Journal
MOLECULAR CELL
Volume 67, Issue 3, Pages 498-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.06.024
Keywords
-
Categories
Funding
- Robertson Foundation/Cancer Research Institute fellowship
- Jane Coffin Childs Fund fellowship
- Howard Hughes Medical Institute
- NIH, NIAID [P01 AI091580]
- NIAMS [K01 AR065481]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available