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Public Library of Science, PLoS ONE, 10(8), p. e75200, 2013

DOI: 10.1371/journal.pone.0075200

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The Discovery of a Reciprocal Relationship between Tyrosine-Kinase Signaling and Cullin Neddylation

Journal article published in 2013 by Samantha F. Friend, Lisa K. Peterson, Eric Treacy, Adrianne L. Stefanski, Tomasz Sosinowski, Nathan D. Pennock ORCID, Allison J. Berger, Virginia D. Winn, Leonard L. Dragone
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.