title: Tyrosine-phosphorylation-dependent translocation of the SLAT protein to the immunological synapse is required for NFAT transcription factor activation.
abstract: SWAP-70-like adaptor of T cells (SLAT) is a guanine nucleotide exchange factor for Rho GTPases that regulates the development of T helper 1 (Th1) and Th2 cell inflammatory responses by controlling the Ca(2+)-NFAT signaling pathway. However, the mechanism used by SLAT to regulate these events is unknown. Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway. Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. Therefore, tyrosine-phosphorylation-mediated relocalization of SLAT to the site of antigen recognition is required for SLAT to exert its pivotal role in NFAT-dependent CD4(+) T cell differentiation.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bécart
authors.forename: Ann J Canonigo
authors.initials: AJ
authors.lastname: Balancio
authors.forename: Céline
authors.initials: C
authors.lastname: Charvet
authors.forename: Sonia
authors.initials: S
authors.lastname: Feau
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Sedwick
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; C473249:Def6 protein, mouse