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
More filters
Journal ArticleDOI
Molecular networks that regulate cancer metastasis.
TL;DR: This work addresses several genetic events and critical factors that define the metastatic phenotype acquired during tumorigenesis that provide the basis for the development of new aspects in the treatment of metastatic cancers, which involves inhibition of these proteins and their molecular networks.
Journal ArticleDOI
LPS-induced upregulation of SHIP is essential for endotoxin tolerance
TL;DR: It is demonstrated herein that SHIP(-/-) bone marrow-derived macrophages and mast cells do not display endotoxin tolerance, and an initial LPS treatment of wild-type BMmphis or BMMCs increases the level of SHIP, but not SHIP2 or PTEN, and this increase is critical for the hyporesponsiveness to subsequent LPS stimulation.
Journal ArticleDOI
Molecular basis of Pto-mediated resistance to bacterial speck disease in tomato.
TL;DR: Future work on this model system will focus on how the interaction of the Pto kinase with bacterial effector proteins activates signal transduction, defining the specific role of signaling components, and ultimately, determining which host defense responses are most responsible for inhibiting growth of the pathogen and suppressing symptoms of bacterial speck disease.
Journal ArticleDOI
Toll-like receptors: Activation, signalling and transcriptional modulation.
TL;DR: An overview of TLR activation and their downstream signalling cascades is provided, and some of the recent findings concerning the assembly of a TLR oligomeric signalling platform, known as the Myddosome are discussed.
Journal ArticleDOI
The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules
Hao Wu,Hao Wu,Monika Fuxreiter +2 more
TL;DR: It is proposed that the synergy between folded domains, linear motifs, and intrinsically disordered regions regulates the formation and intrinsic fuzziness of all higher-order assemblies, creating a structural and dynamic continuum.
References
More filters
Journal ArticleDOI
Biologic basis for interleukin-1 in disease
TL;DR: This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references, which summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.
Journal ArticleDOI
TRAF6 is a signal transducer for interleukin-1
TL;DR: The identification of a new TRAF family member is reported, designated TRAF6, which indicates that TRAF proteins may function as signal transducers for distinct receptor families and that TRAf6 participates in IL-1 signalling.
Journal ArticleDOI
MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1.
TL;DR: The findings indicate that NIK participates in an NF-KB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.
Journal ArticleDOI
Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction
Katherine A. Fitzgerald,Eva M. Palsson-McDermott,Andrew G. Bowie,Andrew G. Bowie,Caroline A. Jefferies,Ashley Mansell,Gerard Brady,Elizabeth Brint,Aisling Dunne,Pearl Gray,Mary T. Harte,Diane McMurray,Dirk E. Smith,John E. Sims,T. A. Bird,Luke A. J. O'Neill +15 more
TL;DR: A protein is described, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome, which is therefore an adapter in TLR-4 signal transduction.
Journal ArticleDOI
IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK
TL;DR: Overexpression of a catalytically inactive form of IKK-β blocked cytokine-induced NF-κB activation and suggested that an active IκB kinase complex may require three distinct protein kinases.