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Transforming growth factor-β-activated kinase 1 (TAK1) mitogen-activated protein kinase kinase kinase has been shown to be activated by cellular stresses including tumor necrosis factor-α (TNF-α). Here, we characterized the molecular mechanisms of cellular stress-induced TAK1 activation, focusing mainly on the phosphorylation of TAK1 at Thr-187 and Ser-192 in the activation loop. Thr-187 and Ser-192 are conserved among species from Caenorhabditis elegans to human, and their replacement with Ala resulted in inactivation of TAK1. Immunoblotting with a novel phospho-TAK1 antibody revealed that TNF-α significantly induced the phosphorylation of endogenous TAK1 at Thr-187, and subsequently the phosphorylated forms of TAK1 rapidly disappeared. Intermolecular autophosphorylation of Thr-187 was essential for TAK1 activation. RNA interference and overexpression experiments demonstrated that TAK1-binding protein TAB1 and TAB2 were involved in the phosphorylation of TAK1, but they regulated TAK1 phosphorylation differentially. Furthermore, SB203580 and p38α small interfering RNA enhanced TNF-α-induced Thr-187 phosphorylation as well as TAK1 kinase activity, indicating that the phosphorylation is affected by p38α/TAB1/TAB2-mediated feedback control of TAK1. These results indicate critical roles of Thr-187 phosphorylation in the stress-induced rapid and transient activation of TAK1 in a signaling complex containing TAB1 and TAB2. Transforming growth factor-β-activated kinase 1 (TAK1) mitogen-activated protein kinase kinase kinase has been shown to be activated by cellular stresses including tumor necrosis factor-α (TNF-α). Here, we characterized the molecular mechanisms of cellular stress-induced TAK1 activation, focusing mainly on the phosphorylation of TAK1 at Thr-187 and Ser-192 in the activation loop. Thr-187 and Ser-192 are conserved among species from Caenorhabditis elegans to human, and their replacement with Ala resulted in inactivation of TAK1. Immunoblotting with a novel phospho-TAK1 antibody revealed that TNF-α significantly induced the phosphorylation of endogenous TAK1 at Thr-187, and subsequently the phosphorylated forms of TAK1 rapidly disappeared. Intermolecular autophosphorylation of Thr-187 was essential for TAK1 activation. RNA interference and overexpression experiments demonstrated that TAK1-binding protein TAB1 and TAB2 were involved in the phosphorylation of TAK1, but they regulated TAK1 phosphorylation differentially. Furthermore, SB203580 and p38α small interfering RNA enhanced TNF-α-induced Thr-187 phosphorylation as well as TAK1 kinase activity, indicating that the phosphorylation is affected by p38α/TAB1/TAB2-mediated feedback control of TAK1. These results indicate critical roles of Thr-187 phosphorylation in the stress-induced rapid and transient activation of TAK1 in a signaling complex containing TAB1 and TAB2. Cellular stresses stimulate several intracellular signaling pathways leading to the activation of transcription factors AP-1 1The abbreviations used are: AP-1, activator protein-1; ASK1, apoptosis signal-regulated kinase 1; EGFP, enhanced green fluorescence protein; GST, glutathione S-transferase; HA, hemagglutinin; HEK, human embryonic kidney; His6, hexahistidine; IKK, IκB kinase; IL-1, interleukin 1; JNK, c-Jun NH2-terminal kinase; kd, kinase domain; luc, luciferase; MAPK, mitogen-activated protein kinase; MAP2K (MKK), MAPK kinase; MAP3K, MAPKK kinase; MEKK, MAPK/extracellular signal-related kinase kinase kinase; MLK, mixed lineage kinase; NF-κB, nuclear factor-κB; PCNA, proliferating cell nuclear antigen; PP, protein phosphatase; RNAi, RNA interference; siRNA, small interfering RNA; TAB, TAK1-binding protein; TAK1, transforming growth factor-β-activated kinase 1; TNF, tumor necrosis factor; TRAF, TNF-receptor associated factor; MKK, MAPK kinase. 1The abbreviations used are: AP-1, activator protein-1; ASK1, apoptosis signal-regulated kinase 1; EGFP, enhanced green fluorescence protein; GST, glutathione S-transferase; HA, hemagglutinin; HEK, human embryonic kidney; His6, hexahistidine; IKK, IκB kinase; IL-1, interleukin 1; JNK, c-Jun NH2-terminal kinase; kd, kinase domain; luc, luciferase; MAPK, mitogen-activated protein kinase; MAP2K (MKK), MAPK kinase; MAP3K, MAPKK kinase; MEKK, MAPK/extracellular signal-related kinase kinase kinase; MLK, mixed lineage kinase; NF-κB, nuclear factor-κB; PCNA, proliferating cell nuclear antigen; PP, protein phosphatase; RNAi, RNA interference; siRNA, small interfering RNA; TAB, TAK1-binding protein; TAK1, transforming growth factor-β-activated kinase 1; TNF, tumor necrosis factor; TRAF, TNF-receptor associated factor; MKK, MAPK kinase. and NF-κB. The transcriptional activity of AP-1 is regulated by the stress-activated protein kinases (SAPKs)/mitogen-activated protein kinases (MAPKs) cascades, including the c-Jun NH2-terminal kinase (JNK) and p38 pathways (1Kyriakis J.M. Avruch J. Physiol. Rev. 2001; 81: 807-869Crossref PubMed Scopus (2833) Google Scholar, 2Johnson G.L. Lapadat R. Science. 