Figure 2. Caveolae are required for APC-mediated but not thrombin-mediated activation of PAR1 signaling.

Thrombin (α-Th) activates RhoA but not Rac1 signaling and promotes endothelial barrier permeability. PAR1 is essential for thrombin –induced endothelial cellular responses but does not require caveolae for signaling. EPCR the co-factor for APC, PAR1, and G proteins associate with caveolin-1, a structural component essential for caveolae formation. In contrast to thrombin, APC activates PAR1 and induces robust Rac1 signaling but not RhoA activation, to promote endothelial barrier protection. The expression of PAR1 is required for APC cellular signaling. Moreover, APC activation of PAR1 barrier protective signaling requires compartmentalization in caveolae.