Hypothetical model of crosstalks between EPCR, PAR-1, S1P1, and Tie2. EPCR is associated with caveolin-1 (Cav-1) in lipid-rafts of endothelial cells when the receptor is not occupied by Gla-domain of protein C/APC. Thrombin cleavage of PAR-1 elicits disruptive responses through signaling via Gq and/or G12/13, thereby activating the NF-κB pathway. However, the occupancy of EPCR by protein C (PC) results in the dissociation of EPCR from caveolin-1, thereby switching the specificity of PAR-1 signaling by coupling it to the Gi-protein and/or transactivation of the Gi-protein coupled receptor, S1P1, and mediating the phosphorylation of the receptor by the PI3K/Akt pathway. The EPCR-dependent PAR-1 cleavage by thrombin also increases the expression levels of Ang1 and Tie2, thus initiating/amplifying the PI3K/Akt-dependent protective pathway through the Ang1-mediated phosphorylation of Tie2.