title: A novel RhoA/ROCK-CPI-17-MEF2C signaling pathway regulates vascular smooth muscle cell gene expression.
abstract: Differentiation of vascular smooth muscle cells (VSMC) is a fundamental aspect of normal development and vascular disease. During contraction, VSMCs modulate calcium sensitivity through RhoA/ROCK-mediated inhibition of the myosin light chain phosphatase complex (MLCP). Previous studies have demonstrated that this signaling pathway functions in parallel to increase the expression of smooth muscle genes through the myocardin-family of co-activators. MEF2C fulfills a critical role in VSMC differentiation and regulates myocardin expression, leading us to investigate whether the RhoA/ROCK signaling cascade might regulate MEF2 activity. Depolarization-induced calcium signaling increased the expression of myocardin, which was sensitive to ROCK and p38 MAPK inhibition. We previously identified protein phosphatase 1α (PP1α), a known catalytic subunit of the MLCP in VSMCs, as a potent repressor of MEF2 activity. PP1α inhibition resulted in increased expression of myocardin, while ectopic expression of PP1α inhibited the induction of myocardin by MEF2C. Consistent with these data, shRNA-mediated suppression of a PP1α inhibitor, CPI-17, reduced myocardin expression and inhibited VSMC differentiation, suggesting a pivotal role for CPI-17 in regulating MEF2 activity. These data constitute evidence of a novel signaling cascade that links RhoA-mediated calcium sensitivity to MEF2-dependent myocardin expression in VSMCs through a mechanism involving p38 MAPK, PP1α, and CPI-17.
authors.affiliation: Department of Biology, York University,Toronto M3J 1P3, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Pagiatakis
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Gordon
authors.forename: Saviz
authors.initials: S
authors.lastname: Ehyai
authors.forename: John C
authors.initials: JC
authors.lastname: McDermott
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D064326:MEF2 Transcription Factors; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099251:Myocardin
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000099251:Myocardin; C578040:MEF2C protein, human; C578042:MEF2C protein, rat; C578041:Mef2c protein, mouse; C107507:PPP1R14A protein, human; C491520:Ppp1r14a protein, mouse; C491519:Ppp1r14a protein, rat; C066737:RHOA protein, human; C526380:RhoA protein, mouse