title: HSP90 is required for TAK1 stability but not for its activation in the pro-inflammatory signaling pathway.
abstract: The protein kinase transforming-growth-factor-beta-activated kinase-1 (TAK1) is a key regulator in the pro-inflammatory signaling pathway and is activated by tumor necrosis factor-alpha, interleukin-1 (IL-1) and lipopolysaccharide (LPS). We describe the identification of TAK1 as a client protein of the 90 kDa heat-shock protein (Hsp90)/cell division cycle protein 37 (Cdc37) chaperones. However, Hsp90 is not required for the activation of TAK1 as short exposure to the Hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) did not affect its activation by LPS or IL-1. Prolonged treatment of cells with 17-AAG inhibits Hsp90 and downregulates TAK1. Our results suggest that Hsp90 is required for the folding and stability of TAK1 but is displaced and no longer required when TAK1 is complexed to TAK1-binding protein-1 (TAB1).
authors.affiliation: Division of Molecular and Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Xin Yu
authors.initials: XY
authors.lastname: Liu
authors.forename: Cheah Chen
authors.initials: CC
authors.lastname: Seh
authors.forename: Peter C F
authors.initials: PC
authors.lastname: Cheung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D018833:Chaperonins / Q000378:metabolism; D004789:Enzyme Activation; D004795:Enzyme Stability; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D017510:Protein Folding; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018833:Chaperonins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C498362:CDC37 protein, human; C486300:TAB1 protein, human; C112765:tanespimycin