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

Autor:	Courtney AH; 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., Amacher JF; Departments of Molecular and Cell Biology and Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA., Kadlecek TA; The Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 04143, USA., Mollenauer MN; The Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 04143, USA., Au-Yeung BB; 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., Kuriyan J; 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., Weiss A; 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.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2017 Aug 03; Vol. 67 (3), pp. 498-511.e6. Date of Electronic Publication: 2017 Jul 20.
DOI:	10.1016/j.molcel.2017.06.024
Abstrakt:	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. (Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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