生物
ZAP70型
细胞生物学
T细胞受体
高磷酸化
原癌基因酪氨酸蛋白激酶Src
磷酸化
激酶
信号转导
蛋白激酶结构域
CD28
SH2域
T细胞
生物化学
免疫学
基因
免疫系统
突变体
作者
Adam H. Courtney,J.F. Amacher,Theresa A. Kadlecek,Marianne Mollenauer,Byron B Au-Yeung,John Kuriyan,Arthur Weiss
出处
期刊:Molecular Cell
[Elsevier]
日期:2017-08-01
卷期号:67 (3): 498-511.e6
被引量:51
标识
DOI:10.1016/j.molcel.2017.06.024
摘要
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.
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