Fig. 3: The canonical Par-4 functions.

The extrinsic and intrinsic apoptotic pathway regulated by Par-4 is illustrated. The extrinsic cell death is initiated by the ligation of death-inducing ligands (TNFα, FasL, and TRAIL) to their cognate receptors (TNF receptor, Fas receptor, and death receptors-DR4/DR5). The ligation recruits adaptor proteins and pro-caspases, leading to the assembly of the DISC and the activation of caspase signaling cascade. The intrinsic pathway is characterized by permeabilization and depolarization of the mitochondrial membrane, leading to the release of apoptogenic factors such as cytochrome c, AIF, Smac/DIABLO, etc. Once released, these factors activate caspase signaling cascade and orchestrate the cell death process. Apoptosis is highly regulated by a variety of pro-apoptotic and anti-apoptotic proteins. The members of the Bcl-2 family of proteins are the central regulators of the intrinsic apoptotic pathway. Bcl-2 family proteins composed of both pro-apoptotic (e.g., Bad, Bid, Bax, Bak, Bcl-Xs, Bim, etc.) and anti-apoptotic (e.g., Bcl-2, Bcl-xL, Mcl-1, etc.) members. The balance between these two family members determines whether or not a cell will undergo apoptosis. tBid, truncated Bid; MMP, mitochondrial membrane permeabilization; DISC, death-inducing signaling complex.