demonstrate that Vav1 regulates PLC1 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 PLC1 and the adaptor molecule Src homology 2 domain–containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.

Key Words: thymus • Itk • Tec • Rac1 • SLP-76

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