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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Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction
Satoshi Uematsu,Shintaro Sato,Masahiro Yamamoto,Tomonori Hirotani,Hiroki Kato,Fumihiko Takeshita,Michiyuki Matsuda,Cevayir Coban,Ken Ishii,Taro Kawai,Osamu Takeuchi,Shizuo Akira +11 more
TL;DR: Results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-α induction in pDCs, and IL-1 receptor-associated kinase (IRAK)-1 was necessary for transcriptional activation of IRF7.
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TLR-signaling Networks An Integration of Adaptor Molecules, Kinases, and Cross-talk
TL;DR: The ability of TLRs to engage different intracellular signaling molecules and cross-talk with other regulatory pathways is an important factor in shaping the type, magnitude, and duration of the inflammatory response as discussed by the authors.
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Linking oxidative stress to inflammation: Toll-like receptors
TL;DR: The role of TLRs in various experimental models of oxidative stress such as HS and I/R is examined, and potential mechanisms by which reactive oxygen species from NADPH oxidase can signal the commencement of inflammatory pathways through TLRs are explored.
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TIR-containing Adapter Molecule (TICAM)-2, a Bridging Adapter Recruiting to Toll-like Receptor 4 TICAM-1 That Induces Interferon-β
TL;DR: In LPS signaling TLR4 recruits two types of adapters to its cytoplasmic domain that are indirectly connected to two effective adapters, MyD88 and TICAM-1, respectively, which results in the construction of MyD 88-dependent and -independent pathways separately downstream of the two distinct adapters.
Journal ArticleDOI
Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2.
Tatsukata Kawagoe,Shintaro Sato,Kazufumi Matsushita,Hiroki Kato,Kosuke Matsui,Yutaro Kumagai,Tatsuya Saitoh,Taro Kawai,Osamu Takeuchi,Shizuo Akira +9 more
TL;DR: It is shown that IRAK2 was essential for sustaining TLR-induced expression of genes encoding cytokines and activation of the transcription factor NF-κB, despite the fact that IRAk2 was dispensable foractivation of the initial signaling cascades.
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