气候变化领域集成服务门户(CCPortal): aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis

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DOI	10.1073/pnas.2106623118
	aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis
	Molinar-Inglis O.; Birch C.A.; Nicholas D.; Orduña-Castillo L.; Cisneros-Aguirre M.; Patwardhan A.; Chen B.; Grimsey N.J.; Coronel L.J.; Lin H.; Gomez Menzies P.K.; Lawson M.A.; Patel H.H.; Trejo J.
发表日期	2021
ISSN	1091-6490
卷号	118 期号:49
英文摘要	Endothelial dysfunction is associated with vascular disease and results in disruption of endothelial barrier function and increased sensitivity to apoptosis. Currently, there are limited treatments for improving endothelial dysfunction. Activated protein C (aPC), a promising therapeutic, signals via protease-activated receptor-1 (PAR1) and mediates several cytoprotective responses, including endothelial barrier stabilization and anti-apoptotic responses. We showed that aPC-activated PAR1 signals preferentially via β-arrestin-2 (β-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to promote Rac1 activation and barrier protection. However, the signaling pathways utilized by aPC/PAR1 to mediate anti-apoptotic activities are not known. aPC/PAR1 cytoprotective responses also require coreceptors; however, it is not clear how coreceptors impact different aPC/PAR1 signaling pathways to drive distinct cytoprotective responses. Here, we define a β-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. Using human cultured endothelial cells, we found that endogenous PAR1 and S1PR1 coexist in caveolin-1 (Cav1)-rich microdomains and that S1PR1 coassociation with Cav1 is increased by aPC activation of PAR1. Our study further shows that aPC stimulates β-arr2-dependent SphK1 activation independent of Dvl2 and is required for transactivation of S1PR1-Akt signaling and protection against cell death. While aPC/PAR1-induced, extracellular signal-regulated kinase 1/2 (ERK1/2) activation is also dependent on β-arr2, neither SphK1 nor S1PR1 are integrated into the ERK1/2 pathway. Finally, aPC activation of PAR1-β-arr2-mediated protection against apoptosis is dependent on Cav1, the principal structural protein of endothelial caveolae. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete, β-arr2-driven signaling pathways in caveolae.
英文关键词	biased signaling; cytoprotection; endothelial dysfunction; GPCR
语种	英语
scopus关键词	3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; anilide; antithrombocytic agent; beta arrestin 2; enzyme inhibitor; fused heterocyclic rings; lactone; methanol; PF-543; phosphonic acid derivative; phosphotransferase; protein C; protein kinase B; proteinase activated receptor 1; pyridine derivative; pyrrolidine derivative; S1PR1 protein, human; sphingosine kinase; sulfone; vorapaxar; apoptosis; drug effect; endothelium cell; gene expression regulation; genetics; human; metabolism; physiology; Anilides; Apoptosis; beta-Arrestin 2; Endothelial Cells; Enzyme Inhibitors; Gene Expression Regulation; Heterocyclic Compounds, 3-Ring; Humans; Lactones; Methanol; Organophosphonates; Phosphotransferases (Alcohol Group Acceptor); Platelet Aggregation Inhibitors; Protein C; Proto-Oncogene Proteins c-akt; Pyridines; Pyrrolidines; Receptor, PAR-1; Sphingosine-1-Phosphate Receptors; Sulfones
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250942
作者单位	Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, 92093, Italy; Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697; Department of Pharmaceutical Sciences and Biomedical Sciences, School of Pharmacy, University of Georgia, Athens, United States; Department of Obstetrics, Gynecology, Reproductive Sciences, School of Medicine, University of California San Diego, La Jolla, CA, 92093, Italy; VA San Diego Health Care System, San Diego, CA 92161; Department of Anesthesiology, School of Medicine, University of California San Diego, La Jolla, CA, 92093, Italy; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093
推荐引用方式 GB/T 7714	Molinar-Inglis O.,Birch C.A.,Nicholas D.,et al. aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis[J],2021,118(49).
APA	Molinar-Inglis O..,Birch C.A..,Nicholas D..,Orduña-Castillo L..,Cisneros-Aguirre M..,...&Trejo J..(2021).aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis.Proceedings of the National Academy of Sciences of the United States of America,118(49).
MLA	Molinar-Inglis O.,et al."aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis".Proceedings of the National Academy of Sciences of the United States of America 118.49(2021).