A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45.
A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45.
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DOI：
10.1016/j.molcel.2017.06.024
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发表时间：
2017-08-03
期刊：
影响因子：
16
通讯作者：
Weiss A
中科院分区：
文献类型：
--
作者：
Courtney AH;Amacher JF;Kadlecek TA;Mollenauer MN;Au-Yeung BB;Kuriyan J;Weiss A
Src家族激酶Lck为T细胞活化设定关键阈值，因为它使TCR复合物和Zap 70激酶磷酸化。T细胞如何控制活性Lck分子的丰度仍然知之甚少。我们已经确定了一个不受重视的作用，磷酸化，Y192，在Lck SH 2结构域，这深刻地影响了细胞中的活性Lck的量。值得注意的是，Y192的突变阻断了关键的TCR近端信号传导事件，并损害了逆转录小鼠中的胸腺细胞发育。我们确定这些缺陷是由Lck的抑制性C-末端尾部的过度磷酸化引起的。我们的研究结果表明，Y192的修饰抑制了CD 45在细胞中与Lck结合的能力，并使Lck的C末端尾部去磷酸化，这阻止了其采用活性开放构象。这些结果表明负反馈回路，其响应于调节活性Lck量和TCR敏感性的信号传导事件。尽管Lck启动TCR信号传导的关键要求，但T细胞如何控制活性Lck分子的丰度仍然知之甚少。Courtney等报道了Lck磷酸化位点Y192在修饰时可以通过阻止磷酸酶CD 45激活Lck来负调节TCR信号传导。
The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain which profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck. Our findings reveal that modification of Y192 inhibits the ability of CD45 to associate with Lck in cells and dephosphorylate the C-terminal tail of Lck which prevents its adoption of an active open conformation. These results suggest a negative feedback loop which responds to signaling events that tune active Lck amounts and TCR sensitivity. Despite a critical requirement for Lck to initiate TCR signaling, how a T cell controls the abundance of active Lck molecules remains poorly understood. Courtney et al. report that a Lck phosphosite, Y192, when modified, can negatively regulate TCR signaling by preventing the phosphatase CD45 from activating Lck.
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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DOI：
10.4049/jimmunol.1600178
发表时间：
2016-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Moogk D;Zhong S;Yu Z;Liadi I;Rittase W;Fang V;Dougherty J;Perez-Garcia A;Osman I;Zhu C;Varadarajan N;Restifo NP;Frey AB;Krogsgaard M
通讯作者：
Krogsgaard M