Bax is a major proapoptotic member of the Bcl2 family that is required for 
apoptotic cell death. We have recently discovered that Bax phosphorylation at 
serine 184 induced by nicotine through activation of protein kinase AKT 
abolishes its proapoptotic function in human lung cancer cells. Here we found 
that either treatment of cells with the protein phosphatase 2A (PP2A) inhibitor 
okadaic acid or specific disruption of PP2A activity by expression of SV40 small 
tumor antigen enhanced Bax phosphorylation, whereas C(2)-ceramide, a potent PP2A 
activator, reduced nicotine-induced Bax phosphorylation, suggesting that PP2A 
may function as a physiological Bax phosphatase. PP2A co-localized and 
interacted with Bax. Purified, active PP2A directly dephosphorylated Bax in 
vitro. Overexpression of the PP2A catalytic subunit (PP2A/C) suppressed 
nicotine-stimulated Bax phosphorylation in association with increased apoptotic 
cell death. By contrast, depletion of PP2A/C by RNA interference enhanced Bax 
phosphorylation and prolonged cell survival. Mechanistically 
C(2)-ceramide-induced Bax dephosphorylation caused a conformational change by 
exposure of the 6A7 epitope (amino acids 13-19) that is normally hidden at its N 
terminus that promoted the insertion of Bax into mitochondrial membranes and 
formation of Bax oligomers leading to cytochrome c release and apoptosis. In 
addition, PP2A directly disrupted the Bcl2/Bax association to liberate Bax from 
the heterodimer complex. Thus, PP2A may function as a physiological Bax 
regulatory phosphatase that not only dephosphorylates Bax but also activates its 
proapoptotic function.