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PLoS One. 2013 Oct 4;8(10):e75200. doi: 10.1371/journal.pone.0075200. eCollection 2013.

The discovery of a reciprocal relationship between tyrosine-kinase signaling and cullin neddylation.

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1
Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, United States of America ; Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, Colorado, United States of America.

Abstract

While neddylation is known to activate cullin (CUL)-RING ubiquitin ligases (CRLs), its role in regulating T cell signaling is poorly understood. Using the investigational NEDD8 activating enzyme (NAE) inhibitor, MLN4924, we found that neddylation negatively regulates T cell receptor (TCR) signaling, as its inhibition increases IL-2 production, T cell proliferation and Treg development in vitro. We also discovered that loss of CUL neddylation occurs upon TCR signaling, and CRLs negatively regulate IL-2 production. Additionally, we found that tyrosine kinase signaling leads to CUL deneddylation in multiple cell types. These studies indicate that CUL neddylation is a global regulatory mechanism for tyrosine kinase signaling.

PMID:
24124476
PMCID:
PMC3790728
DOI:
10.1371/journal.pone.0075200
[Indexed for MEDLINE]
Free PMC Article
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