IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase
TLDR
IRAK-4 is the closest human homolog to Pelle and depends on its kinase activity to activate NF-κB, suggesting a role of IRAK- 4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAk-1.Abstract:
Toll/IL-1 receptor family members are central components of host defense mechanisms in a variety of species. One well conserved element in their signal transduction is Ser/Thr kinases, which couple early signaling events in a receptor complex at the plasma membrane to larger signalosomes in the cytosol. The fruit fly Drosophila melanogaster has one member of this family of kinases, termed Pelle. The complexity of this pathway is vastly increased in vertebrates, and several Pelle homologs have been described and termed IL-1 receptor-associated kinase (IRAK). Here we report the identification of a novel and distinct member of the IRAK family, IRAK-4. IRAK-4 is the closest human homolog to Pelle. Endogenous IRAK-4 interacts with IRAK-1 and TRAF6 in an IL-1-dependent manner, and overexpression of IRAK-4 can activate NF-κB as well as mitogen-activated protein (MAP) kinase pathways. Most strikingly, and in contrast to the other IRAKs, IRAK-4 depends on its kinase activity to activate NF-κB. In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.read more
Citations
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Journal ArticleDOI
IL-1 Receptor-Associated Kinase 4 Is Essential for IL-18-Mediated NK and Th1 Cell Responses
Nobutaka Suzuki,Nien Jung Chen,Douglas G. Millar,Shinobu Suzuki,Thomas Horacek,Hiromitsu Hara,Denis Bouchard,Kenji Nakanishi,Josef M. Penninger,Pamela S. Ohashi,Wen Chen Yeh +10 more
TL;DR: It is shown that IL-18-induced responses such as NK cell activity, Th1 IFN-γ production, and Th1 cell proliferation are severely impaired in IRAK-4-deficient mice and this results suggest that IRAk-4 is an essential component of the IL- 18 signaling cascade.
Journal ArticleDOI
Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly
Julie George,Precious G. Motshwene,Hui Wang,Andriy V. Kubarenko,Anna Rautanen,Tara C. Mills,Adrian V. S. Hill,Alexander N.R. Weber +7 more
TL;DR: The functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system are analyzed and it is shown that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD 88 TIR and IRAk4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure.
Journal ArticleDOI
Toll-like receptors signaling: A complex network for NF-κB activation in B-cell lymphoid malignancies
TL;DR: The literature on TLR expression and functionality and its impact on NF-κB activation in different B cell malignancies including chronic lymphocytic leukemia where TLR9 induces activation, cell proliferation and chemoresistance in a proportion of patients while apoptosis can be induced in others.
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The kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells.
Kyung Song,Francisco Xavier Talamas,Rebecca Suttmann,Pam S. Olson,Jim W. Barnett,Simon W. Lee,Kelly D. Thompson,Sue Jin,Mohammad Hekmat-Nejad,Terrence Z. Cai,Anthony M. Manning,Ronald J. Hill,Brian Wong +12 more
TL;DR: In human cells the non-kinase functions of IRAK-4 are essential, whereas the kinase activity of IRAB-4 appears redundant with that of IRAk-1, and pharmacologic inhibition of both kinases appears necessary to block pro-inflammatory cytokine production.
Journal Article
The cytokine network in acute myeloid leukemia (AML)
TL;DR: Current knowledge about the functions of pro- and anti-inflammatory cytokines in AML, their modes of action, and therapeutic interventions with potential to improve clinical outcomes for AML patients are summarized.
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