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

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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 Lys176) fragments. The binding of active site blocked PR3 to sEPCR was studied by surface plasmon resonance. Estimates of the KD of 18.5–102 nmwere 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.
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Keywords: EPCR; PR3; endothelial cells; inflammation; neutrophils

Document Type: Research Article

Affiliations: 1: Haematology 2: Immunology, Imperial College London, London, UK 3: Laboratory of Thrombosis and Haemostasis, Haematology Department and Division of Cardiovascular Sciences, Centre for Applied Medical Research, Clinica Universitaria/School of Medicine, University of Navarra, Pamplona, Spain

Publication date: 01 May 2007

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