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Mol Cell. 2017 Aug 3;67(3):498-511.e6. doi: 10.1016/j.molcel.2017.06.024. Epub 2017 Jul 20.

A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45.

Author information

1
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.
2
Departments of Molecular and Cell Biology and Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
3
The Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 04143, USA.
4
Departments of Molecular and Cell Biology and Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; The Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
5
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; The Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 04143, USA. Electronic address: aweiss@medicine.ucsf.edu.

Abstract

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.

KEYWORDS:

CD45; Lck; SH2 domain; Src family kinase; T cell antigen receptor; T cell signaling; TCR; kinase; phosphatase; phosphorylation

PMID:
28735895
PMCID:
PMC5558854
DOI:
10.1016/j.molcel.2017.06.024
[Indexed for MEDLINE]
Free PMC Article

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