The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway

J Ninomiya-Tsuji; K Kishimoto; A Hiyama; J Inoue; Z Cao; K Matsumoto

doi:10.1038/18465

The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway

Nature. 1999 Mar 18;398(6724):252-6. doi: 10.1038/18465.

Authors

J Ninomiya-Tsuji¹, K Kishimoto, A Hiyama, J Inoue, Z Cao, K Matsumoto

Affiliation

¹ Department of Molecular Biology, Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation.

PMID: 10094049
DOI: 10.1038/18465

Abstract

Interleukin-1 (IL-1) is a proinflammatory cytokine that has several effects in the inflammation process. When it binds to its cell-surface receptor, IL-1 initiates a signalling cascade that leads to activation of the transcription factor NF-kappaB and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-kappaB-inducing kinase (NIK) and I kappaB kinases (IKKs). However, the molecular mechanism by which NIK is activated is not understood. Here we show that the MAPKK kinase TAK1 acts upstream of NIK in the IL-1-activated signalling pathway and that TAK1 associates with TRAF6 during IL-1 signalling. Stimulation of TAK1 causes activation of NF-kappaB, which is blocked by dominant-negative mutants of NIK, and an inactive TAK1 mutant prevents activation of NF-kappaB that is mediated by IL-1 but not by NIK. Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
Cell Line
Enzyme Activation
I-kappa B Kinase
Interleukin-1 / metabolism*
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinases*
Mitogen-Activated Protein Kinases*
Multienzyme Complexes / metabolism
Mutagenesis
NF-kappa B / metabolism
NF-kappaB-Inducing Kinase
Phosphorylation
Precipitin Tests
Protein Serine-Threonine Kinases / metabolism*
Proteins / metabolism
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Serine / metabolism
Signal Transduction*
TNF Receptor-Associated Factor 6
Threonine / metabolism
Transfection

Substances

Interleukin-1
Multienzyme Complexes
NF-kappa B
Proteins
Recombinant Fusion Proteins
TNF Receptor-Associated Factor 6
Threonine
Serine
Protein Serine-Threonine Kinases
I-kappa B Kinase
Calcium-Calmodulin-Dependent Protein Kinases
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7