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Coagulation factor Xa cleaves protease-activated receptor-1 and mediates signaling dependent on binding to the endothelial protein C receptor


Schuepbach, R A; Riewald, M (2010). Coagulation factor Xa cleaves protease-activated receptor-1 and mediates signaling dependent on binding to the endothelial protein C receptor. Journal of Thrombosis and Haemostasis, 8(2):379-388.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
04 Faculty of Medicine > University Hospital Zurich > Institute of Intensive Care Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:February 2010
Deposited On:14 Feb 2011 14:15
Last Modified:07 Dec 2017 07:20
Publisher:Wiley-Blackwell
ISSN:1538-7836
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/j.1538-7836.2009.03682.x
PubMed ID:19895674

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