TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway.
Cytokine treatment stimulates the IkappaB kinases, IKKalpha and IKKbeta, which phosphorylate the IkappaB proteins, leading to their degradation and activation of NF-kappaB regulated genes. A clear definition of the specific roles of IKKalpha and IKKbeta in activating the NF-kappaB pathway and the upstream kinases that regulate IKK activity remain to be elucidated. Here, we utilized small interfering RNAs (siRNAs) directed against IKKalpha, IKKbeta and the upstream regulatory kinase TAK1 in order to better define their roles in cytokine-induced activation of the NF-kappaB pathway. In contrast to previous results with mouse embryo fibroblasts lacking either IKKalpha or IKKbeta, which indicated that only IKKbeta is involved in cytokine-induced NF-kappaB activation, we found that both IKKalpha and IKKbeta were important in activating the NF-kappaB pathway. Furthermore, we found that the MAP3K TAK1, which has been implicated in IL-1-induced activation of the NF-kappaB pathway, was also critical for TNFalpha-induced activation of the NF-kappaB pathway. TNFalpha activation of the NF-kappaB pathway is associated with the inducible binding of TAK1 to TRAF2 and both IKKalpha and IKKbeta. This analysis further defines the distinct in vivo roles of IKKalpha, IKKbeta and TAK1 in cytokine-induced activation of the NF-kappaB pathway.
Takaesu
Giichi
G
Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8594, USA.
Surabhi
Rama M
RM
Park
Kyu-Jin
KJ
Ninomiya-Tsuji
Jun
J
Matsumoto
Kunihiro
K
Gaynor
Richard B
RB
D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D007375:Interleukin-1; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human