Related Experiment Video

Updated: Nov 4, 2025

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

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GPCR-mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7

Kyoung Moo Choi1, Andrew J Haak1, Ana M Diaz Espinosa1

  • 1Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.

Journal of Cellular Physiology
|May 28, 2021
PubMed

Insights

Researchers uncovered a signaling pathway involving EPAC1/2, RAP2c, and MAP4K7 that inhibits the fibrotic disease regulators YAP and TAZ. This discovery offers new therapeutic targets for fibrotic diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pharmacology

Background:

  • Yes-associated protein (YAP) and PDZ-binding motif (TAZ) are key drivers of fibroblast activation in fibrotic diseases.
  • G protein-coupled receptor (GPCR) agonists can inhibit YAP/TAZ activity, offering a therapeutic strategy for fibrosis.
  • Dopamine D1 receptor agonism shows promise in preclinical models of lung and liver fibrosis, but downstream mechanisms are unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms linking GPCR agonism to YAP/TAZ inactivation in fibroblasts.
  • To identify key signaling molecules in the pathway from GPCR activation to YAP/TAZ inhibition.

Main Methods:

  • Utilized human lung fibroblasts to investigate signaling pathways.
  • Employed molecular biology techniques to identify and characterize key signaling components.

Main Results:

  • Identified EPAC1/2, RAP2c, and MAP4K7 as critical mediators in the signaling cascade.
  • Demonstrated that this cascade links GPCR agonism to LATS1/2-mediated YAP/TAZ phosphorylation and nuclear exclusion.
  • Confirmed the essential role of this cascade in dopamine D1 receptor agonist effects on fibroblast functions.

Conclusions:

  • The EPAC/RAP2c/MAP4K7 signaling cascade is crucial for GPCR-mediated inhibition of YAP/TAZ in fibroblasts.
  • Targeting this cascade presents a potential therapeutic strategy for fibrotic diseases by modulating fibroblast activity.
Keywords:
DRD1HippocAMPdihydrexidinedopaminefibrosis

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