title: Transforming growth factor-beta (TGF-beta1) activates TAK1 via TAB1-mediated autophosphorylation, independent of TGF-beta receptor kinase activity in mesangial cells.
abstract: Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that signals through the interaction of type I (TbetaRI) and type II (TbetaRII) receptors to activate distinct intracellular pathways. TAK1 is a serine/threonine kinase that is rapidly activated by TGF-beta1. However, the molecular mechanism of TAK1 activation is incompletely understood. Here, we propose a mechanism whereby TAK1 is activated by TGF-beta1 in primary mouse mesangial cells. Under unstimulated conditions, endogenous TAK1 is stably associated with TbetaRI. TGF-beta1 stimulation causes rapid dissociation from the receptor and induces TAK1 phosphorylation. Deletion mutant analysis indicates that the juxtamembrane region including the GS domain of TbetaRI is crucial for its interaction with TAK1. Both TbetaRI-mediated TAK1 phosphorylation and TGF-beta1-induced TAK1 phosphorylation do not require kinase activity of TbetaRI. Moreover, TbetaRI-mediated TAK1 phosphorylation correlates with the degree of its association with TbetaRI and requires kinase activity of TAK1. TAB1 does not interact with TGF-beta receptors, but TAB1 is indispensable for TGF-beta1-induced TAK1 activation. We also show that TRAF6 and TAB2 are required for the interaction of TAK1 with TbetaRI and TGF-beta1-induced TAK1 activation in mouse mesangial cells. Taken together, our data indicate that TGF-beta1-induced interaction of TbetaRI and TbetaRII triggers dissociation of TAK1 from TbetaRI, and subsequently TAK1 is phosphorylated through TAB1-mediated autophosphorylation and not by the receptor kinase activity of TbetaRI.
authors: Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Sung Il
authors: SI
authors: Kim
authors: Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Joon Hyeok
authors: JH
authors: Kwak
authors: Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Hee-Jun
authors: HJ
authors: Na
authors: Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Internal Medicine, Bucheon Hospital, Soonchunhyang University, Bucheon, 420-767, Korea.
authors: Jin Kuk
authors: JK
authors: Kim
authors: Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Yan
authors: Y
authors: Ding
authors: Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Mary E
authors: ME
authors: Choi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008957:Models, Genetic; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008024:Ligands; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse