Jonathan Rapley

Publications (3)20.97 Total impact

• Article: Mechanism and function of Vav1 localization in TCR signaling.

  Olga Ksionda, Alexander Saveliev, Robert Köchl, Jonathan Rapley, Mustapha Faroudi, Jennifer E Smith-Garvin, Christoph Wülfing, Katrin Rittinger, Tom Carter, Victor L J Tybulewicz
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  ABSTRACT: The antigen-specific binding of T cells to antigen presenting cells results in recruitment of signaling proteins to microclusters at the cell-cell interface known as the immunological synapse (IS). The Vav1 guanine nucleotide exchange factor plays a critical role in TCR signaling, leading to the activation of multiple pathways. We now show that it is recruited to microclusters and to the IS in primary CD4(+) and CD8(+) T cells. Furthermore we show that this recruitment depends on the SH2 and C-terminal SH3 (SH3(B)) domains of Vav1, and on phosphotyrosines 112 and 128 of the SLP76 adaptor protein. Biophysical measurements show that Vav1 binds directly to these residues on SLP76 and that efficient binding depends on the SH2 and SH3(B) domains of Vav1. Finally, we show that the same two domains are critical for the phosphorylation of Vav1 and its signaling function in TCR-induced calcium flux. We propose that Vav1 is recruited to the IS by binding to SLP76 and that this interaction is critical for the transduction of signals leading to calcium flux.
  Journal of Cell Science 09/2012; · 6.11 Impact Factor
• Article: Function of the nucleotide exchange activity of vav1 in T cell development and activation.

  Alexander Saveliev, Lesley Vanes, Olga Ksionda, Jonathan Rapley, Stephen J Smerdon, Katrin Rittinger, Victor L J Tybulewicz
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  ABSTRACT: The guanine nucleotide exchange factor (GEF) Vav1 is essential for transducing T cell antigen receptor (TCR) signals and therefore plays a critical role in the development and activation of T cells. It has been presumed that the GEF activity of Vav1 is important for its function; however, there has been no direct demonstration of this. Here, we generated mice expressing enzymatically inactive, but normally folded, Vav1 protein. Analysis of these mice showed that the GEF activity of Vav1 was necessary for the selection of thymocytes and for the optimal activation of T cells, including signal transduction to Rac1, Akt, and integrins. In contrast, the GEF activity of Vav1 was not required for TCR-induced calcium flux, activation of extracellular signal-regulated kinase and protein kinase D1, and cell polarization. Thus, in T cells, the GEF activity of Vav1 is essential for some, but not all, of its functions.
  Science Signaling 01/2009; 2(101):ra83. · 7.50 Impact Factor
• Source

  Available from: Katrin Rittinger

  Article: Crucial structural role for the PH and C1 domains of the Vav1 exchange factor.

  Jonathan Rapley, Victor L J Tybulewicz, Katrin Rittinger
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  ABSTRACT: The Vav family of proteins are guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases, which regulate various cellular functions, including T-cell activation. They contain a catalytic Dbl homology (DH) domain that is invariably followed by a pleckstrin homology (PH) domain, which is often required for catalytic activity. Vav proteins are the first GEFs for which an additional C1 domain is required for full biological activity. Here, we present the structure of a Vav1 fragment comprising the DH-PH-C1 domains bound to Rac1. This structure shows that the PH and C1 domains form a single structural unit that packs against the carboxy-terminal helix of the DH domain to stabilize its conformation and to promote nucleotide exchange. In contrast to previous reports, this structure shows that there are no direct contacts between the GTPase and C1 domain but instead suggests new mechanisms for the regulation of Vav1 activity.
  EMBO Reports 08/2008; 9(7):655-61. · 7.36 Impact Factor