title: Myocardin-Related Transcription Factor A and Yes-Associated Protein Exert Dual Control in G Protein-Coupled Receptor- and RhoA-Mediated Transcriptional Regulation and Cell Proliferation.
abstract: The ability of a subset of G protein-coupled receptors (GPCRs) to activate RhoA endows them with unique growth-regulatory properties. Two transcriptional pathways are activated through GPCRs and RhoA, one utilizing the transcriptional coactivator myocardin-related transcription factor A (MRTF-A) and serum response factor (SRF) and the other using the transcriptional coactivator Yes-associated protein (YAP) and TEA domain family members (TEAD). These pathways have not been compared for their relative levels of importance and potential interactions in RhoA target gene expression. GPCRs for thrombin and sphingosine-1-phosphate (S1P) on human glioblastoma cells robustly couple to RhoA and induce the matricelluar protein CCN1. Knockdown of either MRTF-A or YAP abrogates S1P-stimulated CCN1 expression, demonstrating that both coactivators are required. MRTF-A and YAP are also both required for transcriptional control of other S1P-regulated genes in various cell types and for S1P-stimulated glioblastoma cell proliferation. Interactions between MRTF-A and YAP are suggested by their synergistic effects on SRE.L- and TEAD-luciferase expression. Moreover, MRTF-A and YAP associate in coimmunoprecipitations from S1P-stimulated cells. Chromatin immunoprecipitation (ChIP) analysis of the CCN1 gene promoter demonstrated that S1P increases coactivator binding at the canonical transcription factor sequences. Unexpectedly, S1P also enhances MRTF-A binding at TEA sites. Our findings reveal that GPCR- and RhoA-regulated gene expression requires dual input and integration of two distinct transcriptional pathways.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California, USA Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California, USA.
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California, USA jhbrown@ucsd.edu.
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055515:Cysteine-Rich Protein 61; C431575:MRTFA protein, human; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D020742:rhoA GTP-Binding Protein