An investigation of the activation of protein kinase complexes in the MyD88 signalling network
type: CreativeWork
description: The TAK1 and canonical IKK complexes are the two master protein kinases of the innate immune system that control the production of inflammatory mediators, but the mechanisms by which they are activated in this system are still unclear. In this thesis, I present the research I have carried out to solve these problems. The IKKb component of the canonical IKK complex is required to activate the transcription factors NF-kB and IRF5 and the protein kinase Tpl2, 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 first part of this thesis, I describe my work that has resolved this controversy by demonstrating that the activation of IKK 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 catalysed phosphorylation of Ser177 and, secondly, the IKKb-catalysed autophosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKk to phosphorylate exogenous substrates. I also present genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of Met1-linked/linear ubiquitin (Met1-Ub) chains and their interaction with the NEMO (NF-kB essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKb at Ser177 and IKKa at Ser176. These findings may be of general significance for the activation of other protein kinases. The activation of the TAK1 complex by inflammatory stimuli is thought to be triggered by the binding of Lys63-linked ubiquitin chains to the TAB2 or TAB3 components of the TAB1-TAK1-TAB2 and TAB1-TAK1-TAB3 complexes. In the second part of the th…
abstract: The TAK1 and canonical IKK complexes are the two master protein kinases of the innate immune system that control the production of inflammatory mediators, but the mechanisms by which they are activated in this system are still unclear. In this thesis, I present the research I have carried out to solve these problems. The IKKb component of the canonical IKK complex is required to activate the transcription factors NF-kB and IRF5 and the protein kinase Tpl2, 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 first part of this thesis, I describe my work that has resolved this controversy by demonstrating that the activation of IKK 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 catalysed phosphorylation of Ser177 and, secondly, the IKKb-catalysed autophosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKk to phosphorylate exogenous substrates. I also present genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of Met1-linked/linear ubiquitin (Met1-Ub) chains and their interaction with the NEMO (NF-kB essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKb at Ser177 and IKKa at Ser176. These findings may be of general significance for the activation of other protein kinases. The activation of the TAK1 complex by inflammatory stimuli is thought to be triggered by the binding of Lys63-linked ubiquitin chains to the TAB2 or TAB3 components of the TAB1-TAK1-TAB2 and TAB1-TAK1-TAB3 complexes. In the second part of the th…
author: Zhang, Jiazhen
language: eng
keywords: TAK1, Canonical IKK complex, MyD88, Kinase
date published: 2017
date modified: 2026-07-24T02:08:26Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee