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

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.

SUBMITTER: Friend SF

PROVIDER: S-EPMC3790728 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Friend Samantha F SF Peterson Lisa K LK Treacy Eric E Stefanski Adrianne L AL Sosinowski Tomasz T Pennock Nathan D ND Berger Allison J AJ Winn Virginia D VD Dragone Leonard L LL

PloS one 20131004 10

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 regulat ...[more]

PMID: 24124476

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