title: β-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition.
abstract: Injury to the adherens junctions (AJs) synergizes with transforming growth factor-β1 (TGFβ) to activate a myogenic program (α-smooth muscle actin [SMA] expression) in the epithelium during epithelial-myofibroblast transition (EMyT). Although this synergy plays a key role in organ fibrosis, the underlying mechanisms have not been fully defined. Because we recently showed that Smad3 inhibits myocardin-related transcription factor (MRTF), the driver of the SMA promoter and many other CC(A/T)-rich GG element (CArG) box-dependent cytoskeletal genes, we asked whether AJ components might affect SMA expression through interfering with Smad3. We demonstrate that E-cadherin down-regulation potentiates, whereas β-catenin knockdown inhibits, SMA expression. Contact injury and TGFβ enhance the binding of β-catenin to Smad3, and this interaction facilitates MRTF signaling by two novel mechanisms. First, it inhibits the Smad3/MRTF association and thereby allows the binding of MRTF to its myogenic partner, serum response factor (SRF). Accordingly, β-catenin down-regulation disrupts the SRF/MRTF complex. Second, β-catenin maintains the stability of MRTF by suppressing the Smad3-mediated recruitment of glycogen synthase kinase-3β to MRTF, an event that otherwise leads to MRTF ubiquitination and degradation and the consequent loss of SRF/MRTF-dependent proteins. Thus β-catenin controls MRTF-dependent transcription and emerges as a critical regulator of an array of cytoskeletal genes, the "CArGome."
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Charbonney
authors.forename: Pam
authors.initials: P
authors.lastname: Speight
authors.forename: András
authors.initials: A
authors.lastname: Masszi
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
authors.forename: András
authors.initials: A
authors.lastname: Kapus
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D058628:Myofibroblasts / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D051381:Rats; D026362:Serum Response Factor / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000199:Actins; D015820:Cadherins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D026362:Serum Response Factor; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C569168:myocardin-related transcription factor-B, rat; C498862:Acta2 protein, rat; C000605508:Gsk3b protein, rat