ArticleArteriosclerosis, thrombosis, and vascular biology2024
Thrombomodulin Switches Signaling and Protease-Activated Receptor 1 Cleavage Specificity of Thrombin.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 13 citations in OpenAlex.
- Thrombin concentration shapes endothelial extracellular vesicle profiles with divergent inflammatory functions.Blood advances · 2026Article
- Thrombin reprograms endothelial extracellular vesicles.Blood advances · 2026Article
- Mechanisms and clinical implications of radiation-induced endothelial dysfunction.Radiation oncology (London, England) · 2026Review
- Aerobic exercise inhibits oxidative stress and improves diabetic cardiomyopathy in rats by activating the PROC/PAR1/Nrf2/HO-1 signaling pathway.Frontiers in physiology · 2026Article
- The Influence of PAR 1 and Endothelin 1 on the Course of Specific Kidney Diseases.Journal of clinical medicine · 2025Article
- Human tissue kallikrein 14 induces the expression of IL-6, IL-8, and CXCL1 in skin fibroblasts through protease-activated receptor 1 signaling.The FEBS journal · 2025Article
- The thrombin receptor PAR1 orchestrates changes in lymphatic endothelial cell junction morphology to augment lymphatic drainage during lung injury.Nature cardiovascular research · 2025Article
- Human endothelial colony forming cells (ECFCs) require endothelial protein C receptor (EPCR) for cell cycle progression and angiogenic activity.Angiogenesis · 2025Article
- The Influence of Anti-PAR 1 and Anti-ACE 2 Antibody Levels on the Course of Specific Glomerulonephritis Types.Journal of clinical medicine · 2025Article
- Article
- Thrombomodulin: a multifunctional receptor modulating the endothelial quiescence.Journal of thrombosis and haemostasis : JTH · 2024Review
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4 authors at 1 institution in 1 country.
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Abstract
backgroundCleavage of the extracellular domain of PAR1 (protease-activated receptor 1) by thrombin at Arg41 and by APC (activated protein C) at Arg46 initiates paradoxical cytopathic and cytoprotective signaling in endothelial cells. In the latter case, the ligand-dependent coreceptor signaling by EPCR (endothelial protein C receptor) is required for the protective PAR1 signaling by APC. Here, we investigated the role of thrombomodulin in determining the specificity of PAR1 signaling by thrombin.
methodsWe prepared a PAR1 knockout (PAR1
resultsCharacterization of transfected cells in signaling and receptor cleavage assays revealed that, upon interaction with thrombomodulin, thrombin cleaves Arg46 to elicit cytoprotective effects by a β-arrestin-2 biased signaling mechanism. Analysis of functional data and cleavage rates indicated that thrombin-thrombomodulin cleaves Arg46>10-fold faster than APC. Upon interaction with thrombin, the cytoplasmic domain of thrombomodulin recruited both β-arrestin-1 and -2 to the plasma membrane. Thus, the thrombin cleavage of Arg41 was also cytoprotective in thrombomodulin-expressing cells by β-arrestin-1-biased signaling. APC in the absence of EPCR cleaved Arg41 to initiate disruptive signaling responses like thrombin.
conclusionsThese results suggest that coreceptor signaling by thrombomodulin and EPCR determines the PAR1 cleavage and signaling specificity of thrombin and APC, respectively.
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