Role of Tec kinase in nuclear factor of activated T cells signaling.
The Tec protein kinase family includes Btk, Itk, Tec, Rlk and Bmx, which are critically involved in signals mediated by various cytokines and antigen receptors. Btk mutations cause severe immunodeficiencies, with defective B cell function. In T cells, Tec regulates cytokine production. However, the downstream targets of these Tec kinases are poorly defined. Here we report that overexpression of Tec in T cells can regulate gene transcription through the nuclear factor of activated T cells (NF-AT). Using different reporter gene constructs, we establish that Tec in transfected T cells dramatically induced NF-AT-dependent gene transcription, which was prevented by a dominant-negative mutant of NF-AT or by the immunosuppressive drug cyclosporin A. Tec appears to regulate NF-AT nuclear import. In addition, Tec influences cytoplasmic free calcium increase. Taken together, our results identify NF-AT as a major downstream target of Tec kinases that is critically involved in transcriptional gene regulation. These observations highlight signaling pathways regulated by Tec kinases and provide new pharmacological targets to regulate immune functions.
Yang
W C
WC
INSERM U119, Institut d'Immunologie et de Cancérologie de Marseille, Université de la Méditerranée, 27 Bd Leï Roure, 13009 Marseille, France.
Ghiotto
M
M
Castellano
R
R
Collette
Y
Y
Auphan
N
N
Nunès
J A
JA
Olive
D
D
D001692:Biological Transport / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008407:Mast Cells; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases