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48887Pathway662

Source:http://www.reactome.org/biopax/48887Pathway662

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Authored: Shamovsky, V, 2010-06-01, Edited: Shamovsky, V, 2010-11-15, Reviewed: Gillespie, ME, 2010-10-29, The role of IRAK-1 kinase activity in the activation of NFkB by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK-1 mutants can still activate NFkB. Furthermore, stimulation of IRAK-1-deficient I1A 293 cells with LMP1 (latent membrane protein 1 - a known viral activator of NF-?B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK-1 enhances p65 S536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NFkB dependent target genes [Liu et al 2008].<p> IRAK-1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK-1 prevented interaction with NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NFkB activation [Conze et al 2008]. These data suggest that kinase activity of IRAK-1 is not essential for its ability to activate NFkB, while its Lys63-polyubuquitination allows IRAK-1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NFkB. </p><p>Upon IL-1/TLR stimulation IRAK-1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK-1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NFkB [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003].
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IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation
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