Tyrosine-phosphorylation-dependent translocation of the SLAT protein to the immunological synapse is required for NFAT transcription factor activation.
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.
Bécart
Stéphane
S
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Balancio
Ann J Canonigo
AJ
Charvet
Céline
C
Feau
Sonia
S
Sedwick
Caitlin E
CE
Altman
Amnon
A
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
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