GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

Zmajkovicova, Katarina; Bauer, Yasmina; Menyhart, Katalin; Schnoebelen, Marie; Freti, Diego; Boucher, Maxime; Renault, Bérengère; Studer, R. O.; Birker‐Robaczewska, Magdalena; Klenk, Axel; Nayler, Oliver; Gatfield, John

doi:10.1371/journal.pone.0228195

Cited by 26 publications

(22 citation statements)

References 89 publications

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“…One upstream mechanism for controlling YAP and TAZ is agonism of G protein coupled receptors (GPCRs) (Yu et al, 2012(Yu et al, , 2013. Ligands that activate GPCRs of the Gα12/13, Gαq/11 and Gαi/o classes, such as LPA, S1P and thrombin, inhibit the Hippo pathway large tumor suppressor 1 and 2 (LATS1/2) kinases, thereby promoting nuclear accumulation of YAP/TAZ (Yu et al, 2012(Yu et al, , 2013Zmajkovicova et al, 2020). In contrast, Gαscoupled GPCRs, which signal through increases in cyclic adenosine monophosphate (cAMP), activate the Hippo pathway LATS1/2 kinases (Yu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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

Choi

Haak

Espinosa

et al. 2021

Journal Cellular Physiology

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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.

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Section: Introductionmentioning

confidence: 99%

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

Choi

Haak

Espinosa

et al. 2021

Journal Cellular Physiology

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“…In addition to TGF-β, lysophosphatidic acid (LPA) stimulation induces the differentiation of fibroblasts to myofibroblasts [ 53 , 54 ]. LPA binds its own GPCRs to activate cellular responses [ 55 ].…”

Section: Signaling Controlling Differentiation To Myofibroblastsmentioning

confidence: 99%

Cardiac Fibrosis and Fibroblasts

Kurose

2021

Cells

100

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Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are differentiated primarily from resident fibroblasts. Collagen can compensate for the dead cells produced by injury. The appropriate production of collagen is beneficial for preserving the structural integrity of the heart, and protects the heart from cardiac rupture. However, excessive deposition of collagen causes cardiac dysfunction. Recent studies have demonstrated that myofibroblasts can change their phenotypes. In addition, myofibroblasts are found to have functions other than ECM production. Myofibroblasts have macrophage-like functions, in which they engulf dead cells and secrete anti-inflammatory cytokines. Research into fibroblasts has been delayed due to the lack of selective markers for the identification of fibroblasts. In recent years, it has become possible to genetically label fibroblasts and perform sequencing at single-cell levels. Based on new technologies, the origins of fibroblasts and myofibroblasts, time-dependent changes in fibroblast states after injury, and fibroblast heterogeneity have been demonstrated. In this paper, recent advances in fibroblast and myofibroblast research are reviewed.

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“…To this end, several studies have shed further light on the signaling mechanisms that mediate Yap/Taz activation in fibroblasts. G-protein-couple receptors have been shown to regulate Yap activity in response to TGFβ stimulation ( 44 ). In the bleomycin injury model, the profibrotic effects of Yap have been shown to be regulated by TGFβ via sphingosine-1-phosphate (S1p), a signaling lipid, and use of an antibody blocking S1p receptors reduced TGFβ-mediated YAP activation ( 45 ).…”

Section: Yap Activity In the Lung Fibroblastsmentioning

confidence: 99%

The Role of Hippo/YAP Signaling in Alveolar Repair and Pulmonary Fibrosis

Gokey

Kropski

2021

Front. Med.

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Pulmonary fibrosis is characterized by loss of normal alveoli, accumulation of pathologic activated fibroblasts, and exuberant extracellular matrix deposition that over time can lead to progressive loss of respiratory function and death. This loss of respiratory function is associated with the loss of alveolar type 1 cells (AT1) that play a crucial role in gas exchange and the depletion of the alveolar type 2 cells (AT2) that act as progenitor cells to regenerate the AT1 and AT2 cell populations during repair. Understanding the mechanisms that regulate normal alveolar repair and those associated with pathologic repair is essential to identify potential therapeutic targets to treat or delay progression of fibrotic diseases. The Hippo/YAP developmental signaling pathway has been implicated as a regulator of normal alveolar development and repair. In idiopathic pulmonary fibrosis, aberrant activation of YAP/TAZ has been demonstrated in both the alveolar epithelium and activated fibroblasts associated with increased fibrotic remodeling, and there is emerging interest in this pathway as a target for antifibrotic therapies. In this review, we summarize current evidence as to the role of the Hippo-YAP/TAZ pathway in alveolar development, homeostasis, and repair, and highlight key questions that must be resolved to determine effective strategies to modulate YAP/TAZ signaling to prevent progressive pulmonary fibrosis and enhance adaptive alveolar repair.

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GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

Cited by 26 publications

References 89 publications

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

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

Cardiac Fibrosis and Fibroblasts

The Role of Hippo/YAP Signaling in Alveolar Repair and Pulmonary Fibrosis

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