Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1.
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 activity of JNK and IKK. TRAF1 phosphorylation by the ubiquitously expressed kinase PKN1 thereby plays a critical role in the negative regulation of tonic activity of the two central inflammatory signaling pathways.
Kato
Tomohisa
T
Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan. tkato@kuhp.kyoto-u.ac.jp
Gotoh
Yusuke
Y
Hoffmann
Alexander
A
Ono
Yoshitaka
Y
D002460:Cell Line; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D047889:Receptors, Tumor Necrosis Factor, Type II; D047990:TNF Receptor-Associated Factor 1; C061570:protein kinase N; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D048670:MAP Kinase Kinase 4