title: The occupancy of endothelial protein C receptor by its ligand modulates the par-1 dependent signaling specificity of coagulation proteases.
abstract: Several recent studies have demonstrated that the activation of protease-activated receptor 1 (PAR-1) by thrombin and activated protein C (APC) on cultured vascular endothelial cells elicits paradoxical proinflammatory and antiinflammatory responses, respectively. Noting that the protective intracellular signaling activity of APC requires the interaction of the protease with its receptor, endothelial protein C receptor (EPCR), we recently hypothesized that the occupancy of EPCR by protein C may also change the PAR-1-dependent signaling specificity of thrombin. In support of this hypothesis, we demonstrated that EPCR is associated with caveolin-1 in lipid rafts of endothelial cells and that the occupancy of EPCR by the Gla-domain of protein C/APC leads to its dissociation from caveolin-1 and recruitment of PAR-1 to a protective signaling pathway through the coupling of PAR-1 to the pertussis toxin sensitive G(i) -protein. Thus, when EPCR is bound by protein C, a PAR-1-dependent protective signaling response in cultured endothelial cells can be mediated by either thrombin or APC. This article will briefly review the mechanism by which the occupancy of EPCR by its natural ligand modulates the PAR-1-dependent signaling specificity of coagulation proteases.
authors: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104, USA. rezaiear@slu.edu
authors: Alireza R
authors: AR
authors: Rezaie
mesh_terms: D000925:Anticoagulants / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains / Q000737:chemistry; D011486:Protein C / Q000378:metabolism*; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013917:Thrombin / Q000235:genetics / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D015703:Antigens, CD; D051242:Caveolin 1; D000074283:Endothelial Protein C Receptor; D008024:Ligands; C478370:PROCR protein, human; D011486:Protein C; D011498:Protein Precursors; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D013917:Thrombin; D015951:Factor Xa