TAK1 is a ubiquitin-dependent kinase of MKK and IKK

Chen Wang, Li Deng, Mei Hong, Giridhar R. Akkaraju, Jun Ichiro Inoue, Zhijian J. Chen

Research output: Contribution to journalArticle

1412 Citations (Scopus)

Abstract

TRAF6 is a signal transducer that activates IκB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS)1-4. IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and INK.

Original languageEnglish (US)
Pages (from-to)346-351
Number of pages6
JournalNature
Volume412
Issue number6844
DOIs
StatePublished - Jul 19 2001

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TNF Receptor-Associated Factor 6
Ubiquitin
Phosphotransferases
MAP Kinase Kinase 4
Polyubiquitin
Ubiquitin-Conjugating Enzymes
MAP Kinase Signaling System
Ubiquitination
Proteasome Endopeptidase Complex
Transducers
Interleukin-1
Protein Kinases
Lipopolysaccharides

ASJC Scopus subject areas

  • General

Cite this

Wang, C., Deng, L., Hong, M., Akkaraju, G. R., Inoue, J. I., & Chen, Z. J. (2001). TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature, 412(6844), 346-351. https://doi.org/10.1038/35085597

TAK1 is a ubiquitin-dependent kinase of MKK and IKK. / Wang, Chen; Deng, Li; Hong, Mei; Akkaraju, Giridhar R.; Inoue, Jun Ichiro; Chen, Zhijian J.

In: Nature, Vol. 412, No. 6844, 19.07.2001, p. 346-351.

Research output: Contribution to journalArticle

Wang, C, Deng, L, Hong, M, Akkaraju, GR, Inoue, JI & Chen, ZJ 2001, 'TAK1 is a ubiquitin-dependent kinase of MKK and IKK', Nature, vol. 412, no. 6844, pp. 346-351. https://doi.org/10.1038/35085597
Wang C, Deng L, Hong M, Akkaraju GR, Inoue JI, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346-351. https://doi.org/10.1038/35085597
Wang, Chen ; Deng, Li ; Hong, Mei ; Akkaraju, Giridhar R. ; Inoue, Jun Ichiro ; Chen, Zhijian J. / TAK1 is a ubiquitin-dependent kinase of MKK and IKK. In: Nature. 2001 ; Vol. 412, No. 6844. pp. 346-351.
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