Premium
MRTF‐A and YAP exert dual control in GPCR and RhoA‐mediated transcriptional regulation and cell proliferation
Author(s) -
Yu Olivia M.,
Miyamoto Shigeki,
Brown Joan Heller
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.714.6
Subject(s) - rhoa , gene knockdown , activator (genetics) , microbiology and biotechnology , g protein coupled receptor , transcription factor , signal transduction , biology , transcriptional regulation , cell growth , receptor , gene , chemistry , genetics
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 co‐activator MRTF‐A and SRF, the other the transcriptional co‐activator YAP and TEAD. These pathways have not been compared for their relative importance and potential interactions in RhoA target gene expression. GPCRs for thrombin and 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 co‐activators 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 co‐IPs from S1P stimulated cells. ChIP analysis of the CCN1 promoter demonstrates that S1P increases co‐activator binding at their canonical transcription factor sequences. Unexpectedly, SIP 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. Support or Funding Information This work was supported by NIH Grant GM036927, HL028143, and PPG/HL085577 to JHB, and by HL097037 and AHA Grant 15GRNT22970009 to SM. OY was supported by T32 GM007752 (Graduate Training in Cellular and Molecular Pharmacology) and T32 DK007541 (Endocrinology and Metabolism Training Grant).