Noncanonical PAR3 activation and signaling selection by the PAR3 interactome. Activation of PAR3 can occur by thrombin (IIa)-mediated cleavage at Lys38 (canonical cleavage) or by APC and factor (F)Xa cleavage at noncanonical Arg41.^41,42  The latter cleavage results in selective activation of Tie2 and ZO-1 that promotes stabilization of the tight junctions, whereas the former cleavage enhances PAR1-induced ERK1/2 activation that results in barrier-disruptive effects. Because PAR3 is considered a nonsignaling receptor, other PAR3 effectors appear to be required for signaling induction, diversification, and regulation. Collectively referred to as the PAR interactome, these components may include EPCR, which binds extracellular proteases and membrane proteins; PAR1 and/or PAR2, which can form heterodimers; other receptors such as Mac1 (CD11b/CD18), ApoER2, and Tie2, which initiate signaling; and intracellular signaling system components such as G proteins or β-arrestins.