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Coagulation factor Xa cleaves protease‐activated receptor‐1 and mediates signaling dependent on binding to the endothelial protein C receptor
Author(s) -
SCHUEPBACH R. A.,
RIEWALD M.
Publication year - 2010
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03682.x
Subject(s) - endothelial protein c receptor , protein c , microbiology and biotechnology , tissue factor , signal transduction , proinflammatory cytokine , protease activated receptor , coagulation , receptor , thrombin , protease activated receptor 2 , inflammation , chemistry , factor x , biology , biochemistry , immunology , enzyme linked receptor , platelet , medicine
Summary. Background and objective: Coagulation is intrinsically tied to inflammation, and both proinflammatory and anti‐inflammatory responses are modulated by coagulation protease signaling through protease‐activated receptor‐1 (PAR1). Activated factor X (FXa) can elicit cellular signaling through PAR1, but little is known about the role of cofactors in this pathway. Endothelial protein C receptor (EPCR) supports PAR1 signaling by the protein C pathway, and in the present study we tested whether EPCR mediates surface recruitment and signaling of FXa. Methods and results: Here, we show that FXa binds to overexpressed as well as native endothelial EPCR. PAR1 cleavage by FXa as analyzed with conformation‐sensitive antibodies and a tagged PAR1 reporter construct was strongly enhanced if EPCR was available. Anti‐EPCR failed to affect the tissue factor‐dependent activation of FX, but high concentrations of FXa decreased EPCR‐dependent protein C activation. Most importantly, the FXa‐mediated induction of Erk1/2 activation, expression of the transcript for connective tissue growth factor and barrier protection in endothelial cells required binding to EPCR. Conclusions: Our results demonstrate that EPCR plays an unexpected role in supporting cell surface recruitment, PAR1 activation, and signaling by FXa.