Figure 1. The principal cell death signaling pathways.

Figure 1

The principal cell death signaling pathways. Two best-characterized apoptotic pathways are indicated. Ligation of a death receptor leads to the recruitment of the adapter protein FADD and procaspase-8, which becomes cleaved and activated at the receptor complex, initiating caspase cascade. The mitochondria/apoptosome pathway (right) is triggered by a number of apoptotic stimuli. An early, not well understood step is the mitochondrial release of apoptosis inducing molecules (incl. cytochrome c, AIF, HtrA2 and Smac/DIABLO) into the cytosol. Initially, cytochrome c, together with dATP, associates with Apaf1. This event unmasks the CARD motif in Apaf1 and allows binding and activation of procaspase-9. Once activated, caspase-9 propagates the apoptotic signal. Positive feedback loops involving Bid, mitochondria, apoptosome, caspase-9, effector caspases and caspase 8 are able to amplify the death signal. The apoptosome pathway is further potentiated by AIF, through augmentation of mitochondrial release of cytochrome c and procaspase-9. Negative modulators of apoptosis such as FLIPs and IAPs may negatively influence the transmission of the apoptotic signal. Smac/DIABLO and HtrA2 may abolish apoptosis-inhibitory action of IAPs.

From: Caspases as Targets for Drug Development

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