Fig. 1.

Cartoons of protein C activation and APC signaling in the membrane lipid-rafts of endothelial cells. Thrombin binds to thrombomodulin and activates the EPCR-bound protein C zymogen to APC in the membrane lipid-rafts of endothelial cells. APC, remained associated with EPCR, activates PAR1 through the cleavage of Arg-41 and/or Arg-46 on the extracellular domain of the receptor. The activation of PAR1 by APC results in a conformational change on the C-terminal intracellular loop of the receptor, thereby mediating its phosphorylation by a member of G protein coupled receptor kinases (GRK). The phosphorylated receptor recruits β-arrestin2, thereby preventing the interaction of the receptor with α subunit of one of the heterotrimeric G proteins and transmitting the intracellular message via β-arrestin2 biased signaling mechanism. This mode of activation of PAR1 by APC results in the activation of the PI-3K/Akt survival pathway, transactivation of the G_i protein coupled receptor, S1P₁ and activation of Rac1 GTPase. These signaling events lead to improvement in the barrier permeability function and inhibition of the NF-κB pathway in endothelial cells.