ArticleProceedings of the National Academy of Sciences of the United States of America2022
Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Targeting tumor-associated G-protein coupled receptors: beyond single-axis inhibition toward multidimensional regulation.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Constitutive AMPK activation prevents hepatocellular carcinoma development through inhibition of HNF4α activity.Science advances · 2026Article
- Computational Identification of Triphala-Derived Sterol Compounds as Putative Agonists of the Human Takeda G Protein-Coupled Receptor (TGR5).International journal of molecular sciences · 2026Article
- Conformation-programmed DNA computing.Science advances · 2026Article
- Regulation of G protein-coupled receptor kinase 2 and its role in tumors.Journal of translational medicine · 2026Review
- Research Progress on the Mechanism and Targeted Intervention of G Protein-Coupled Bile Acid Receptor 1 (GPBAR1)-Mediated "Inflammation-Apoptosis-Metabolism-Microcirculation" Regulatory Network in Hepatitis B-Associated Liver Failure.Drug design, development and therapy · 2026Review
- G protein-coupled receptors as novel therapeutic targets in non-small-cell lung cancer.Medical review (2021) · 2025Review
- Down-regulation of MFNG promotes the metastatic potential of lung adenocarcinoma by regulating TGF-β/Smad signaling.iScience · 2025Article
- Identification of metabolic driver genes and targeted drug screening for lung adenocarcinoma metastasis at the single-cell resolution.Translational cancer research · 2025Article
- Differential roles of individual bile acid in physiology and disease.Pharmacological research · 2025Review
- Discovery ofActa pharmaceutica Sinica. B · 2025Article
- Biological Actions of Bile Acids via Cell Surface Receptors.International journal of molecular sciences · 2025Review
- S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity.Nature communications · 2025Article
- Interplay between bile acids, gut microbiota, and the tumor immune microenvironment: mechanistic insights and therapeutic strategies.Frontiers in immunology · 2025Review
- The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach.Archiv der Pharmazie · 2025Article
- Mechanism of action of the bile acid receptor TGR5 in obesity.Acta pharmaceutica Sinica. B · 2024Review
- Analyzing lung cancer risks in patients with impaired pulmonary function through characterization of gut microbiome and metabolites.BMC pulmonary medicine · 2024Article
- Role of YAP Signaling in Regulation of Programmed Cell Death and Drug Resistance in Cancer.International journal of biological sciences · 2024Review
- Review
- Single hormone or synthetic agonist induces GProceedings of the National Academy of Sciences of the United States of America · 2023Article
Corrections and comments
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Authors and funding
22 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for β-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-β-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.