title: A dominant negative TAK1 inhibits cellular fibrotic responses induced by TGF-beta.
abstract: Transforming growth factor-beta (TGF-beta) is crucially virulent in the progression of fibrotic disorders. TAK1 (TGF-beta activated kinase 1) is one of the mitogen-activated kinase kinase kinase (MAPKKK) that is involved in TGF-beta signal transduction. To elucidate the importance of TAK1 in TGF-beta-induced fibrotic marker expression, we investigated whether dominant negative TAK1 could suppress TGF-beta signaling. Based on the finding that TAB1 (TAK1 binding protein 1) binding to TAK1 is required for TAK1 activation, a minimal portion of TAK1 lacking kinase activity that binds to TAB1 was designed as a TAK1 dominant negative inhibitor (TAK1-DN). The effect of TAK1-DN was assessed in the cells that respond to TGF-beta stimulation and that lead to the increase in production of extracellular matrix (ECM) proteins. TAK1-DN, indeed, decreased the ECM protein production, indicating that TAK1-DN retains the ability to intercept the TGF-beta signaling effectively.
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Gotemba-shi, Shizuoka-ken, Japan. onokui@chugai-pharm.co.jp
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ono
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ohtomo
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuchiya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015415:Biomarkers; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D002352:Carrier Proteins; D024042:Collagen Type I; D024141:Collagen Type IV; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human