TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo.

By Jae-hyuck Shim, Changchun Xiao, Amber E Paschal, S. Bailey, P. Rao, M. Hayden, Ki-Young Lee, C. Bussey, M. Steckel, N. Tanaka and 4 more. Genes & Development, 2005

787 citations recorded by the source corpus.

TGF-beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is thought to be a key modulator of the inducible transcription factors NF-kappaB and AP-1 and, therefore, plays a crucial role in regulating the genes that mediate inflammation. Although in vitro biochemical studies have revealed the existence of a TAK1 complex, which includes TAK1 and the adapter proteins TAB1 and TAB2, it remains unclear which members of this complex are essential for signaling. To analyze the function of TAK1 in vivo, we have deleted the Tak1 gene in mice, with the resulting phenotype being early embryonic lethality. Using embryonic fibroblasts lacking TAK1, TAB1, or TAB2, we have found that TNFR1, IL-1R, TLR3, and TLR4-mediated NF-kappaB and AP-1 activation are severely impaired in Tak1(m/m) cells, but they are normal in Tab1(-/-) and Tab2(-/-) cells. In addition, Tak1(m/m) cells are highly sensitive to TNF-induced apoptosis. TAK1 mediates IKK activation in TNF-alpha and IL-1 signaling pathways, where it functions downstream of RIP1-TRAF2 and MyD88-IRAK1-TRAF6, respectively. However, TAK1 is not required for NF-kappaB activation through the alternative pathway following LT-beta signaling. In the TGF-beta signaling pathway, TAK1 deletion leads to impaired NF-kappaB and c-Jun N-terminal kinase (JNK) activation without impacting Smad2 activation or TGF-beta-induced gene expression. Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKKbeta and JNK, but not IKKalpha, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways.

Subfields: Cancer Research, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/8cd32ea2ef68dfd9ccfdddef756740c582d553eb

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Citations in the corpus

• Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses (2009, background): “The essential and nonredundant role played by TAK1 is strongly suggested by significantly reduced NF- B, JNK, and p38 responses to various TLR ligands in cells derived from mice deficient in this kinase (317, 332).”
• NF-κB and the immune response (2006, background): “Signaling downstream of RIP1 requires TAK1 for the activation of IKK (Sato et al., 2000; Shim et al., 2005).”
• Interleukin-1 (IL-1) Pathway (2010, background): “well documented by numerous experimental approaches, including genetics in mice (60, 67) and in Drosophila (68, 69), that TAK1 and MEKK3 are core components that link TIR innate immune receptors to gene activation (4).”
• ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) (2019, background): “In support of this concept, genetic deletion of TAK1 in mice was shown to result in spontaneous cell death and embryonic lethality (Sato et al., 2005; Shim et al., 2005).”
• The IKK complex, a central regulator of NF-kappaB activation. (2010, background): “Although TAB2 or TAB3 seems to be involved in NF-kB activation, this does not seem to be the case for TAB1 (Shim et al. 2005).”
• Signaling in innate immunity and inflammation. (2012, background): “Elevated intracellular calcium together with protein kinase C (PKC) activation by DAG is important for vesicle exocytosis, superoxide production by the NADPH oxidase, and JNK activation (Li et al. 2000).”
• Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. (2009, background): “For example, TAK1 kinase has been shown to be critical for TNF-a-induced activation of both MAPK and NF-kB pathways (Shim et al., 2005).”
• Toll-Like Receptor Signaling Pathways (2014, background): “Furthermore, the physiological roles of TAB proteins in TLR signaling also remain controversial: TAB1- or TAB2-deficient mice do not show any abnormality in TLR signaling pathways (48), and mice doubly deficient for TAB2 and TAB3 also exhibit normal cytokine production after TLR simulation in MEFs a”
• Regulation of NF-κB by TNF Family Cytokines (2014, background): “However, such a model does not account for the requirement for TAK1, for TNF induced IKK activation [72, 73].”
• The adaptor Act1 is required for interleukin 17–dependent signaling associated with autoimmune and inflammatory disease (2007, background): “Because TAK1 has been shown to activate NF-κB and Jn”
• Signaling mechanisms of the epithelial-mesenchymal transition (2014, background): “Activation of TAK1 is postulated to promote NF-κB signaling, which may lead to EMT (133).”