Protein ubiquitylation and protein phosphorylation are the two major mechanisms that regulate the functions of proteins in eukaryotic cells. However, these different posttranslational modifications do not operate independently of one another, but are frequently interlinked to enable biological processes to be controlled in a more complex and sophisticated manner. Studying how protein phosphorylation events control the ubiquitin system and how ubiquitylation regulates protein phosphorylation has become a focal point of the study of cell regulation and human disease. Cloning of human TAK1 (TGFβ-activated protein kinase 1) was first described by Kondo et al. (1998). In vivo, TAK1 activation requires its association with TAK1 binding protein 1 (TAB1), which triggers TAK1 autophosphorylation at Thr184 and Thr187 (Sakurai et al., 2000; Shibuya et al., 1996). TAK1 plays a central role in the innate immune system by activating the canonical IKK complex and hence the transcription factor NFκB, as well as several MAP kinase cascades. Its activation in the MyD88 signaling pathway of the innate immune system depends on TRAF6. This E3 ubiquitin ligase generates Lys63-linked polyubiquitin chains that interact with the TAB2 and TAB3 regulatory components of the TAK1 complex. This induces a conformational change that allows TAK1 to activate itself (Wang et al., 2001; Xia et al., 2009).
Hastie CJ, McLauchlan HJ, Cohen P (2006) Assay of protein kinases using radiolabeled ATP: a protocol. Nat Protoc 1, 968-71.
Kondo M, Osada H, Uchida K, Yanagisawa K, Masuda A, Takagi K, Takahashi T (1998) Molecular cloning of human TAK1 and its mutational analysis in human lung cancer. Int J Cancer 75, 559-63.
Sakurai H, Miyoshi H, Mizukami J, Sugita T (2000) Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1. FEBS Lett 474, 141-5.
Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, Matsumoto K (1996) TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 272, 1179-82.
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346-51.
Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ (2009) Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 461, 114-9.
Background kindly written by:
Sir Philip Cohen FRS, FRSE
University of Dundee
Director of the Medical Research Council Protein Phosphorylation Unit (1990-2012)
Director of the Scottish Institute for Cell Signalling incorporating the Protein Ubiquitylation Unit (2008-2012)
Co-Director of the Division of Signal Transduction Therapy (1998-2012)
Deputy Director of the Division of Signal Transduction Therapy (from July 2012)
Professor Cohen's research group is studying the interplay between protein phosphorylation and protein ubiquitylation in the regulation of innate immunity.