Proteinase‐activated receptor activation by coagulation proteinases

Abstract

AbstractCoagulation proteinases signal through proteinase activated receptors (PARs). Thrombin‐dependent PAR signaling on platelets is essential for hemostasis, but regulation of inflammation by PAR‐signaling is increasingly recognized as an important aspect of other pro‐ and anticoagulant pathways. In tissue factor (TF)‐dependent initiation of coagulation, factor Xa is the PAR1 or PAR2 activating proteinase while associated in the transient TF‐VIIa‐Xa complex. In the anticoagulant protein C (PC) pathway, the thrombin‐thrombomodulin complex activates PC bound to the endothelial PC receptor (EPCR) and EPCR functions as an essential co‐receptor for activated PC‐mediated signaling through endothelial cell PAR1. Thus, the pro‐ and anti‐inflammatory receptor cascades are mechanistically coupled to cell signaling that precedes systemic coagulant or anticoagulant effects. In contrast with the substrate‐like recognition of PARs by thrombin, TF, or EPCR targeted activation of PARs generates cell‐type specificity, PAR selectivity, and proteinase receptor co‐signaling with the G‐protein coupled PAR response. Cellular proteinase receptors are thus major determinants of the biological outcome of coagulation factor signaling on vascular cells. Drug Dev. Res. 59:400–407, 2003. © 2003 Wiley‐Liss, Inc.