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IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B.
Upon IL-1/TLR stimulation IRAK1 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, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003].
IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B.
Upon IL-1/TLR stimulation IRAK1 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, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003].
The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.
Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).
JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK.
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