Journal
NATURE CHEMICAL BIOLOGY
Volume 8, Issue 5, Pages 437-446Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.916
Keywords
-
Categories
Funding
- Exploratory Pharmacology Core at Sanford-Burnham Medical Research Institute
- US National Institutes of Health [1R21CA132121]
- Norwegian Cancer Society
- American Cancer Society [RSG-08-067-01-LIB]
- Oxnard Foundation
- Belgian Research National Scientific Fund
- Liege University
Ask authors/readers for more resources
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.
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