Dataset Information

Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation.

ABSTRACT: IL-1 receptor-associated kinase (IRAK) is phosphorylated, ubiquitinated, and degraded upon interleukin-1 (IL-1) stimulation. In this study, we showed that IRAK can be ubiquitinated through both Lys-48- and Lys-63-linked polyubiquitin chains upon IL-1 induction. Pellino 3b is the RING-like motif ubiquitin protein ligase that promotes the Lys-63-linked polyubiquitination on IRAK. Pellino 3b-mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48-linked IRAK polyubiquitination for the same ubiquitination site, Lys-134 of IRAK, thereby blocking IL-1-induced IRAK degradation. Importantly, the negative impact of Pellino 3b on IL-1-induced IRAK degradation correlated with the inhibitory effect of Pellino 3b on the IL-1-induced TAK1-dependent pathway, suggesting that a positive role of IRAK degradation in IL-1 induced TAK1 activation. Taken together, our results suggest that Pellino 3b acts as a negative regulator for IL-1 signaling by regulating IRAK degradation through its ubiquitin protein ligase activity.

SUBMITTER: Xiao H

PROVIDER: S-EPMC2386918 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation.

Xiao Hui H Qian Wen W Staschke Kirk K Qian Youcun Y Cui Grace G Deng Li L Ehsani Mariam M Wang Xiliang X Qian Yue-Wei YW Chen Zhijian J ZJ Gilmour Raymond R Jiang Zhengfan Z Li Xiaoxia X

The Journal of biological chemistry 20080307 21

IL-1 receptor-associated kinase (IRAK) is phosphorylated, ubiquitinated, and degraded upon interleukin-1 (IL-1) stimulation. In this study, we showed that IRAK can be ubiquitinated through both Lys-48- and Lys-63-linked polyubiquitin chains upon IL-1 induction. Pellino 3b is the RING-like motif ubiquitin protein ligase that promotes the Lys-63-linked polyubiquitination on IRAK. Pellino 3b-mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48-linked IRAK polyubiquitination for the s ...[more]

PMID: 18326498

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Project description:NF?B signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NF?B activation has not been previously described, although FGFs have been known to antagonize TNF?-induced apoptosis.Here, we demonstrate an interaction between FGFR4 and IKK? (Inhibitor of NF?B Kinase ? subunit), an essential component in the NF?B pathway. This novel interaction was identified utilizing a yeast two-hybrid screen [1] and confirmed by coimmunoprecipitation and mass spectrometry analysis. We demonstrate tyrosine phosphorylation of IKK? in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNF? (Tumor Necrosis Factor ?) to activate NF?B pathways, FGFR4 activation results in significant inhibition of NF?B signaling as measured by decreased nuclear NF?B localization, by reduced NF?B transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKK? kinase activity towards the substrate GST-I?B? in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNF?-treated DU145 prostate cancer cells also leads to a decrease in IKK? activity, concomitant reduction in NF?B nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNF? treatment of DU145 cells, in comparison with TNF? alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NF?B signaling.These results identify a compelling link between FGFR4 signaling and the NF?B pathway, and reveal that FGFR4 activation leads to a negative effect on NF?B signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NF?B signaling will not be limited to FGFR4 alone.

Dataset Information

Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation.

Publications

Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation.

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