Specificity of coagulation factor signaling

Abstract

Summary. Coagulation serine proteases signal through protease‐activated receptors (PARs). Thrombin‐dependent PAR signaling on platelets is essential for the hemostatic response and vascular thrombosis, but regulation of inflammation by PAR signaling is now recognized as an important aspect of the pro‐ and anti‐coagulant pathways. In tissue factor (TF)‐dependent initiation of coagulation, factor (F) Xa is the PAR‐1 or PAR‐2‐activating protease when associated with the transient TF–FVIIa–FXa complex. In the anticoagulant protein C (PC) pathway, the thrombin–thrombomodulin complex activates PC bound to the endothelial cell PC receptor (EPCR), which functions as a required coreceptor for activated PC‐mediated signaling through endothelial cell PAR‐1. Thus, the pro‐ and anti‐inflammatory receptor cascades are mechanistically coupled to immediate cell signaling, which precedes systemic coagulant or anticoagulant effects. In contrast to the substrate‐like recognition of PARs by thrombin, TF‐ or EPCR‐targeted activation of PARs generates cell‐type specificity, PAR selectivity and protease receptor cosignaling with the G‐protein‐coupled PAR response. Protease receptors are thus major determinants of the biological outcome of coagulation factor signaling on vascular cells.

Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

“…Thrombin utilizes the basic residues of exosite-1 to interact with the hirudin-like sequence on PAR-1 (24,25) or the acidic residues of epidermal growth factor-like domains on TM (26,27) to function in either the procoagulant/proinflammatory or the anticoagulant/antiinflammatory pathways, respectively (24,28). Noting the high affinity of thrombin for TM (Ͻ1 nM) (29), physiological concentrations of thrombin may primarily interact with TM in lipid rafts, thereby blocking its interaction with PAR-1 and activating EPCR-bound protein C that is located next to PAR-1 in the same lipid raft and/or PAR-1 recruited from another nearby raft through a regulated mechanism.…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…Coagulation enzymes have additional functions such as activating signaling cascades via PARs (8,15). For example, the tissue factor-factor VIIa complex and factor Xa activate PAR-2 (16), while thrombin activates PAR-1, PAR-3, and PAR-4 (for review, see ref.…”

The Endothelial Protein C Receptor Supports Tissue Factor Ternary Coagulation Initiation Complex Signaling through Protease-activated Receptors

“…Signaling through the G protein-coupled protease-activated receptors (PARs) 2 is crucial for cellular responses that sense the activation of the pro-and anticoagulant pathways. Although thrombin activation of PAR1 is governed by the direct recognition and protease-mediated cleavage of the receptor (1), other proteases rely on co-receptors of the integrin and immune receptor families for specificity and efficiency of PAR cleavage (2).…”

“…Although thrombin activation of PAR1 is governed by the direct recognition and protease-mediated cleavage of the receptor (1), other proteases rely on co-receptors of the integrin and immune receptor families for specificity and efficiency of PAR cleavage (2). The endothelial protein C receptor (EPCR), which belongs to the lipid-presenting CD1d receptor family, binds the Gla domain of protein C (PC) or activated PC (aPC) (3) and supports aPC-dependent activation of PAR1 (4) to achieve cytoprotective and anti-inflammatory activities in stroke, sepsis, and autoimmune diseases (5,6).…”