Courtney Adam H, Amacher Jeanine F, Kadlecek Theresa A, Mollenauer Marianne N, Au-Yeung Byron B, Kuriyan John, Weiss Arthur
Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Departments of Molecular and Cell Biology and Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
Mol Cell. 2017 Aug 3;67(3):498-511.e6. doi: 10.1016/j.molcel.2017.06.024. Epub 2017 Jul 20.
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 that 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 that responds to signaling events that tune active Lck amounts and TCR sensitivity.
Src家族激酶Lck为T细胞激活设定了一个关键阈值，因为它能使TCR复合物和Zap70激酶磷酸化。T细胞如何控制活性Lck分子的丰度仍知之甚少。我们发现Lck的SH2结构域内的一个磷酸化位点Y192具有一个未被重视的作用，它深刻影响细胞中活性Lck的数量。值得注意的是，Y192的突变会阻断关键的TCR近端信号事件，并损害转基因小鼠的胸腺细胞发育。我们确定这些缺陷是由Lck抑制性C末端尾巴的过度磷酸化引起的。我们的研究结果表明，Y192的修饰会抑制CD45在细胞中与Lck结合并使Lck的C末端尾巴去磷酸化的能力，从而阻止其采用活性开放构象。这些结果提示了一个负反馈回路，该回路对调节活性Lck数量和TCR敏感性的信号事件作出反应。
