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

Kyoung Moo Choi; Andrew J Haak; Ana M Diaz Espinosa; Katherine A Cummins; Patrick A Link; Aja Aravamudhan; David K Wood; Daniel J Tschumperlin

doi:10.1002/jcp.30459

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

Journal article

Peer reviewed

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

Kyoung Moo Choi, Andrew J Haak, Ana M Diaz Espinosa, Katherine A Cummins, Patrick A Link, Aja Aravamudhan, David K Wood and Daniel J Tschumperlin

Journal of cellular physiology, Vol.236(11), pp.7759-7774

11/2021

DOI: 10.1002/jcp.30459

PMCID: PMC8530868

PMID: 34046891

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https://www.ncbi.nlm.nih.gov/pmc/articles/8530868View

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Abstract

Yes-associated protein (YAP) and PDZ-binding motif (TAZ) have emerged as important regulators of pathologic fibroblast activation in fibrotic diseases. Agonism of Gαs-coupled G protein coupled receptors (GPCRs) provides an attractive approach to inhibit the nuclear localization and function of YAP and TAZ in fibroblasts that inhibits or reverses their pathological activation. Agonism of the dopamine D1 GPCR has proven effective in preclinical models of lung and liver fibrosis. However, the molecular mechanisms coupling GPCR agonism to YAP and TAZ inactivation in fibroblasts remain incompletely understood. Here, using human lung fibroblasts, we identify critical roles for the cAMP effectors EPAC1/2, the small GTPase RAP2c, and the serine/threonine kinase MAP4K7 as the essential elements in the downstream signaling cascade linking GPCR agonism to LATS1/2-mediated YAP and TAZ phosphorylation and nuclear exclusion in fibroblasts. We further show that this EPAC/RAP2c/MAP4K7 signaling cascade is essential to the effects of dopamine D1 receptor agonism on reducing fibroblast proliferation, contraction, and extracellular matrix production. Targeted modulation of this cascade in fibroblasts may prove a useful strategy to regulate YAP and TAZ signaling and fibroblast activities central to tissue repair and fibrosis.

Cells, Cultured

Dopamine Agonists - pharmacology

Fibroblasts - drug effects

Fibroblasts - enzymology

Fibroblasts - pathology

Fibrosis

Guanine Nucleotide Exchange Factors - genetics

Guanine Nucleotide Exchange Factors - metabolism

Humans

Phenanthridines - pharmacology

Phosphorylation

Protein Serine-Threonine Kinases - metabolism

ras Proteins - genetics

ras Proteins - metabolism

Receptors, Dopamine D1 - agonists

Receptors, Dopamine D1 - metabolism

Signal Transduction

Transcriptional Coactivator with PDZ-Binding Motif Proteins - genetics

Transcriptional Coactivator with PDZ-Binding Motif Proteins - metabolism

YAP-Signaling Proteins - genetics

YAP-Signaling Proteins - metabolism

Details

Title: Subtitle: GPCR-mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7
Creators: Kyoung Moo Choi - Mayo Clinic
Andrew J Haak - Mayo Clinic
Ana M Diaz Espinosa - Mayo Clinic
Katherine A Cummins - University of Minnesota
Patrick A Link - Mayo Clinic
Aja Aravamudhan - Mayo Clinic
David K Wood - University of Minnesota
Daniel J Tschumperlin - Mayo Clinic
Resource Type: Journal article
Publication Details: Journal of cellular physiology, Vol.236(11), pp.7759-7774
DOI: 10.1002/jcp.30459
PMID: 34046891
PMCID: PMC8530868
NLM abbreviation: J Cell Physiol
ISSN: 0021-9541
eISSN: 1097-4652
Grant note: R01 HL092961 / NHLBI NIH HHS HL105355 / NHLBI NIH HHS R01 HL133320 / NHLBI NIH HHS HL132256 / NHLBI NIH HHS R21 HL132256 / NHLBI NIH HHS T32 HL105355 / NHLBI NIH HHS HL092961 / NHLBI NIH HHS
Language: English
Date published: 11/2021
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center
Record Identifier: 9984948142302771

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