PLoS ONE (Jan 2013)

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

  • Samantha F Friend,
  • Lisa K Peterson,
  • Eric Treacy,
  • Adrianne L Stefanski,
  • Tomasz Sosinowski,
  • Nathan D Pennock,
  • Allison J Berger,
  • Virginia D Winn,
  • Leonard L Dragone

DOI
https://doi.org/10.1371/journal.pone.0075200
Journal volume & issue
Vol. 8, no. 10
p. e75200

Abstract

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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.