Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity

Ma, Lijuan; Yang, Fan; Wu, Xiang; Mao, Chunyou; Guo, Lulu; Miao, Tianshu; Zang, Shaokun; Jiang, Xiaoyu; Shen, Dan‐Dan; Wei, Tianhui; Zhou, Hengxing; Wei, Qin; Li, Shiyang; Shu, Qiang; Feng, Shiqing; Jiang, Changtao; Chu, Bo; Du, Lutao; Sun, Jin Peng; Yu, Xiao; Zhang, Yan; Zhang, Pengju

doi:10.1073/pnas.2117054119

Cited by 10 publications

(9 citation statements)

References 59 publications

(89 reference statements)

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“…The GPBAR is highly expressed in non-small cell lung cancer (NSCLC), and a positive correlation exists between GPBAR expression levels and the clinical progression of NSCLC (Liu et al, 2018). Ma et al (Ma et al, 2022) recently identified a novel GPBAR agonist, R399, that preferentially promotes βarr1 signaling. Studies with NSCLC cells showed that R399 stimulated YAP signaling and cell proliferation in a βarr1-dependent fashion (Ma et al, 2022).…”

Section: Medulloblastoma Medulloblastoma (Mb) Is the Most Common Pedi...mentioning

confidence: 99%

“…Ma et al (Ma et al, 2022) recently identified a novel GPBAR agonist, R399, that preferentially promotes βarr1 signaling. Studies with NSCLC cells showed that R399 stimulated YAP signaling and cell proliferation in a βarr1-dependent fashion (Ma et al, 2022). In contrast, treatment of NSCLC cells with a G protein-biased GPBAR agonist, INT-777, interfered with YAP signaling, inhibited cell proliferation, and induced apoptosis (Ma et al, 2022).…”

Section: Medulloblastoma Medulloblastoma (Mb) Is the Most Common Pedi...mentioning

confidence: 99%

“…Studies with NSCLC cells showed that R399 stimulated YAP signaling and cell proliferation in a βarr1-dependent fashion (Ma et al, 2022). In contrast, treatment of NSCLC cells with a G protein-biased GPBAR agonist, INT-777, interfered with YAP signaling, inhibited cell proliferation, and induced apoptosis (Ma et al, 2022). These new data are highly relevant for the design of novel anticancer agents targeting the GPBAR.…”

Section: Medulloblastoma Medulloblastoma (Mb) Is the Most Common Pedi...mentioning

confidence: 99%

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β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

Wess¹,

Oteng²,

Rivera‐Gonzalez³

et al. 2023

Pharmacol Rev

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The two β-arrestins, β-arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiological functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both β-arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent orindependent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how β-arrestins bind to activated GPCRs and downstream effector proteins.Studies with β-arrestin mutant mice have identified numerous physiological and pathophysiological processes regulated by β-arrestin-1 and/or -2. Following a short summary of recent structural studies, this review will primarily focus on β-arrestin-regulated physiological functions, with particular focus on the central nervous system and the roles of β-arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review will also highlight potential therapeutic implications of these studies and discuss strategies that could prove useful for targeting specific β-arrestin-regulated signaling pathways for therapeutic purposes.

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Section: Medulloblastoma Medulloblastoma (Mb) Is the Most Common Pedi...mentioning

confidence: 99%

Section: Medulloblastoma Medulloblastoma (Mb) Is the Most Common Pedi...mentioning

confidence: 99%

Section: Medulloblastoma Medulloblastoma (Mb) Is the Most Common Pedi...mentioning

confidence: 99%

See 1 more Smart Citation

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

Wess¹,

Oteng²,

Rivera‐Gonzalez³

et al. 2023

Pharmacol Rev

View full text Add to dashboard Cite

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“…On the other hand, when complexing with INT-777, which is also an agonist, priority is given to activating GPBAR-Gs signalling, inhibiting cell proliferation and inducing apoptosis. The reason for this difference is that different ligands have different complexed residual sites with TGR5, which leads to biased activation of the signal 32 . Unexpectedly, the study found that there is a second ligand-binding cavity in TGR5.…”

Section: The Bile Acid Receptor Tgr5mentioning

confidence: 99%

Mechanism of action of the bile acid receptor TGR5 in obesity

Lun,

Yan,

Guo

et al. 2024

Acta Pharmaceutica Sinica B

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“…[16] G protein-coupled bile acid receptor activation can control YAP activity and regulate distinct functions of cell growth and apoptosis. [20] Therefore, we hypothesized that GRK2, a regulator of GPCR, modulated the YAP signaling and contributed to PAH in mice and humans.…”

Section: Introductionmentioning

confidence: 99%

GRK2–YAP signaling is implicated in pulmonary arterial hypertension development

Ye,

Deng,

et al. 2024

Chinese Medical Journal

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Background: Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown. Methods: GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice (Grk2 Δ SM22), and littermate controls (Grk2 flox/flox) were grouped into control and hypoxia mice (n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays. Results: The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2 Δ SM22 mice compared with littermate controls. The amelioration of PH in Grk2 Δ SM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions. Conclusion: Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment.

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Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity

Cited by 10 publications

References 59 publications

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

Mechanism of action of the bile acid receptor TGR5 in obesity

GRK2–YAP signaling is implicated in pulmonary arterial hypertension development

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