title: An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation.
abstract: IKKβ {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase β} is required to activate the transcription factor NF-κB, but how IKKβ 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 IKKβ 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 [TGFβ (transforming growth factor β)-activated kinase-1]-catalysed phosphorylation of Ser¹⁷⁷ and, secondly, the IKKβ-catalysed autophosphorylation of Ser¹⁸¹. The phosphorylation of Ser¹⁷⁷ by TAK1 is a priming event required for the subsequent autophosphorylation of Ser¹⁸¹, which enables IKKβ 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-κB essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKβ at Ser¹⁷⁷ and IKKα at Ser¹⁷⁶. These findings may be of general significance for the activation of other protein kinases.
authors.affiliation: *MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Jiazhen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: *MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Clark
authors.affiliation: †Centre d'Immunologie de Marseille-Luminy, Parc Scientifique & Technologique de Luminy, Case 906, 13288 Marseille cedex 09, France.
authors.forename: Toby
authors.initials: T
authors.lastname: Lawrence
authors.affiliation: *MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Peggie
authors.affiliation: *MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D012694:Serine; D000099151:MAP Kinase Kinase Kinase 7; C514981:NEMO protein, mouse; C496560:IKBKB protein, human; C496562:Ikbkb protein, mouse