The cytoprotective protein C pathway for APC antiapoptotic activity. APC antiapoptotic activity requires the APC receptors EPCR and PAR-1. APC antiapoptotic activity is at least partially dependent on modulation of gene expression (green arrow). APC down-regulates proapoptotic p53 and Bax protein (red blocks) and maintains protective antiapoptotic Bcl-2 protein levels (green arrow), thereby beneficially affecting the Bax/Bcl-2 ratio. APC inhibits activation (red block) of both initiator caspases (eg, tPA-induced caspase-8 activation⁶⁰ ) as well as activation of effector caspases (eg, staurosporine or hypoxia/hypoglycemia-induced caspase-3 activation^16,18 ). Further work is needed to clarify exactly how APC exerts antiapoptotic activity and what the relative contributions of APC's effects on gene expression, of APC-specific signaling, and of APC-specific proteolysis involving particular receptors or effectors might be for APC's antiapoptotic actions. Green arrows indicate stimulation by APC, red blocks indicate inhibition by APC, and black arrows/blocks denote stimulation/inhibition of (downstream) reactions.