Abstract
Mechanical forces regulate cell functions through multiple pathways. G protein-coupled estrogen receptor (GPER) is a seven-transmembrane receptor that is ubiquitously expressed across tissues and mediates the acute cellular response to estrogens. Here, we demonstrate an unidentified role of GPER as a cellular mechanoregulator. G protein-coupled estrogen receptor signaling controls the assembly of stress fibers, the dynamics of the associated focal adhesions, and cell polarization via RhoA GTPase (RhoA). G protein-coupled estrogen receptor activation inhibits F-actin polymerization and subsequently triggers a negative feedback that transcriptionally suppresses the expression of monomeric G-actin. Given the broad expression of GPER and the range of cytoskeletal changes modulated by this receptor, our findings position GPER as a key player in mechanotransduction.
Highlights
The G protein-coupled estrogen receptor (GPER) belongs to the heptahelical transmembrane family of G protein-coupled receptors (GPCRs) and initiates rapid signaling cascades in response to both endogenous estrogens such as 17β-estradiol and man-made compounds (Revankar et al, 2005; Prossnitz and Barton, 2011)
We used immunoassays to measure activated (GTP-bound) and total levels of RhoA and observed a significant 40% decrease in the levels of GTP-bound RhoA in Human foreskin fibroblasts (HFFs) treated with the selective GPER agonist (Bologa et al, 2006) G1 compared with control HFFs, whereas no significant change in total RhoA was observed between the control and G1-treated HFFs (Figure 1A)
Using Western blot, we confirmed that there was no change in the total levels of RhoA between the control and G1-treated HFFs, and observed around 45% increase in the levels of RhoA phosphorylated in serine 188 in G1-treated HFFs compared with control HFFs (Figure 1C and Supplementary Figure 1)
Summary
The G protein-coupled estrogen receptor (GPER) belongs to the heptahelical transmembrane family of G protein-coupled receptors (GPCRs) and initiates rapid signaling cascades in response to both endogenous estrogens such as 17β-estradiol and man-made compounds (Revankar et al, 2005; Prossnitz and Barton, 2011). The RhoA GTPase (RhoA) is one of the most prominent members of the Rho GTPase family, which controls and shapes actin cytoskeleton by promoting actin polymerization via formins (mDia), and through actomyosin contractility by triggering the phosphorylation of the regulatory myosin light chain-2 (MLC-2) via Rho kinase (ROCK; Sadok and Marshall, 2014) This RhoA-dependent induction of cytoskeletal contractility is required for the nuclear translocation and activation of the transcriptional factor yes-associated protein 1 (YAP), a mechanotransducer that has cardinal roles in development, tissue homeostasis (Dupont et al, 2011), cancer (Calvo et al, 2013), and cardiovascular diseases (Wang et al, 2016). Yes-associated protein 1 activation influences further mechanical processes including genomic regulation of focal adhesion formation (Nardone et al, 2017)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
