Cooperative signaling by TGF-β1 and WNT-11 drives sm-α-actin expression in smooth muscle via Rho kinase-actin-MRTF-A signaling.

Autor:	Kumawat K; Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and., Koopmans T; Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and., Menzen MH; Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and., Prins A; Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands;, Smit M; Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; and., Halayko AJ; Departments of Physiology and Pathophysiology & Internal Medicine, University of Manitoba, Winnipeg, Canada., Gosens R; 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.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2016 Sep 01; Vol. 311 (3), pp. L529-37. Date of Electronic Publication: 2016 Jul 15.
DOI:	10.1152/ajplung.00387.2015
Abstrakt:	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. (Copyright © 2016 the American Physiological Society.)
Databáze:	MEDLINE
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