ArticleProceedings of the National Academy of Sciences of the United States of America2000
Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 222 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
222 citing papers in PubMed, 670 citations in OpenAlex.
- CRS-related coagulopathy in BCMA targeted CAR-T therapy: a retrospective analysis in a phase I/II clinical trial.Bone marrow transplantation · 2021Trial
- Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy.International journal of molecular sciences · 2026Review
- Multi-Omics Reveals Early Pregnancy Placental Dysfunction Associated With Preterm and Term Preeclampsia.MedComm · 2026Article
- Patient-Derived Procoagulant Breast Fibroblasts Expressing Tissue Factor Promote Breast Cancer Cell Migration.Journal of mammary gland biology and neoplasia · 2026Article
- Procoagulant Extracellular Vesicles Increase Neuronal Tau expression, Metabolism and Processing Through Tissue Factor and Protease Activated Receptor 2.Cellular and molecular neurobiology · 2026Article
- Reframing ATR: from the immunologic/nonimmunologic dichotomy to adaptive, innate, and physicochemical drivers within the allergy-inflammation-coagulation axis.Frontiers in immunology · 2026Review
- Serine proteases and protease-activated receptors signaling in the kidney.American journal of physiology. Cell physiology · 2025Review
- Extravascular coagulation regulates haemostasis independently of activated platelet surfaces in an in vivo mouse model.Communications biology · 2025Article
- Comparison of the procoagulant activity between extracellular vesicles obtained from cellular monolayers and spheroids.Journal of thrombosis and thrombolysis · 2025Article
- Non-classical neutrophil extracellular traps induced by PAR2-signaling proteases.Cell death & disease · 2025Article
- The Many Faces of Protease-Activated Receptor 2 in Kidney Injury.Biomedicines · 2025Review
- Coagulo-Net: Enhancing the mathematical modeling of blood coagulation using physics-informed neural networks.Neural networks : the official journal of the International Neural Network Society · 2024Article
- FXa-mediated PAR-2 promotes the efficacy of immunotherapy for hepatocellular carcinoma through immune escape and anoikis resistance by inducing PD-L1 transcription.Journal for immunotherapy of cancer · 2024Article
- Review
- Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions.International journal of molecular sciences · 2024Review
- Coagulation and Inflammation in COVID-19: Reciprocal Relationship between Inflammatory and Coagulation Markers.Annals of hematology · 2024Review
- Coagulation Protease-Driven Cancer Immune Evasion: Potential Targets for Cancer Immunotherapy.Cancers · 2024Review
- Endotoxemia and Platelets: 2 Players of Intrahepatic Microthrombosis in NAFLD.JACC. Basic to translational science · 2024Review
- The Role of Tissue Factor In Signaling Pathways of Pathological Conditions and Angiogenesis.Current molecular medicine · 2024Review
- Endothelial-derived microvesicles promote pro-migratory cross-talk with smooth muscle cells by a mechanism requiring tissue factor and PAR2 activation.Frontiers in cardiovascular medicine · 2024Article
162 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Protease-activated receptor 2 (PAR2) is expressed by vascular endothelial cells and other cells in which its function and physiological activator(s) are unknown. Unlike PAR1, PAR3, and PAR4, PAR2 is not activatable by thrombin. Coagulation factors VIIa (FVIIa) and Xa (FXa) are proteases that act upstream of thrombin in the coagulation cascade and require cofactors to interact with their substrates. These proteases elicit cellular responses, but their receptor(s) have not been identified. We asked whether FVIIa and FXa might activate PARs if presented by their cofactors. Co-expression of tissue factor (TF), the cellular cofactor for FVIIa, together with PAR1, PAR2, PAR3, or PAR4 conferred TF-dependent FVIIa activation of PAR2 and, to lesser degree, PAR1. Responses to FXa were also observed but were independent of exogenous cofactor. The TF/FVIIa complex converts the inactive zymogen Factor X (FX) to FXa. Strikingly, when FX was present, low picomolar concentrations of FVIIa caused robust signaling in cells expressing TF and PAR2. Responses in keratinocytes and cytokine-treated endothelial cells suggested that PAR2 may be activated directly by TF/FVIIa and indirectly by TF/FVIIa-generated FXa at naturally occurring expression levels of TF and PAR2. These results suggest that PAR2, although not activatable by thrombin, may nonetheless function as a sensor for coagulation proteases and contribute to endothelial activation in the setting of injury and inflammation. More generally, these findings highlight the potential importance of cofactors in regulating PAR function and specificity.
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Registered trials
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 OpenQuestion graph.