Header

UZH-Logo

Maintenance Infos

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.

Statistics

Citations

36 citations in Web of Science®
31 citations in Scopus®
Google Scholar™

Altmetrics

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 > Division of Surgical Intensive Care Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:February 2010
Deposited On:14 Feb 2011 14:15
Last Modified:05 Apr 2016 14:46
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

Download

Full text not available from this repository.
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations