Irie, T., Muta, T. & Takeshige, K. TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-B in lipopolysaccharide-stimulated macrophages. FEBS Lett. 467, 160-164

Department of Molecular Biochemistry, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, Japan.
FEBS Letters (Impact Factor: 3.17). 03/2000; 467(2-3):160-4. DOI: 10.1016/S0014-5793(00)01146-7
Source: PubMed


Stimulation of monocytes/macrophages with lipopolysaccharide (LPS) results in activation of nuclear factor-kappaB (NF-kappaB), which plays crucial roles in regulating expression of many genes involved in the subsequent inflammatory responses. Here, we investigated roles of transforming growth factor-beta activated kinase 1 (TGF-TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), in the LPS-induced signaling cascade. A kinase-negative mutant of TAK1 inhibited the LPS-induced NF-kappaB activation both in a macrophage-like cell line, RAW 264.7, and in human embryonic kidney 293 cells expressing toll-like receptor 2 or 4. Furthermore, we demonstrated that endogenous TAK1 is phosphorylated upon simulation of RAW 264.7 cells with LPS. These results indicate that TAK1 functions as a critical mediator in the LPS-induced signaling pathway.

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    • "Drosophila TAK1 is essential for antibacterial innate immunity27. When TAK1 is kinase-negatively mutated, the LPS induced NF-κB activation is inhibited28. Thus, TAK1 is a critical mediator in the LPS-induced signaling pathway. "
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    Acta Pharmacologica Sinica 08/2012; 33(10):1293-300. DOI:10.1038/aps.2012.100 · 2.91 Impact Factor
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    • "TAK1 regulates NF-κB-inducing kinase activity that activates IKKα/β downstream of MyD88 and TRAF6. TAK1 is also a MAP kinase kinase kinase for p38 that is critical for the production of pro-inflammatory cytokines (Irie et al., 2000). Stimulation of TLRs results in the downstream activation of the cytoplasmic Toll/IL-1 receptor (TIR) domain portion of the TLR, which then recruits MyD88/IRAK/TRAF6 and activates the MAPK superfamily cascade (Dalpke and Heeg, 2002; O'Neill, 2002; Akira, 2003) and the transcription factors, NF-κB and AP- 1 that leads to the expression of genes that participate in the innate immune response including pro-inflammatory cytokines. "
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    Frontiers in Genetics 07/2012; 3:121. DOI:10.3389/fgene.2012.00121
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    • "In addition to TGF-b1, TAK1 can also be activated by various stimuli including proinflammatory cytokines such as tumor necrosis factora (TNF-a) [58] and interleukin-1 (IL-1) [59], lipopolysaccharides [60], and environmental stress [61]. Phosphorylation of Thr-187 and Ser-192 in the activation loop of TAK1 induces TAK1 activation [62,63] and subsequently triggers the activation of several downstream signaling cascades, including MKK4/7–JNK, MKK3/6-p38 MAPK, and nuclear factor-kappa B (NF-kB)-inducing kinase-IkB kinase (Fig. 2) [58] [59] [60]. "
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    06/2012; 31(2):94–105. DOI:10.1016/j.krcp.2012.04.322
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