ArticleThe Journal of biological chemistry2008
Dissociation of activated protein C functions by elimination of protein S cofactor enhancement.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 42 citations in OpenAlex.
- Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction.Journal of thrombosis and haemostasis : JTH · 2022Article
- Hemostatic and protein C pathway dysfunction in the pathogenesis of experimental cerebral malaria.Haematologica · 2022Article
- Persistent endotheliopathy in the pathogenesis of long COVID syndrome.Journal of thrombosis and haemostasis : JTH · 2021Article
- Protein C Pathway in Paediatric and Neonatal Sepsis.Frontiers in pediatrics · 2021Review
- Article
- C-terminal residues of activated protein C light chain contribute to its anticoagulant and cytoprotective activities.Journal of thrombosis and haemostasis : JTH · 2020Article
- PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Activated protein C light chain provides an extended binding surface for its anticoagulant cofactor, protein S.Blood advances · 2017Article
- Activated protein C inhibits neutrophil extracellular trap formationThe Journal of biological chemistry · 2017Article
- Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice.Blood · 2015Article
- Protective effects of non-anticoagulant activated protein C variant (D36A/L38D/A39V) in a murine model of ischaemic stroke.PloS one · 2015Article
- Cytoprotective-selective activated protein C therapy for ischaemic stroke.Thrombosis and haemostasis · 2014Review
- Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway.Journal of thrombosis and haemostasis : JTH · 2013Review
- Down-regulation of the clotting cascade by the protein C pathway.Hematology education. European Hematology Association. Congress. Education Program · 2013Article
- Protein C anticoagulant and cytoprotective pathways.International journal of hematology · 2012Review
- Function of the activated protein C (APC) autolysis loop in activated FVIII inactivation.British journal of haematology · 2011Article
- Proteases as therapeutics.The Biochemical journal · 2011Review
- Activated protein C N-linked glycans modulate cytoprotective signaling function on endothelial cells.The Journal of biological chemistry · 2011Article
- Article
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activated protein C (APC) plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va and factor VIIIa and thus down-regulating thrombin generation. In addition, APC bound to the endothelial cell protein C receptor can initiate protease-activated receptor-1 (PAR-1)-mediated cytoprotective signaling. Protein S constitutes a critical cofactor for the anticoagulant function of APC but is not known to be involved in regulating APC-mediated protective PAR-1 signaling. In this study we utilized a site-directed mutagenesis strategy to characterize a putative protein S binding region within the APC Gla domain. Three single amino acid substitutions within the APC Gla domain (D35T, D36A, and A39V) were found to mildly impair protein S-dependent anticoagulant activity (<2-fold) but retained entirely normal cytoprotective activity. However, a single amino acid substitution (L38D) ablated the ability of protein S to function as a cofactor for this APC variant. Consequently, in assays of protein S-dependent factor Va proteolysis using purified proteins or in the plasma milieu, APC-L38D variant exhibited minimal residual anticoagulant activity compared with wild type APC. Despite the location of Leu-38 in the Gla domain, APC-L38D interacted normally with endothelial cell protein C receptor and retained its ability to trigger PAR-1 mediated cytoprotective signaling in a manner indistinguishable from that of wild type APC. Consequently, elimination of protein S cofactor enhancement of APC anticoagulant function represents a novel and effective strategy by which to separate the anticoagulant and cytoprotective functions of APC for potential therapeutic gain.
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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.