title: A novel role for RhoA GTPase in the regulation of airway smooth muscle contraction.
abstract: Recent studies have demonstrated a novel molecular mechanism for the regulation of airway smooth muscle (ASM) contraction by RhoA GTPase. In ASM tissues, both myosin light chain (MLC) phosphorylation and actin polymerization are required for active tension generation. RhoA inactivation dramatically suppresses agonist-induced tension development and completely inhibits agonist-induced actin polymerization, but only slightly reduces MLC phosphorylation. The inhibition of MLC phosphatase does not reverse the effects of RhoA inactivation on contraction or actin polymerization. Thus, RhoA regulates ASM contraction through its effects on actin polymerization rather than MLC phosphorylation. Contractile stimulation of ASM induces the recruitment and assembly of paxillin, vinculin, and focal adhesion kinase (FAK) into membrane adhesion complexes (adhesomes) that regulate actin polymerization by catalyzing the activation of cdc42 GTPase by the G-protein-coupled receptor kinase-interacting target (GIT) - p21-activated kinase (PAK) - PAK-interacting exchange factor (PIX) complex. Cdc42 is a necessary and specific activator of the actin filament nucleation activator, N-WASp. The recruitment and activation of paxillin, vinculin, and FAK is prevented by RhoA inactivation, thus preventing cdc42 and N-WASp activation. We conclude that RhoA regulates ASM contraction by catalyzing the assembly and activation of membrane adhesome signaling modules that regulate actin polymerization, and that the RhoA-mediated assembly of adhesome complexes is a fundamental step in the signal transduction process in response to a contractile agonist.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Zhang
authors.forename: Youliang
authors.initials: Y
authors.lastname: Huang
authors.forename: Yidi
authors.initials: Y
authors.lastname: Wu
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Gunst
mesh_terms: D000199:Actins / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D020558:GTP Phosphohydrolases; D020742:rhoA GTP-Binding Protein
keywords: actin polymerization; adhesion junction; cdc42; jonction adhésives; myosin light chain phosphorylation; paxiline cdc42; paxillin; phosphorylation de la chaine légère de la myosine; polymérisation d’actine; vinculin; vinculine