PAR1 transactivation of S1P₁ signaling. Thrombin activation of PAR1 disrupts endothelial barrier function via G_12/13 and Rho (illustrated in red). In this issue ofBlood,Feistritzer and Riewald report that APC or picomolar thrombin can engage the same receptor with the opposite outcome, endothelial barrier protection, by transactivation of S1P₁ (illustrated in green). Several questions remain to be answered (illustrated in blue). (1) Thrombin and APC can trigger both protective as well as disruptive responses depending on the rate of receptor activation. How is a difference in the level of receptor activation translated into activation of different signaling pathways? Do differences in coupling efficiency and/or intrinsic shutoff rates for different G proteins account for this? Or are different thresholds set by downstream pathways? (2) Does PAR1 indeed activate Sphk1 and S1P release? How? (3) PAR1 and S1P₁ both couple to G_i. Why is transactivation required? Is it about amplification, tempo or subcellular localization of signaling, different effector pathways specified by receptor rather than G protein, or something else? (4) Does transactivation of S1P₁ contribute to antiapoptotic or other effects of APC and thrombin?