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

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

doi:10.1002/jcp.30459

Cited by 11 publications

(12 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this, we have observed prominent nuclear staining for YAP and TAZ in interstitial cells of IPF, but not control lungs (Liu et al, 2015). In previous work, we performed a GPCR-focused transcriptome screen to reveal the D1 dopamine receptor as a target to inactivate YAP/TAZ in lung fibroblasts, and we showed that an agonist of the D1 receptor, dihydrexidine, blocks YAP/TAZ nuclear localization, stimulates collagen degradation, and promotes lung fibrosis resolution in a 6 bleomycin lung injury model of fibrosis, consistent with the D1 receptor exclusively coupling to G alpha s (Choi et al, 2021;Diaz-Espinosa et al, 2020;Haak et al, 2019).…”

Section: Introductionsupporting

confidence: 52%

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Gao

Espinosa

Nguyen

et al. 2023

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and TGF-β1 signaling which together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors which couple to G alpha s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of "antifibrotic GPCRs"-receptors which couple to G alpha s, in IPF patient-derived fibroblasts compared to non-IPF samples. Of the 14 G alpha s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 (DRD1) was one of only two not repressed by TGF-β1 signaling, with the β2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and β2 receptor agonists +/-TGF-β1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of β2 receptor agonists was lost, while D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-β1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-β1 signaling.

show abstract

Section: Introductionsupporting

confidence: 52%

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Gao

Espinosa

Nguyen

et al. 2023

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…115 The Hippo pathway has been shown to be regulated by GPCR signalling. [116][117][118][119] For example, it was shown that GPCR ligands such as thrombin or lysophosphatidic acid (LPA) could activate YAP in fibroblasts and sensitize them to TGF-β1. 120 Additionally, sphingosine-1-phosphate (SIP) is a ligand of GPCR.…”

Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

219

View full text Add to dashboard Cite

As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

show abstract

“…LATS phosphorylation on S909 and T1079 is carried out by MST kinase (Chan et al, 2005; Hoa et al, 2016), but LATS can also be phosphorylated by MAP4 kinases (MAP4Ks) (Meng et al, 2015; Zheng et al, 2015) or STK25 kinase (Lim et al, 2019). In addition, both GPCR‐Rho‐F‐actin and cAMP‐PKA‐F‐actin (Choi et al, 2021; Yu et al, 2012) can activate the phosphorylation of LATS independently of MST, similar to the apparent effects of DMPCA on LATS. While it is tempting to speculate that a molecule in these actin pathways may be involved, the kinases or mechanisms responsible for DMPCA‐induced LATS phosphorylation remain under investigation.…”

Section: Discussionmentioning

confidence: 94%

N‐(3,4‐dimethoxyphenethyl)‐6‐methyl‐2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐amine inhibits bladder cancer progression by suppressing YAP1/TAZ

et al. 2022

View full text Add to dashboard Cite

Bladder cancer (BlC) is the fourth most common cancer in males worldwide, but few systemic chemotherapy options for its effective treatment exist. The development of new molecularly‐targeted agents against BlC is therefore an urgent issue. The Hippo signaling pathway, with its upstream LATS kinases and downstream transcriptional co‐activators YAP1 and TAZ, plays a pivotal role in diverse cell functions, including cell proliferation. Recent studies have shown that overexpression of YAP1 occurs in advanced BlCs and is associated with poor patient prognosis. Accessing data from our previous screening of a chemical library of compounds targeting the Hippo pathway, we identified DMPCA (N‐(3,4‐dimethoxyphenethyl)‐6‐methyl‐2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐amine) as an agent able to induce the phosphorylation of LATS1 and YAP1/TAZ in BlC cells, thereby suppressing their viability both in vitro and in mouse xenografts. Our data indicate that DMPCA has a potent anti‐tumor effect, and raise the possibility that this agent may represent a new and effective therapeutic option for BlC.

show abstract

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

Cited by 11 publications

References 53 publications

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

The Hippo signalling pathway and its implications in human health and diseases

N‐(3,4‐dimethoxyphenethyl)‐6‐methyl‐2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐amine inhibits bladder cancer progression by suppressing YAP1/TAZ

Contact Info

Product

Resources

About