TCR 信号的强度和持续时间受到 ZAP-70 的 p38 磷酸化和信号osome 的不稳定性的限制。
Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP-70 and destabilization of the signalosome.
机构信息
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
出版信息
Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2174-2179. doi: 10.1073/pnas.1713301115. Epub 2018 Feb 12.
Abstract
ZAP-70 is a tyrosine kinase that is essential for initiation of T cell antigen receptor (TCR) signaling. We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. Mutant T cells expressing ZAP-70 with an alanine substitution at this residue (ZAP-70) had enhanced TCR proximal signaling and increased effector responses. Lack of ZAP-70 phosphorylation increased association of ZAP-70 with the TCR and prolonged the existence of TCR signaling microclusters. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.
摘要
ZAP-70 是一种酪氨酸激酶，对于 T 细胞抗原受体（TCR）信号的起始至关重要。我们发现，T 细胞 p38 MAP 激酶（MAPK）可被 TCR 下游的 ZAP-70 直接磷酸化和激活，进而磷酸化 ZAP-70 结构域 B 区的 Thr-293。在该残基处表达 ZAP-70 具有丙氨酸取代的突变 T 细胞（ZAP-70）具有增强的 TCR 近端信号和增加的效应器反应。缺乏 ZAP-70 磷酸化增加了 ZAP-70 与 TCR 的结合，并延长了 TCR 信号微簇的存在时间。这些结果表明，在这个紧密的负反馈回路中，ZAP-70 激活的 p38 相互磷酸化 ZAP-70，并使信号复合物不稳定。
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Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2174-2179. doi: 10.1073/pnas.1713301115. Epub 2018 Feb 12.
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