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J Thromb Haemost. 2007 May;5(5):980-8.

Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3.

Author information

1
Department of Haematology, Imperial College London, London, UK. villegas@ujf-grenoble.fr

Abstract

BACKGROUND:

The endothelial cell protein C receptor (EPCR) presents protein C to the thrombin:thrombomodulin complex on the endothelium of large vessels, and enhances the generation of activated protein C (APC) and activation of protease-activated receptor-1. A previous report has demonstrated binding of soluble (s) EPCR to activated neutrophils via surface proteinase 3 (PR3).

METHODS:

We now report further characterization of this interaction. Activated neutrophils and purified PR3 both decrease endothelial cell (EC) surface EPCR, suggestive of its proteolysis.

RESULTS:

When added to purified recombinant sEPCR, PR3 produced multiple cleavages, with early products including 20 kDa N-terminal and C-terminal (after Lys(176)) fragments. The binding of active site blocked PR3 to sEPCR was studied by surface plasmon resonance. Estimates of the K(D) of 18.5-102 nM were obtained with heterogeneous binding, suggestive of more than a single interaction site.

CONCLUSIONS:

This work demonstrates PR3 binding to and proteolysis of EPCR and suggests a mechanism by which anticoagulant and cell protective pathways can be down-regulated during inflammation.

PMID:
17459006
PMCID:
PMC1890847
DOI:
10.1111/j.1538-7836.2007.02480.x
[Indexed for MEDLINE]
Free PMC Article
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