2002; 298: 1911-1912Crossref PubMed Scopus (3393) Google Scholar, 3Tamura S. Hanada M. Ohnishi M. Katsura K. Sasaki M. Kobayashi T. Eur. J. Biochem. 2002; 269: 1060-1066Crossref PubMed Scopus (91) Google Scholar, 4Lee T.H. Huang Q. Oikemus S. Shank J. Ventura J.J. Cusson N. Vaillancourt R.R. Su B. Davis R.J. Kelliher M.A. Mol. Cell. Biol. 2003; 23: 8377-8385Crossref PubMed Scopus (74) Google Scholar, 5Shirakabe K. Yamaguchi K. Shibuya H. Irie K. Matsuda S. Moriguchi T. Gotoh Y. Matsumoto K. Nishida E. J. Biol. Chem. 1997; 272: 8141-8144Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). 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Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were in of 1 1 and and on for of was and the was for were from the of at for The nuclear were with of and in of 1 1 1 1 1 and The was on for with were by at for and at were with of 1 1 1 and were with antibody antibody on for and with protein at for The were with of cell and were by and to The was with and with as The were and and with the of endogenous antibody was with the and were with phosphorylated TAK1 at TAK1 was with antibody and endogenous TAK1 was with were for TAK1 kinase activity as a JNK and were with and The protein kinase of the were by in kinase and respectively H. H. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were with and a containing a AP-1 The activity was by the of and AP-1 by the and activation of TAK1 in the The protein kinase of TAK1, including human, and are The activation of TAK1 is to that of TAK1. TAK1 and a TAK1 in Caenorhabditis the corresponding to Thr-187 of TAK1. Ser-192 of TAK1, phosphorylation is conserved among the for the replacement of with in the of Thr-187 we to the of Thr-187 in the and AP-1 signaling of TAK1 with TAB1 kinase activity and of and nuclear of the the as well as to cellular of p38 and JNK is in with the activation of pathways resulted in transcriptional activation of and AP-1 by and These results indicate that Thr-187 is essential for the activation of TAK1 by Thr-187 of the roles of TAK1 we a novel antibody TAK1 phosphorylated at Thr-187 has been shown that overexpression of TAK1 with TAB1 resulted in activation of TAK1 H. Yamaguchi K. Shirakabe K. Gotoh Y. N. Irie K. Nishida E. Matsumoto K. Science. 1996; 272: PubMed Scopus Google Scholar, H. H. J. T. Scopus Google Scholar). we to Thr-187 phosphorylation of TAK1 in overexpression and were in and were with The and activity of TAK1 were with TAB1 phosphorylation and kinase activity were in and on the with TAB1 indicating that the of TAK1. with the activation of the AP-1 and signaling pathways by TAK1 in Ser-192 in the activation of TAK1 is phosphorylation TAK1 activation K. Matsumoto K. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that Ser-192 with Ala TAK1 kinase activity, in Thr-187 phosphorylation was was from Thr-187 phosphorylation in the the of Ser-192 for the antibody to TAK1 in the of to was by in the of several phospho-TAK1 as TAK1 was by with phosphorylation and phosphorylation at Ser-192 and with and the of to the of TAK1. These results demonstrated that and the is on the of Ser-192 The of revealed that the of Ser-192 resulted in Thr-187 phosphorylation of TAK1 in Intermolecular of to Thr-187 phosphorylation were with TAK1 a that the kinase to from TAK1, with TAK1 and in induced Thr-187 indicating that kinase activity the TAK1 was phosphorylated at Thr-187 with the These results that Thr-187 phosphorylation is at in by The autophosphorylation of TAK1 to the of Thr-187 and Ser-192 in TAK1 activation. and were with and Immunoblotting of that as well as of conserved the Thr-187 indicating that Ser-192 is for the of kinase activity with TAB1 the autophosphorylation of by induced kinase activity the kinase activity of was on the of and was with These results indicate that Thr-187 a in TAK1 activation by the kinase activity of was that of TAK1 that Ser-192 a in activation of TAK1. of TAK1 by with the of TAK1 and is essential for TAK1 activation in TNF-α and signaling the of TAB2 to TAK1 were with for TAK1 and TAB2. The phosphorylation of TAK1, but TAK1 be with TAB2 TAK1 phosphorylation was at a with and TAK1 kinase activity was in the of TAB1 that TAB1 is essential for TAK1 kinase TNF-α-induced of Thr-187 of the roles of TAK1 we to TNF-α-induced phosphorylation of endogenous TAK1. Immunoblotting with demonstrated that at be in cell from The phospho-TAK1 were at and were at of the phosphorylated the forms were mainly at The endogenous but TAK1, was by and indicating that were from forms of TAK1 rapid and transient phosphorylation was with the TAK1 kinase activity These results indicate that TAK1 in to TNF-α and that the of Thr-187 phosphorylation is the to and the kinase to the of TAK1, TAK1-binding TAB1 and were phosphorylated from the the phosphorylation is essential for TAK1 activation the kinase activity was at phosphorylation of TAB1 and TAB2. was the of TAK1 kinase activity in with the of forms of TAK1 at has been shown that phosphorylation of TAB1 and TAB2 is involved in the of TAK1 kinase activity J. 2003; PubMed Scopus Google Scholar, Biochem. J. PubMed Scopus Google and phosphorylation of the complex is to the transient TAK1 kinase of TAB1 in TAK1 of the TAB1 TAB1 of a p38α and TAK1 activation and indicate the and NH2-terminal and were were with for with and The of was with to of at Thr-187 was by of The were to in kinase activation as a and was by of with were with for and were with TNF-α for the and cell were with and TAK1 activity was by in kinase with as a of and TAK1 on JNK, and the of TNF-α-induced TAK1 we to the of on transcriptional TNF-α-induced was by was with the by a of that phosphorylation of Thr-187 is involved in the TNF-α-induced TAK1 activation. roles of TAK1 in the signaling we to the of TAK1 on TNF-α-induced signaling were with TAK1 control and with TNF-α TAK1 siRNA, but siRNA, induced of TAK1 was with the phosphorylation of TAK1 the of the phospho-TAK1 antibody to TAK1. the and phosphorylation of TAB1 and TAB2 were Furthermore, TAK1 JNK, and activation roles of TAK1 in the TNF-α-induced signaling induced a phosphorylation of TAK1, phosphorylation of TAB1 and TAB2 was induced and stress-induced activation was by TAK1 that TAK1 is the the stress-induced activation of a the that TAK1 is for activation of JNK by but in M.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of TAB1 and the of TAB1 and TAB2 in cellular stress-induced TAK1 activation. were with TAB1 siRNA, resulted in the of TAB1 the of TAK1 and TAB1 the of TAK1 kinase activity and the of TAB2 in with TNF-α for be that with phospho-TAK1 antibody that the of phosphorylated TAK1 were These results that forms of TAK1 but forms of TAK1. the activation of but IKK, was by TAB1 Furthermore, TAB1 stress-induced phosphorylation of and activation of These results indicate that TAB1 is essential for TAK1 but Thr-187 phosphorylation of TAK1 is induced in the of the TAB2 induced of TAB2 resulted in phosphorylation and activation of TAK1 of TAB2 in the and stress-induced activation of and were to the results from experiments TAB1 These results that TAB2 is essential for the Thr-187 phosphorylation of TAK1 and activation of TAK1. of Thr-187 in the of TAK1 by has been shown that phosphorylation of TAB1 and TAB2 is with feedback of TAK1 activity J. 2003; PubMed Scopus Google Scholar, Biochem. J. PubMed Scopus Google Scholar). Here, we the of a p38 on cellular stress-induced TAK1 were with SB203580 for by with TNF-α for TNF-α-induced phosphorylation of TAB1 was by SB203580 the the phosphorylation of TAB2 The of Thr-187 phosphorylation of TAK1, the was enhanced by SB203580 at Thr-187 was rapidly at in the of the The of TAK1 phosphorylation the TAK1 kinase activity, the of the results were with the stress-induced activation of the in the enhanced phosphorylation and kinase activity of TAK1 were at for the of p38α SB203580 p38α and of the but JNK and IKK, signaling by p38α resulted in the enhanced of of phospho-TAK1 and the kinase activity of TAK1. results that of Thr-187 a in feedback of TAK1 kinase of TAB1 Thr-187 has The TAK1 activation is in the and the TAK1 is the The for the feedback of TAK1 is to the TAK1 activation J. 2003; PubMed Scopus Google Scholar, B. Q. J.L. D. Huang S. J. J. Biol. 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TAB1 a in TAK1 to the is that of TAB1 phosphorylation resulted in the of forms of phospho-TAK1 and the that the feedback control by phosphorylation of TAB1 the of TAK1 to TAK1 kinase the the of TAB2 the activation and phosphorylation of TAK1 that intracellular to the corresponding is essential for phosphorylation of several a has been shown to a in TNF-α and signaling pathways T. J. Shibuya H. Matsumoto K. J. 2003; PubMed Scopus Google Scholar, Biochem. J. PubMed Scopus Google Scholar, E. 2002; PubMed Scopus Google Scholar, M. B. J. J. B. S. PubMed Scopus Google Scholar, M. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). of in the phosphorylation of Thr-187 as well as of TAB2 and is the to the of TAK1 activation by TAB2 and of TAK1 by phosphorylation of is a in the of TAK1 activation J. 2003; PubMed Scopus Google Scholar, Biochem. J. 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Singhirunnusorn et al. (Wed,) studied this question.
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