title: 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.
authors.affiliation: 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.
authors.forename: Samantha F
authors.initials: SF
authors.lastname: Friend
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Peterson
authors.forename: Eric
authors.initials: E
authors.lastname: Treacy
authors.forename: Adrianne L
authors.initials: AL
authors.lastname: Stefanski
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sosinowski
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Pennock
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Berger
authors.forename: Virginia D
authors.initials: VD
authors.lastname: Winn
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Dragone
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015151:Immunoblotting; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D044842:Cullin Proteins; D007376:Interleukin-2; D011505:Protein-Tyrosine Kinases