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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: 3.34). 03/2000; 467(2-3):160-4. DOI: 10.1016/S0014-5793(00)01146-7
Source: PubMed

ABSTRACT 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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    • "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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    • "In studies with small sample populations, Tpl-2 was found to be overexpressed without gene amplification in some large granular lymphocyte proliferative disorders (Christoforidou et al., 2004), whereas Sourvinos et al. (1999) detected gene amplification and corresponding increased Tpl-2 expression in some human breast cancers. TAK1 TAK1 is activated in response to IL-1b, TNFa, and LPS stimulation (Irie et al., 2000; Takaesu et al., 2003). In response to these pro-inflammatory stimuli, active TAK1 forms a complex with an accessory protein TAB1 (Brown et al., 2005), and activated TAK1 phosphorylates MKK4 and MKK6, thereby promoting JNK and p38 activation, respectively (Shim et al., 2005). "
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