scholarly journals Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

Blood ◽  
2014 ◽  
Vol 124 (10) ◽  
pp. 1553-1562 ◽  
Author(s):  
L. Vijaya Mohan Rao ◽  
Charles T. Esmon ◽  
Usha R. Pendurthi
Keyword(s):  
Endothelial Cell ◽  
Protein C ◽  
Factor Viia ◽  
Activated Protein C ◽  
Cell Receptor ◽  
Cell Protein ◽  
Future Research ◽  
Proinflammatory Response ◽  
Therapeutic Modalities ◽  
Protease Activated Receptor 1

Abstract Endothelial cell protein C receptor (EPCR) was first identified and isolated as a cellular receptor for protein C on endothelial cells. EPCR plays a crucial role in the protein C anticoagulant pathway by promoting protein C activation. In the last decade, EPCR has received wide attention after it was discovered to play a key role in mediating activated protein C (APC)-induced cytoprotective effects, including antiapoptotic, anti-inflammatory, and barrier stabilization. APC elicits cytoprotective signaling through activation of protease activated receptor-1 (PAR1). Understanding how EPCR-APC induces cytoprotective effects through activation of PAR1, whose activation by thrombin is known to induce a proinflammatory response, has become a major research focus in the field. Recent studies also discovered additional ligands for EPCR, which include factor VIIa, Plasmodium falciparum erythrocyte membrane protein, and a specific variant of the T-cell receptor. These observations open unsuspected new roles for EPCR in hemostasis, malaria pathogenesis, innate immunity, and cancer. Future research on these new discoveries will undoubtedly expand our understanding of the role of EPCR in normal physiology and disease, as well as provide novel insights into mechanisms for EPCR multifunctionality. Comprehensive understanding of EPCR may lead to development of novel therapeutic modalities in treating hemophilia, inflammation, cerebral malaria, and cancer.

scholarly journals Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor

2003 ◽  
Vol 373 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Laurent O. MOSNIER ◽  
John H. GRIFFIN
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Active Site ◽  
Protein C ◽  
Activated Protein C ◽  
Cell Protein ◽  
Protease Activated Receptor 1 ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Dose Dependent

In a model of staurosporine-induced apoptosis using EAhy926 endothelial cells, inhibition of apoptosis by activated protein C was dose-dependent and required the enzyme's active site, implicating activated protein C-mediated proteolysis. Consistent with this implication, both protease-activated receptor-1 (PAR-1) and endothelial cell protein C receptor (EPCR) were required for the anti-apoptotic effects of activated protein C.

scholarly journals Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3199-3208 ◽  
Author(s):  
Prosenjit Sen ◽  
Ramakrishnan Gopalakrishnan ◽  
Hema Kothari ◽  
Shiva Keshava ◽  
Curtis A. Clark ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Signaling ◽  
Protective Effect ◽  
Protein C ◽  
Factor Viia ◽  
Mitogen Activated Protein Kinase ◽  
Cell Protein ◽  
Mapk Activation ◽  
Protease Activated Receptor 1

Abstract Recent studies have shown that factor VIIa (FVIIa) binds to the endothelial cell protein C receptor (EPCR), a cellular receptor for protein C and activated protein C, but the physiologic significance of this interaction is unclear. In the present study, we show that FVIIa, upon binding to EPCR on endothelial cells, activates endogenous protease activated receptor-1 (PAR1) and induces PAR1-mediated p44/42 mitogen-activated protein kinase (MAPK) activation. Pretreatment of endothelial cells with FVIIa protected against thrombin-induced barrier disruption. This FVIIa-induced, barrier-protective effect was EPCR dependent and did not involve PAR2. Pretreatment of confluent endothelial monolayers with FVIIa before thrombin reduced the development of thrombin-induced transcellular actin stress fibers, cellular contractions, and paracellular gap formation. FVIIa-induced p44/42 MAPK activation and the barrier-protective effect are mediated via Rac1 activation. Consistent with in vitro findings, in vivo studies using mice showed that administration of FVIIa before lipopolysaccharide (LPS) treatment attenuated LPS-induced vascular leakage in the lung and kidney. Overall, our present data provide evidence that FVIIa bound to EPCR on endothelial cells activates PAR1-mediated cell signaling and provides a barrier-protective effect. These findings are novel and of great clinical significance, because FVIIa is used clinically for the prevention of bleeding in hemophilia and other bleeding disorders.

