title: Cooperative signaling by TGF-β1 and WNT-11 drives sm-α-actin expression in smooth muscle via Rho kinase-actin-MRTF-A signaling.
abstract: Airway smooth muscle (ASM) remodeling is a key feature in asthma and includes changes in smooth muscle-specific gene and protein expression. Despite this being a major contributor to asthma pathobiology, our understanding of the mechanisms governing ASM remodeling remains poor. Here, we studied the functional interaction between WNT-11 and TGF-β1 in ASM cells. We demonstrate that WNT-11 is preferentially expressed in contractile myocytes and is strongly upregulated following TGF-β1-induced myocyte maturation. Knock-down of WNT-11 attenuated TGF-β1-induced smooth muscle (sm)-α-actin expression in ASM cells. We demonstrate that TGF-β1-induced sm-α-actin expression is mediated by WNT-11 via RhoA activation and subsequent actin cytoskeletal remodeling, as pharmacological inhibition of either Rho kinase by Y27632 or actin remodeling by latrunculin A attenuated sm-α-actin induction. Moreover, we show that TGF-β1 regulates the nuclear expression of myocardin-related transcription factor-A (MRTF-A) in a Rho kinase-dependent fashion, which in turn mediates sm-α-actin expression. Finally, we demonstrate that TGF-β1-induced MRTF-A nuclear translocation is dependent on endogenous WNT-11. The present study thus demonstrates a WNT-11-dependent Rho kinase-actin-MRTF-A signaling axis that regulates the expression of sm-α-actin in ASM cells.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and.
authors.forename: Kuldeep
authors.initials: K
authors.lastname: Kumawat
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and.
authors.forename: Tim
authors.initials: T
authors.lastname: Koopmans
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands;
authors.forename: Alita
authors.initials: A
authors.lastname: Prins
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and.
authors.forename: Marieke
authors.initials: M
authors.lastname: Smit
authors.affiliation: Departments of Physiology and Pathophysiology & Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and r.gosens@rug.nl.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D056151:Airway Remodeling; D002478:Cells, Cultured; D006801:Humans; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000199:Actins; C431575:MRTFA protein, human; C508960:TGFB1 protein, human; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; C540523:Wnt11 protein, human; D054460:rho-Associated Kinases
keywords: WNT; airway smooth muscle; asthma; maturation; phenotype