Source:http://linkedlifedata.com/resource/pubmed/id/21149441
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
7
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| pubmed:dateCreated |
2011-2-14
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| pubmed:abstractText |
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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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD,
http://linkedlifedata.com/resource/pubmed/chemical/Factor VIIa,
http://linkedlifedata.com/resource/pubmed/chemical/Factor X,
http://linkedlifedata.com/resource/pubmed/chemical/Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/PROCR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Procr protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Protein C,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, PAR-1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, PAR-2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cell Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Thrombin,
http://linkedlifedata.com/resource/pubmed/chemical/Thromboplastin
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| pubmed:status |
MEDLINE
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| pubmed:month |
Feb
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| pubmed:issn |
1083-351X
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:day |
18
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| pubmed:volume |
286
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
5756-67
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| pubmed:dateRevised |
2011-4-12
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| pubmed:meshHeading |
pubmed-meshheading:21149441-Animals,
pubmed-meshheading:21149441-Antigens, CD,
pubmed-meshheading:21149441-Cells, Cultured,
pubmed-meshheading:21149441-Factor VIIa,
pubmed-meshheading:21149441-Factor X,
pubmed-meshheading:21149441-Glycoproteins,
pubmed-meshheading:21149441-Humans,
pubmed-meshheading:21149441-Mice,
pubmed-meshheading:21149441-Mice, Knockout,
pubmed-meshheading:21149441-Multienzyme Complexes,
pubmed-meshheading:21149441-Myocytes, Smooth Muscle,
pubmed-meshheading:21149441-Protein C,
pubmed-meshheading:21149441-Protein Structure, Tertiary,
pubmed-meshheading:21149441-Receptor, PAR-1,
pubmed-meshheading:21149441-Receptor, PAR-2,
pubmed-meshheading:21149441-Receptors, Cell Surface,
pubmed-meshheading:21149441-Signal Transduction,
pubmed-meshheading:21149441-Thrombin,
pubmed-meshheading:21149441-Thromboplastin
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| pubmed:year |
2011
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| pubmed:articleTitle |
The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors.
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| pubmed:affiliation |
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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