An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation

Jiazhen Zhang, Kristopher Clark, Toby Lawrence, Mark W. Peggie, Philip Cohen (Lead / Corresponding author)

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    Abstract

    IKKß {IkB [inhibitor of NF-?B (nuclear factor ?B)] kinase ß} is required to activate the transcription factor NF-?B, but how IKKß itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more 'upstream' protein kinases in some reports, but by autophosphorylation in others. In the present study, we resolve this contro-versy by demonstrating that the activation of IKKß induced by IL-1 (interleukin-1) or TNF (tumour necrosis factor) in embryonic fibroblasts, or by ligands that activate Toll-like receptors in macrophages, requires two distinct phosphorylation events: first, the TAK1 [TGFß (transforming growth factor ß)-activated kinase-1]-catalysed phosphorylation of Ser177 and, secondly, the IKKß-catalysed autophosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKß to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of linear ubiquitin chains and their interaction with the NEMO (NF-?B essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKß at Ser177 and IKKa at Ser176. These findings may be of general significance for the activation of other protein kinases.

    Original languageEnglish
    Pages (from-to)531-537
    Number of pages7
    JournalBiochemical Journal
    Volume461
    Issue number3
    DOIs
    Publication statusPublished - 1 Aug 2014

    Fingerprint

    I-kappa B Kinase
    Phosphorylation
    Transforming Growth Factors
    Phosphotransferases
    Chemical activation
    Ubiquitin
    Interleukin-1
    Protein Kinases
    Macrophages
    Toll-Like Receptors
    Fibroblasts
    Modulators
    Transcription Factors
    Tumor Necrosis Factor-alpha
    Ligands
    Substrates

    Cite this

    Zhang, Jiazhen ; Clark, Kristopher ; Lawrence, Toby ; Peggie, Mark W. ; Cohen, Philip. / An unexpected twist to the activation of IKKβ : TAK1 primes IKKβ for activation by autophosphorylation. In: Biochemical Journal. 2014 ; Vol. 461, No. 3. pp. 531-537.
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    abstract = "IKK{\ss} {IkB [inhibitor of NF-?B (nuclear factor ?B)] kinase {\ss}} is required to activate the transcription factor NF-?B, but how IKK{\ss} itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more 'upstream' protein kinases in some reports, but by autophosphorylation in others. In the present study, we resolve this contro-versy by demonstrating that the activation of IKK{\ss} induced by IL-1 (interleukin-1) or TNF (tumour necrosis factor) in embryonic fibroblasts, or by ligands that activate Toll-like receptors in macrophages, requires two distinct phosphorylation events: first, the TAK1 [TGF{\ss} (transforming growth factor {\ss})-activated kinase-1]-catalysed phosphorylation of Ser177 and, secondly, the IKK{\ss}-catalysed autophosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKK{\ss} to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of linear ubiquitin chains and their interaction with the NEMO (NF-?B essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKK{\ss} at Ser177 and IKKa at Ser176. These findings may be of general significance for the activation of other protein kinases.",
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    An unexpected twist to the activation of IKKβ : TAK1 primes IKKβ for activation by autophosphorylation. / Zhang, Jiazhen; Clark, Kristopher; Lawrence, Toby; Peggie, Mark W.; Cohen, Philip (Lead / Corresponding author).

    In: Biochemical Journal, Vol. 461, No. 3, 01.08.2014, p. 531-537.

    Research output: Contribution to journalArticle

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