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Ubiquitin-mediated activation of TAK1 and IKK

Oncogene volume 26, pages 3214–3226 (2007)Cite this article

Abstract

Transforming growth factor β activated kinase-1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, has emerged as a key regulator of signal transduction cascades leading to the activation of the transcription factors nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). Stimulation of cells with cytokines and microbial pathogens results in the activation of TAK1, which subsequently activates the I-kappa B kinase complex (IKK) and mitogen-activated protein (MAP) kinases, culminating in the activation of NF-κB and AP-1, respectively. Recent studies have shown that polyubiquitination of signalling proteins through lysine (Lys)-63-linked polyubiquitin chains plays an important role in the activation of TAK1 and IKK. Unlike Lys-48-linked polyubiquitination, which normally targets proteins for degradation by the proteasome, Lys-63-linked polyubiquitin chains act as scaffolds to assemble protein kinase complexes and mediate their activation through proteasome-independent mechanisms. The concept of ubiquitin-mediated activation of protein kinases is supported by the discoveries of ubiquitination and deubiquitination enzymes as well as ubiquitin-binding proteins that function upstream of TAK1 and IKK. Recent biochemical and genetic studies provide further insights into the mechanism and function of ubiquitin signalling and these advances will be the focus of this review.

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Acknowledgements

Research in the Chen laboratory is supported by grants from NIH and the Welch Foundation. ZJC is a Burroughs Wellcome Investigator in Pathogenesis of Infectious Diseases and an Investigator of the Howard Hughes Medical Institute.

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  1. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    A Adhikari, M Xu & Z J Chen

  2. Department of Molecular Biology, Howard Hughes Medical Institute, Dallas, TX, USA

    Z J Chen

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  1. A Adhikari
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  2. M Xu
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Correspondence to Z J Chen.

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Adhikari, A., Xu, M. & Chen, Z. Ubiquitin-mediated activation of TAK1 and IKK. Oncogene 26, 3214–3226 (2007). https://doi.org/10.1038/sj.onc.1210413

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