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Nat Chem Biol. 2012 Mar 18;8(5):437-46. doi: 10.1038/nchembio.916.

LYP inhibits T-cell activation when dissociated from CSK.

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  • 1Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.

Abstract

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here we studied the spatiotemporal dynamics of the LYP-CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it downmodulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T-cell activation when removed from CSK. Our findings may explain the reduced TCR-mediated signaling associated with a single-nucleotide polymorphism that confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a mutant LYP that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity.

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PMID:
22426112
[PubMed - indexed for MEDLINE]
PMCID:
PMC3329573
Free PMC Article
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