title: Mechanism and function of Vav1 localisation in TCR signalling.
abstract: The antigen-specific binding of T cells to antigen presenting cells results in recruitment of signalling 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 T cell antigen receptor (TCR) signalling, 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 signalling 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.
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA,  UK.
authors.forename: Olga
authors.initials: O
authors.lastname: Ksionda
authors.forename: Alexander
authors.initials: A
authors.lastname: Saveliev
authors.forename: Robert
authors.initials: R
authors.lastname: Köchl
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rapley
authors.forename: Mustapha
authors.initials: M
authors.lastname: Faroudi
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Smith-Garvin
authors.forename: Christoph
authors.initials: C
authors.lastname: Wülfing
authors.forename: Katrin
authors.initials: K
authors.lastname: Rittinger
authors.forename: Tom
authors.initials: T
authors.lastname: Carter
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav / Q000737:chemistry / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D018909:src Homology Domains
chemical_list: D050505:Mutant Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D002118:Calcium