Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
Tomohisa KatoYoshitaka Ono

Abstract

Inhibitor of NF-kappaB (IkappaB) kinase (IKK) and c-Jun NH(2)-terminal kinase (JNK) are stress inducible kinases that critically regulate numerous physiological and pathological processes. Transient activation of the downstream transcription factors NF-kappaB and AP-1, allows for stress inducible, inflammatory and innate immune gene expression programs. However, elevated chronic activity is associated with cancer and chronic inflammatory disease. Despite its relevance to human health, little is known about the molecular mechanisms that control constitutive activity of IKK and JNK. Here, we demonstrate that the serine/threonine kinase PKN1 plays a critical role in regulating constitutive IKK/JNK activity in unstimulated cells and report on the molecular mechanism. We identify TRAF1 as a substrate of PKN1 kinase activity in vitro and in vivo, and show that this phosphorylation event is required for attenuating downstream kinase activities. Furthermore, this silencing was dependent on TNFR2. Mutagenesis of the phospho-acceptor residue in TRAF1 abrogated PKN1-dependent recruitment to TNFR2. Our results suggest a model by which the stoichiometric ratio of TRAF1 and TRAF2 heteromeric complexes associated with TNFR2 control the tonic ...Continue Reading

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Citations

Sep 4, 2013·Rheumatology International·Katrine Brække NorheimRoald Omdal
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Apr 5, 2020·International Journal of Molecular Sciences·Constanze BuhrmannMehdi Shakibaei
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Jan 22, 2021·PLoS Pathogens·Hannah E HanfordYousef Abu Kwaik
Mar 26, 2021·Journal of Molecular Neuroscience : MN·Soudeh Ghafouri-FardMohammad Taheri

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