Xa receptor EPR‐1

Abstract

Cellular inflammatory responses and early mechanisms of vascular injury are invariably associated with activation of blood coagulation and deposition of insoluble fibrin. This process occurs on vascular cell surfaces through the ability of the coagulation protease factor Xa to generate thrombin. However, experimental evidence accumulated during the past decade underscores how prothrombin activation is only one of the biological consequences of factor Xa assembly on vascular cells. Instead, binding of factor Xa to leukocytes, endothelium, and smooth muscle cells triggers complex pathways of intracellular signal transduction that participate, directly or indirectly, in the regulation of cellular growth. One of the cellular binding sites for factor Xa, designated effector cell protease receptor-1 (EPR-1), has recently emerged as a novel potential regulator of factor Xa-mediated mitogenic signaling. For its activation-dependent phenotype on leukocyte subsets, its ability to costimulate lymphocyte proliferation through release of intracellular second messengers, and its regulated cellular expression by alternative mRNA splicing, EPR-1 may influence vascular cell growth and aberrantly contribute to the earliest pathogenetic processes of vascular diseases.

Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo.

“…This pathway was mediated by binding of Factor Xa to its cellular receptor EPR-1 (26), as judged by the ability of small synthetic peptides mimicking this interaction to induce inflammation and modulate carrageenin-induced edema, in vivo.…”

“…On the other hand, the ability of the EPR-1-Factor Xa interaction to enhance prothrombin activation on several vascular and perivascular cell types (19,20,23,26) may provide an additional mechanism to potentiate this inflammatory response in vivo. Increase in vascular permeability (25) with extravasation of coagulation zymogens may favor monocyte/macrophage activation of Factor X to Xa (30) in a localized membrane microenvironment, with enhanced inflammation by Factor Xa (this study) or thrombin (24), generated through the EPR-1 pathway.…”

Transcriptional targeting of tumors with a novel tumor-specific survivin promoter

“…A novel gene, survivin, was recently identified by hybridization screening of human genomic libraries with the cDNA of a factor Xa receptor (EPR-1) 14 and might be a good candidate for this goal. Survivin is a novel member of the inhibitor of apoptosis (IAP) protein family, which plays an important role in the survival of cancer cells and the progression of malignancies.…”

Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53

“…Survivin was discovered by the screening of a human genomic library with the cDNA encoding the effector cell protease receptor-1 (EPR-1). 1 Expressed in embryonic tissue and in most types of cancer cells, survivin plays a pivotal role in embryogenesis and tumorigenesis, but little is detected in terminally differentiated normal tissue. 2 It has been reported that survivin mRNA is among the four most highly expressed transcripts in tumor cells but not in normal ones.…”