ArticleThe Journal of biological chemistry2011
The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 94 citations in OpenAlex.
- Epithelial TMPRSS2 impairs glucose homeostasis in obese mice by regulating ghrelin-GLP-1 receptor signaling pathway.JCI insight · 2026Article
- Tissue factor and regenerative medicine: shaping cell and extracellular vesicle-based therapeutic approaches.Frontiers in cell and developmental biology · 2026Review
- Protease-activated receptors in vascular smooth muscle cells: a bridge between thrombo-inflammation and vascular remodelling.Cell communication and signaling : CCS · 2025Review
- Endothelial Protein C Receptor and Its Impact on Rheumatic Disease.Journal of clinical medicine · 2024Review
- Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development.Blood · 2024Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Recombinant Human Thrombomodulin Reduces Mortality and Acute Lung Injury Caused by Septic Peritonitis in Rats.ImmunoHorizons · 2023Article
- EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia.JCI insight · 2022Article
- Regulation of coagulation by tissue factor pathway inhibitor: Implications for hemophilia therapy.Journal of thrombosis and haemostasis : JTH · 2022Review
- Markers for human haematopoietic stem cells: The disconnect between an identification marker and its function.Frontiers in physiology · 2022Review
- The Evolving Concept of Neuro-Thromboinflammation for Neurodegenerative Disorders and Neurotrauma: A Rationale for PAR1-Targeting Therapies.Biomolecules · 2021Review
- Uncovering Membrane-Bound Models of Coagulation Factors by Combined Experimental and Computational Approaches.Thrombosis and haemostasis · 2021Review
- Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19.Journal of thrombosis and haemostasis : JTH · 2021Article
- Roles of factor Xa beyond coagulation.Journal of thrombosis and thrombolysis · 2021Article
- Lipid presentation by the protein C receptor links coagulation with autoimmunity.Science (New York, N.Y.) · 2021Article
- Macrophage protease-activated receptor 2 regulates fetal liver erythropoiesis in mice.Blood advances · 2020Article
- Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2.RSC medicinal chemistry · 2020Article
- A Pathophysiological Perspective on the SARS-CoV-2 Coagulopathy.HemaSphere · 2020Review
- Beyond thrombosis: the impact of tissue factor signaling in cancer.Journal of hematology & oncology · 2020Review
- Antiviral anticoagulation.Research and practice in thrombosis and haemostasis · 2020Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Protease-activated receptor (PAR) signaling is closely linked to the cellular activation of the pro- and anticoagulant pathways. The endothelial protein C receptor (EPCR) is crucial for signaling by activated protein C through PAR1, but EPCR may have additional roles by interacting with the 4-carboxyglutamic acid domains of procoagulant coagulation factors VII (FVII) and X (FX). Here we show that soluble EPCR regulates the interaction of FX with human or mouse tissue factor (TF)-FVIIa complexes. Mutagenesis of the FVIIa 4-carboxyglutamic acid domain and dose titrations with FX showed that EPCR interacted primarily with FX to attenuate FX activation in lipid-free assay systems. In human cell models of TF signaling, antibody inhibition of EPCR selectively blocked PAR activation by the ternary TF-FVIIa-FXa complex but not by the non-coagulant TF-FVIIa binary complex. Heterologous expression of EPCR promoted PAR1 and PAR2 cleavage by FXa in the ternary complex but did not alter PAR2 cleavage by TF-FVIIa. In murine smooth muscle cells that constitutively express EPCR and TF, thrombin and FVIIa/FX but not FVIIa alone induced PAR1-dependent signaling. Although thrombin signaling was unchanged, cells with genetically reduced levels of EPCR no longer showed a signaling response to the ternary complex. These results demonstrate that EPCR interacts with the ternary TF coagulation initiation complex to enable PAR signaling and suggest that EPCR may play a role in regulating the biology of TF-expressing extravascular and vessel wall cells that are exposed to limited concentrations of FVIIa and FX provided by ectopic synthesis or vascular leakage.
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Registered trials
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