Sci. Signal., 30 November 2010
Immunology Zap70 as an Adaptor
Science Signaling, AAAS, Washington, DC 20005, USA
Ligation of the T cell receptor (TCR) induces the recruitment, phosphorylation, and activation of the tyrosine kinase Zap70 (tyrosine kinase chain–associated protein kinase of 70 kD). Zap70 subsequently phosphorylates the adaptor proteins Lat and SLP-76, which triggers the assembly of molecular complexes and downstream signaling. To examine the temporal requirement for Zap70 during TCR signaling, Au-Yeung et al. generated mice [Zap70(AS)] expressing a form of Zap70 with an alanine substitution at the gatekeeper residue that confers sensitivity to inhibition by 3-MB-PP1, an analog of the kinase inhibitor PP1. Wild-type kinases are not inhibited by 3-MB-PP1. Signaling events downstream of TCR activation that require Zap70 occurred to a similar extent in Zap70+/– and Zap70(AS) CD4+ T cells stimulated with antibody ligation of CD3 but were reduced in 3-MB-PP1–treated cells from Zap70(AS) mice. Proliferation of Zap70(AS) CD4+ T cells in response to antibodies to CD3 and CD28 was also decreased in a dose-dependent manner by 3-MB-PP1. Furthermore, Zap70 kinase activity was necessary for the function of effector CD4+ and CD8+ T cells and memory CD8+ T cells. However, Treg cells from Zap70(AS) mice suppressed proliferation of Zap70+/– CD4+ CD25– T cells in the presence of 3-MB-PP1, suggesting that this did not require Zap70s kinase activity. Phosphorylation of Zap70 on Tyr319 and Tyr493 in stimulated Zap70(AS) T cells was not affected by treatment with 3-MB-PP1, presumably because these phosphorylation events are catalyzed by Lck. The authors reasoned that catalytically inactive Zap70 could still function as a scaffold in TCR-induced activation of Rap1 and adhesion of the integrin LFA-1 to its ligand, ICAM-1. In TCR-stimulated cells, Zap70(AS) associated with the adaptor protein CrkII, which indirectly activates Rap1 through the guanine nucleotide-exchange factor C3G. In cells from mice expressing a form of Zap70 with alanine mutations at Tyr319 and Tyr493, Rap1 activation and adhesion to ICAM-1 were impaired. Thus, the authors conclude that Zap70 kinase activity is required for various signaling events downstream of TCR activation and for effector and memory T cell function, but not for Treg cell function. Zap70 may also function as a scaffold during integrin-mediated adhesion.
B. B. Au-Yeung, S. E. Levin, C. Zhang, L.-Y. Hsu, D. A. Cheng, N. Killeen, K. M. Shokat, A. Weiss, A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity. Nat. Immunol. 11, 1085–1092 (2010). [PubMed]
Citation: W. Wong, Zap70 as an Adaptor. Sci. Signal. 3, ec363 (2010).
The editors suggest the following Related Resources on Science sites:
In Science Signaling
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882