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

Autor: Ma L; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China., Yang F; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China.; Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.; Advanced Medical Research Institute, Shandong University, Jinan 250012, China., Wu X; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China., Mao C; Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China., Guo L; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China., Miao T; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China., Zang SK; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 310058, China.; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.; Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou 310058, China., Jiang X; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China., Shen DD; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 310058, China.; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.; Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou 310058, China., Wei T; Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Zhou H; Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Center for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Wei Q; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China., Li S; Advanced Medical Research Institute, Shandong University, Jinan 250012, China., Shu Q; Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Jinan 250033, China., Feng S; Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Center for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan 250012, China., Jiang C; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China., Chu B; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China., Du L; Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China., Sun JP; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China.; Advanced Medical Research Institute, Shandong University, Jinan 250012, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China., Yu X; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China.; Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China., Zhang Y; Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 310058, China.; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.; Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou 310058, China., Zhang P; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250012, China.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Jul 19; Vol. 119 (29), pp. e2117054119. Date of Electronic Publication: 2022 Jul 15.
DOI: 10.1073/pnas.2117054119
Abstrakt: 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.
Databáze: MEDLINE
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