A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45
- Author(s): Courtney, AH
- Amacher, JF
- Kadlecek, TA
- Mollenauer, MN
- Au-Yeung, BB
- Kuriyan, J
- Weiss, A
- et al.
Published Web Locationhttps://doi.org/10.1016/j.molcel.2017.06.024
© 2017 Elsevier Inc. 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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