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Negative regulation of constitutive NF‐κB and JNK signaling by PKN1‐mediated phosphorylation of TRAF1
Author(s) -
Kato Jr Tomohisa,
Gotoh Yusuke,
Hoffmann Alexander,
Ono Yoshitaka
Publication year - 2008
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2008.01182.x
Subject(s) - kinase , iκb kinase , phosphorylation , biology , microbiology and biotechnology , map kinase kinase kinase , innate immune system , protein kinase a , signal transduction , cancer research , nf κb , immunology , immune system
Inhibitor of NF‐κB (IκB) 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‐κB 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.