ArticleProceedings of the National Academy of Sciences of the United States of America2021
aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 27 citations in OpenAlex.
- Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment.EMBO molecular medicine · 2026Article
- Targeting PAR1 biased signaling with parmodulin reduces thromboinflammation and acute lung injury in sickle cell disease.Blood advances · 2026Article
- Signaling bias of the protease-activated receptor-1 is dictated by distinct GRK5 and β-arrestin-2 determinants.Cell reports · 2026Article
- Activated protein C drives β-arrestin-2- and c-Src-dependent phosphorylation of Cav1 and modulates Cav1 association with PAR1 and GRK5.The Journal of biological chemistry · 2026Article
- Activated Protein C and the Retina: From Physiology to Therapeutic Potential.International journal of molecular sciences · 2026Review
- Regulation of histones in thromboinflammation.Frontiers in immunology · 2026Review
- Biomechanical properties of the trabecular meshwork in intraocular pressure regulation: a review.International ophthalmology · 2025Review
- Endothelial protease-activated receptor 4: impotent or important?Frontiers in cardiovascular medicine · 2025Review
- An optimized fractionation method reveals insulin-induced membrane surface localization of GLUT1 to increase glycolysis in LβT2 cells.Molecular and cellular endocrinology · 2025Article
- Platelets at the intersection of inflammation and coagulation in the APC-mediated response to myocardial ischemia/reperfusion injury.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Review
- Hemostasis and endothelial functionality: the double face of coagulation factors.Haematologica · 2024Review
- Endothelial cell sphingosine 1-phosphate receptor 1 restrains VE-cadherin cleavage and attenuates experimental inflammatory arthritis.JCI insight · 2024Article
- Autoantibodies Targeting G-Protein-Coupled Receptors: Pathogenetic, Clinical and Therapeutic Implications in Systemic Sclerosis.International journal of molecular sciences · 2024Review
- Involvement of PAR-2 in the Induction of Cell-Specific Matrix Metalloproteinase-2 by Activated Protein C in Cutaneous Wound Healing.International journal of molecular sciences · 2023Article
- Factor VIIa releases phosphatidylserine-enriched extracellular vesicles from endothelial cells by activating acid sphingomyelinase.Journal of thrombosis and haemostasis : JTH · 2023Article
- Mechanosensitive ion channel gene survey suggests potential roles in primary open angle glaucoma.Scientific reports · 2023Article
- Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.Cell research · 2023Article
- Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice.Blood advances · 2023Article
- The APC-EPCR-PAR1 axis in sickle cell disease.Frontiers in medicine · 2023Review
- Endothelial APC/PAR1 distinctly regulates cytokine-induced pro-inflammatory VCAM-1 expression.Frontiers in molecular biosciences · 2023Article
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
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.
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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 Socratic graph.