Sci. STKE, 24 April 2007
Kinases Giving ITK the SLP
John F. Foley
Sciences STKE, AAAS, Washington, DC 20005, USA
Tyrosine phosphorylation and activation of phospholipase C- (PLC-) after stimulation of the T cell antigen receptor (TCR) is dependent on the activities of the tyrosine kinases Lck, ZAP-70 ( chain-associated protein kinase of 70 kD), and ITK (IL-2-inducible T cell kinase). Other important components are adaptor molecules, such as SLP-76 (SH2-domain-containing leukocyte protein of 76 kD), which couple Syk family kinases, such as ZAP-70, to PLC- activation. Two tyrosine residues important for TCR-mediated phosphorylation and activation of PLC-1 are Y783 and Y775. Although previous studies suggest that ZAP-70 and ITK act together to activate PLC-1, it is not known which is responsible for phosphorylating the critical tyrosines. Bogin et al. performed studies in a SLP-76-deficient T cell line called J14 (derived from the human CD4+ T cell line, Jurkat) to answer this question. In vitro kinase assays with ITK, but not ZAP-70, immunoprecipitated from TCR-stimulated J14 cells (transfected with a tagged form of SLP-76) resulted in the phosphorylation of both Y783 and Y775 in a recombinant form of PLC-1, whereas both kinases could phosphorylate SLP-76. The ability of ITK to phosphorylate PLC-1 was dependent on SLP-76. Studies with mutants of SLP-76 found that ITK phosphorylation of recombinant PLC-1 was dependent on the presence of tyrosines in the N-terminal region of SLP-76. Coimmunoprecipitation studies revealed that stimulation of the TCR resulted in the association of SLP-76 with ITK in J14 cells. Immunoprecipitated ITK in complex with SLP-76 was catalytically more active than uncomplexed ITK. These data suggest that SLP-76 is necessary to initiate and maintain the activity of ITK.
Y. Bogin, C. Ainey, D. Beach, D. Yablonski, SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK. Proc. Natl. Acad. Sci. U.S.A. 104, 6638-6643 (2007). [Abstract] [Full Text]
Citation: J. F. Foley, Giving ITK the SLP. Sci. STKE 2007, tw145 (2007).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882