Dataset Information

TAK1 negatively regulates NF-?B and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils.

ABSTRACT: Stringent control of NF-?B and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-? activated kinase-1 (TAK1) is essential for NF-?B activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7(?M/?M)) led to development of splenomegaly and lymphomegaly associated with neutrophilia. Compared with wild-type cells, TAK1-deficient neutrophils enhanced the phosphorylation of the kinases IKK, p38, and JNK and the production of interleukin-1? (IL-1?), IL-6, tumor necrosis factor-? (TNF-?), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7(?M/?M) mice were significantly more susceptible to LPS-induced septic shock and produced higher amounts of IL-1?, IL-6, and TNF-? in plasma than do wild-type mice. Specific ablation of p38 rescued the phenotype and functional properties of Map3k7(?M/?M) mice. Our findings identify a previously unrecognized role of TAK1 as a negative regulator of p38 and IKK activation in a cell type-specific manner.

SUBMITTER: Ajibade AA

PROVIDER: S-EPMC3750978 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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TAK1 negatively regulates NF-κB and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils.

Ajibade Adebusola Alagbala AA Wang Qinfu Q Cui Jun J Zou Jia J Xia Xiaojun X Wang Mingjun M Tong Yanzheng Y Hui Wei W Liu Dou D Su Bing B Wang Helen Y HY Wang Rong-Fu RF

Immunity 20120105 1

Stringent control of NF-κB and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-β activated kinase-1 (TAK1) is essential for NF-κB activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7(ΔM/ΔM)) led to development of splenomegaly and lymphomegaly associated with neutrophilia. Compared with wild-type cells, TAK1-deficient neutrophils enhanced the phosphorylation of the kinases IKK, p38 ...[more]

PMID: 22226633

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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

TAK1 negatively regulates NF-?B and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils.

Publications

TAK1 negatively regulates NF-κB and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils.

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