Hypothetical model of EPCR-dependent PAR1 signaling by APC and thrombin in endothelial cells. When EPCR is not ligated by protein C/APC, EPCR is associated with caveolin-1 in lipid rafts of endothelial cells.²¹  In this case, thrombin cleavage of PAR1 after Arg-41 recognition site couples the receptor to G_q and/or G_12/13, thereby enhancing the cellular permeability through the activation of RhoA GTPase and NF-κB signaling pathways. When EPCR is occupied by protein C/APC, the receptor dissociates from caveolin-1,²¹  which is a process somehow linked to the recruitment of GRK5 to the plasma membrane. In this case, the cleavage of PAR1 by either thrombin after Arg-41 or APC after Arg-46 sites result in the GRK-dependent phosphorylation of the N-terminal cytoplasmic domain of the cleaved PAR1 and inhibition of its interaction with anyone of the G_α subunit of the heterotrimeric G proteins. The EPCR-dependent cleavage of either Arg-41 or Arg-46 sites recruits β-arrestin-2 and Dvl-2, thereby transmitting the PAR1 signal through so called “β-arrestin-2 biased” signaling mechanism. The PAR1-dependent β-arrestin-2/Dvl-2 signaling activates Rac1 GTPase, inhibits NF-κB, and increases the barrier integrity of endothelial cells. The EPCR- and PAR1-dependent cytoprotective responses of both APC and thrombin require cross talk with G_i-protein coupled S1P₁ signaling. Whether this latter GPCR signaling is mediated directly via sphingosine 1-phosphate itself or mediated indirectly through the phosphorylation/activation of the cytoplasmic domain of S1P₁ by an activated kinase (ie, phosphatidylinositol 3-kinase/protein kinase B [PI-3K/Akt]) is not known and requires further investigation. See the text for more details. Cav-1, caveolin-1; Exo I, exosite I; PC, protein C; S1P, sphingosine 1-phosphate.