Overview of apoptosis pathways. Apoptosis can be induced by extracellular (extrinsic) or intracellular (intrinsic) stimuli. The extrinsic pathway is initiated via stimulation of DRs, e.g. CD95 or TRAIL-R, on the cell surface. Stimulation of CD95 results in the recruitment of different proteins including FADD, procaspase-8, procaspase-10 and c-FLIP proteins which form the death-inducing signaling complex (DISC). Procaspase-8 is activated at the DISC which is regulated by c-FLIP proteins. Active caspase-8 cleaves and activates effector caspase-3 and −7 and/or the Bcl-2 protein Bid. The truncated form of Bid (tBid) translocates to the mitochondria, triggering outer membrane permeabilization (MOMP) and the release of cytochrome c, as well as other pro-apoptotic proteins into the cytosol. Cytochrome c is involved in the formation of the apoptosome and procaspase-9 activation. Procaspase-9 also activates procaspase-3 and −7 resulting in massive caspase-3 activity and cell death. In CD95 signaling two different cell types are distinguished. Type I cells efficiently activate caspase-8 and subsequently effector caspases without requiring amplification through tBid-mediated MOMP. Type II cells, however, form less DISC and therefore rely on Bid cleavage and the intrinsic amplification loop. Additionally, CD95 can initiate non-apoptotic pathways, such as NF-κB or MAPK and cell survival. The intrinsic pathway is activated by various intracellular stimuli, such as DNA damage or growth factor withdrawal resulting in MOMP and subsequent effector caspase activation. Apoptosis is tightly controlled at the mitochondria by the Bcl-2 family of proteins.