Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation.
Activation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCgamma-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCgamma-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.
Martelli
M P
MP
Laboratory of Lymphocyte Biology, National Heart, Lung, and Blood Institute, Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Lin
H
H
Zhang
W
W
Samelson
L E
LE
Bierer
B E
BE
D048868:Adaptor Proteins, Signal Transducing; D018801:CD2 Antigens / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D004792:Enzyme Precursors / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D015533:Transcriptional Activation; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D018801:CD2 Antigens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; C110810:LAT protein, human; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D020928:Mitogen-Activated Protein Kinases