scholarly journals Factor X binding to endothelial cell protein C receptor: comparison with factor VIIa and activated protein C

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2635-2636 ◽  
Author(s):  
Prosenjit Sen ◽  
Ramesh Nayak ◽  
Curtis A. Clark ◽  
Ramakrishnan Gopalakrishnan ◽  
Charles T. Esmon ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Protein C ◽  
Factor Viia ◽  
Activated Protein C ◽  
Cell Protein ◽  
Factor X

scholarly journals FVIIa (Factor VIIa) Induces Biased Cytoprotective Signaling in Mice Through the Cleavage of PAR (Protease-Activated Receptor)-1 at Canonical Arg41 (Arginine41) Site

2020 ◽  
Vol 40 (5) ◽  
pp. 1275-1288 ◽  
Author(s):  
Vijay Kondreddy ◽  
Usha R. Pendurthi ◽  
Xiao Xu ◽  
John H. Griffin ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Protein C ◽  
Factor Viia ◽  
Vascular Endothelial Cell ◽  
Cell Protein ◽  
Mouse Strains ◽  
Biased Agonism ◽  
Protease Activated Receptor 1

Objective: Recent studies showed that FVIIa (factor VIIa), upon binding to EPCR (endothelial cell protein C receptor), elicits endothelial barrier stabilization and anti-inflammatory effects via activation of PAR (protease-activated receptor)-1–mediated signaling. It is unknown whether FVIIa induces PAR1-dependent cytoprotective signaling through cleavage of PAR1 at the canonical site or a noncanonical site, similar to that of APC (activated protein C). Approach and Results: Mouse strains carrying homozygous R41Q (canonical site) or R46Q (noncanonical site) point mutations in PAR1 (QQ41-PAR1 and QQ46-PAR1 mice) were used to investigate in vivo mechanism of PAR1-dependent pharmacological beneficial effects of FVIIa. Administration of FVIIa reduced lipopolysaccharide-induced inflammation, barrier permeability, and VEGF (vascular endothelial cell growth factor)-induced barrier disruption in wild-type (WT) and QQ46-PAR1 mice but not in QQ41-PAR1 mice. In vitro signaling studies performed with brain endothelial cells isolated from WT, QQ41-PAR1, and QQ46-PAR1 mice showed that FVIIa activation of Akt (protein kinase B) in endothelial cells required R41 cleavage site in PAR1. Our studies showed that FVIIa cleaved endogenous PAR1 in endothelial cells, and FVIIa-cleaved PAR1 was readily internalized, unlike APC-cleaved PAR1 that remained on the cell surface. Additional studies showed that pretreatment of endothelial cells with FVIIa reduced subsequent thrombin-induced signaling. This process was dependent on β-arrestin1. Conclusions: Our results indicate that in vivo pharmacological benefits of FVIIa in mice arise from PAR1-dependent biased signaling following the cleavage of PAR1 at the canonical R41 site. The mechanism of FVIIa-induced cytoprotective signaling is distinctly different from that of APC. Our data provide another layer of complexity of biased agonism of PAR1 and signaling diversity.

Nucleotide Structure and Characterization of the Murine Gene Encoding the Endothelial Cell Protein C Receptor

1999 ◽  
Vol 81 (04) ◽  
pp. 585-588 ◽  
Author(s):  
Zhong Liang ◽  
Elliot D. Rosen ◽  
Francis J. Castellino
Keyword(s):  
Endothelial Cell ◽  
Rna Polymerase Ii ◽  
Protein C ◽  
Transcriptional Control ◽  
Activated Protein C ◽  
Cell Receptor ◽  
Cell Protein ◽  
Regulatory Sequences ◽  
Coding Region ◽  
Gene Encoding

SummaryThe nucleotide sequence of the entire gene encoding the murine endothelial cell receptor for activated protein C (EPCR) has been determined. A total of 5303 bp of DNA was sequenced that included 4 exons and three introns, which constituted the coding region of the gene, as well as 393 bp upstream of the first exon and 841 bp downstream of the last exon. From the locations of the introns in this gene and analysis of the exon structures, it is clear the EPCR gene is a member of the CD1 class of multiple histocompatibility proteins, and its cDNA sequence is nearly identical to that of CCD41, a centrosome-associated protein. All elements needed for RNA polymerase II-based transcription are predicted to exist in the 5’ uncoded region of the gene, and potential 3’ regulatory sequences for efficient polyadenylation have been located at their optimal locations. A variety of highly probable transcription factor binding sites have been located in the 5’ region of the gene. These data suggest that the EPCR gene is under efficient transcriptional control, and support the finding that this gene product may be involved in the inflammatory pathway.

