A hypothetical model of PAR-1 and PAR-2 activation by coagulation proteases when either EPCR or an unknown FX/FXa receptor is occupied by natural ligands

A hypothetical model of PAR-1 and PAR-2 activation by coagulation proteases when either EPCR or an unknown FX/FXa receptor is occupied by natural ligands. In the absence of protein C/APC or FX/FXa, EPCR is associated with caveolin-1 (Cav-1) within the lipid rafts of endothelial cells (left panel in the box). In this case, thrombin appears to signal via Gq and/or G12/13, thereby enhancing cellular permeability through the activation of RhoA and eliciting proinflammatory responses through the activation of NF-κB (). The occupancy of either EPCR by protein C (PC) or FX receptor by its ligand results in dissociation of EPCR from caveolin-1 (right panel). This process appears to be linked with the coupling of PAR-1 to Gi/o. In this case, the activation of PAR-1 by thrombin increases the barrier integrity of endothelial cells by activating Rac1 GTPase and eliciting an anti-inflammatory response through the inhibition of NF-κB (). A similar protective effect is mediated when FXa binds to its receptor on endothelial cells. In this case, not only the activation of PAR-1 by thrombin is protective, but FXa also elicits a protective response directly through the activation of PAR-2, thereby activating Rac1 GTPase and inhibiting the NF-κB pathway. See text for more details.

Publication

Factor X/Xa Elicits Protective Signaling Responses in Endothelial Cells Directly via PAR-2 and Indirectly via Endothelial Protein C Receptor-dependent Recruitment of PAR-1. (2010) Jong-Sup Bae, et al. J Biol Chem. 2010 Nov 5;285(45):34803-34812. Figure: F7. All organisms Homo sapiens Drosophila melanogaster

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