Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

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.

Cross Talk Pathways Between Coagulation and Inflammation

“…That thrombin cleaves PAR-1 at the same site as APC, yet has proinflammatory effects, implies the existence of agonist-dependent biased signaling pathways. There are several proposed mechanisms (reviewed in Mohan Rao et al 57 ). These insights have led to the development of APC variants that are signaling-selective to favor either the anticoagulant or cytoprotective/anti-inflammatory properties of APC (reviewed in Griffin et al 56 ).…”

Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model

“…EPCR also serves as the cellular receptor for activated protein C (APC) and supports APC-mediated vascular protective signaling via activation of protease-activated receptors. (PARs)34. Although originally identified as an endothelial cell receptor, EPCR has since been detected in a variety of cell types5, including hematopoietic, epithelial progenitor cells, and cancer cells6789.…”

“…Although originally identified as an endothelial cell receptor, EPCR has since been detected in a variety of cell types5, including hematopoietic, epithelial progenitor cells, and cancer cells6789. Recent studies discovered novel ligands for EPCR4, such as Plasmodium falciparum erythrocyte membrane protein 110, and a specific variant of the T-cell receptor11. These observations have opened unsuspected new roles for EPCR beyond hemostasis4.…”

“…Recent studies discovered novel ligands for EPCR4, such as Plasmodium falciparum erythrocyte membrane protein 110, and a specific variant of the T-cell receptor11. These observations have opened unsuspected new roles for EPCR beyond hemostasis4.…”

“…EPCR-mediated cell signaling, in general, was shown to contribute to cell survival and anti-apoptotic pathways3412. EPCR-APC-induced cell signaling was shown to inhibit apoptosis in endothelial cells, cancer cells, and other cell types1314151617.…”