scholarly journals Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1974-1986 ◽  
Author(s):  
Ramesh C. Nayak ◽  
Prosenjit Sen ◽  
Samit Ghosh ◽  
Ramakrishnan Gopalakrishnan ◽  
Charles T. Esmon ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Surface ◽  
Protein C ◽  
Cellular Localization ◽  
Factor Viia ◽  
Expression System ◽  
Activated Protein C ◽  
In Vivo Studies ◽  
Cell Protein ◽  
Membrane Microdomains

Although the binding of endothelial cell protein C receptor (EPCR) to its ligands is well characterized at the biochemical level, it remains unclear how EPCR interaction with its ligands at the cell surface impacts its cellular trafficking. We characterized the cellular localization and trafficking of EPCR in endothelial cells and a heterologous expression system. Immunofluorescence confocal microscopy studies revealed that a majority of EPCR is localized on the cell surface in membrane microdomains that are positive for caveolin-1. A small fraction of EPCR is also localized intracellularly in the recycling compartment. Factor VIIa (FVIIa) or activated protein C binding to EPCR promoted the internalization of EPCR. EPCR and EPCR-bound ligands were endocytosed rapidly via a dynamin- and caveolar-dependent pathway. The endocytosed receptor-ligand complexes were accumulated in a recycling compartment before being targeted back to the cell surface. EPCR-mediated FVIIa endocytosis/recycling also resulted in transport of FVIIa from the apical to the basal side. In vivo studies in mice showed that blockade of EPCR with EPCR-blocking antibodies impaired the early phase of FVIIa clearance. Overall, our results show that FVIIa or activated protein C binding to EPCR promotes EPCR endocytosis, and EPCR-mediated endocytosis may facilitate the transcytosis of FVIIa and its clearance from the circulation.

scholarly journals Identification of the Protein C/Activated Protein C Binding Sites on the Endothelial Cell Protein C Receptor

2000 ◽  
Vol 276 (11) ◽  
pp. 8364-8370 ◽  
Author(s):  
Patricia C. Y. Liaw ◽  
Timothy Mather ◽  
Natalia Oganesyan ◽  
Gary L. Ferrell ◽  
Charles T. Esmon
Keyword(s):  
Endothelial Cell ◽  
Binding Sites ◽  
Protein C ◽  
Activated Protein C ◽  
Cell Protein

scholarly journals A critical role of endothelial cell protein C receptor in the intestinal homeostasis in experimental colitis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vijay Kondreddy ◽  
Shiva Keshava ◽  
Charles T. Esmon ◽  
Usha R. Pendurthi ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Endothelial Cell ◽  
Epithelial Cells ◽  
Protein C ◽  
Factor Viia ◽  
Activity Index ◽  
Critical Role ◽  
Experimental Colitis ◽  
Cell Protein ◽  
Bodyweight Loss ◽  
Colon Mucosa

AbstractCrohn’s disease and ulcerative colitis are the two forms of disorders of the human inflammatory bowel disease with unknown etiologies. Endothelial cell protein C receptor (EPCR) is a multifunctional and multiligand receptor, which is expressed on the endothelium and other cell types, including epithelial cells. Here, we report that EPCR is expressed in the colon epithelial cells, CD11c+, and CD21+/CD35+ myeloid cells surrounding the crypts in the colon mucosa. EPCR expression was markedly decreased in the colon mucosa during colitis. The loss of EPCR appeared to associate with increased disease index of the experimental colitis in mice. EPCR−/− mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, manifested by increased weight loss, macrophage infiltration, and inflammatory cytokines in the colon tissue. DSS treatment of EPCR−/− mice resulted in increased bleeding, bodyweight loss, anemia, fibrin deposition, and loss of colon epithelial and goblet cells. Administration of coagulant factor VIIa significantly attenuated the DSS-induced colon length shortening, rectal bleeding, bodyweight loss, and disease activity index in the wild-type mice but not EPCR−/− mice. In summary, our data provide direct evidence that EPCR plays a crucial role in regulating the inflammation in the colon during colitis.

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