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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.
Abstract

© 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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