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
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References
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Journal ArticleDOI
Effects of IL-1 receptor-associated kinase (IRAK) expression on IL-1 signaling are independent of its kinase activity.
J. Knop,Michael U. Martin +1 more
TL;DR: It is shown that overexpression of a kinase‐inactive mutant of IRAK (K239S) inhibits neither IL‐1‐stimulated activation of the transcription factor NF‐κB, nor that of the c‐Jun N‐terminal kinase nor IL‐2 production in murine EL‐4 cells, but enhances these effects in a manner comparable to wild type IRAK, suggesting that the intrinsic kinase activity is not required for downstream signaling via IRAK.
Journal ArticleDOI
Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB.
TL;DR: It is demonstrated that recombinant wild-type IRAK (IRAK-WT), but not a kinase-defective mutant with Asp340 replaced by an asparagine residue (I RAK-Asp340Asn), is highly phosphorylated and is capable of auto-phosphorylation in vitro.
Journal ArticleDOI
Interleukin-1-induced activation of a protein kinase co-precipitating with the type I interleukin-1 receptor in T cells.
TL;DR: Results show that a serine/threonine protein kinase directly interacts with the IL‐1RI at the plasma membrane level of T helper cells forming a novel type of IL‐ 1 inducible signaling complex.
Journal ArticleDOI
The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway.
TL;DR: It is shown through confocal immunofluorescence microscopy that Pelle functions to downregulate the signal-dependent relocalization of Tube, and a mechanism operating to modulate the domain or duration of signaling downstream from Tube and Pelle is pointed to.
Journal ArticleDOI
Primitive Toll signalling: bugs, flies, worms and man.
TL;DR: Insight is considered that might be gained from using nematodes to study immune signalling pathways and Toll receptors' dual roles in pathogen recognition and insect embryo patterning.