Figure 2

Schematic representation of different pathways involved in apoptosis. Extrinsic pathway:1.Ligand-death-receptor pathway (green): death factors such as Fas ligand (FasL) and tumour necrosis factor (TNF) trigger apoptosis by binding on 'death receptors' such as Fas and Tumour Necrosis Factor Receptor 1 (TNFR1). FasL may be solubilized to sFasL by matrix metalloproteinases (MMP's). The death receptors recruit procaspase-8 by means of an adaptor protein, Fas associated death domain protein (FADD). After cleavage the mature caspase-8 then directly activates caspase-3 or cleaves Bid. Truncated Bid (tBid) interacts with Bax and Bak. A pore is formed in the outer mitochondrial membrane through which cytochrome c (Cyt C) is released. 2.Cytolytic effector cell pathway (orange): cytotoxic T cells can release granzyme B and perforin, a pore-forming protein. Granzyme B activates caspase-3 through cleavage. It can also cleave caspase-8. 3.Growth factor depletion pathway (red): deprivation of survival factors triggers Cyt C release through activation of Bax and Bak. Intrinsic pathway:4.Mitochondrial pathway (grey): mitochondria release cytochrome c (Cyt C) in response to stress. Together with apoptotic protease activating factor-1 (Apaf-1) and procaspase-9, Cyt C will form the apoptosome complex. This results in the proteolytic activation of the procaspase. Mature caspase-9 can then proteolytically activate caspase-3 and other executioner caspases. 5.Endoplasmatic reticulum pathway (blue): the ER can also induce apoptosis as a reaction to stress. It might do so by stimulating the mitochondrial pathway or by directly targeting the nucleus. In mice both caspase-7 and -12 are linked to this pathway. These different initiation pathways converge further downstream into activation of caspase-3. The effector caspase-3 cleaves ICAD (inhibitor of CAD) and releases it from CAD (caspase-activated DNAase). CAD translocates from the cytoplasm to the nucleus and can now act as active endonuclease and fragment DNA.