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. Author manuscript; available in PMC: 2011 May 1.
Published in final edited form as: J Thromb Haemost. 2010 Feb 17;8(5):1107–1115. doi: 10.1111/j.1538-7836.2010.03812.x

Figure 7.

Figure 7

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.