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Exp Cell Res. 2012 Jul 1;318(11):1213-20. doi: 10.1016/j.yexcr.2012.02.013. Epub 2012 Feb 28.

The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome.

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Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.


Key structural and catalytic features are conserved across the entire family of cysteine-dependent aspartate-specific proteases (caspases). Of the caspases involved in apoptosis signal transduction, the initiator caspases-2, -8 and -9 are activated at multi-protein activation platforms, and activation is thought to involve homo-dimerisation of the monomeric zymogens. Caspase-9, the essential initiator caspase required for apoptosis signalling through the mitochondrial pathway, is activated on the apoptosome complex, and failure to activate caspase-9 has profound pathophysiological consequences. Here, we review the pertinent literature on which the currently prevalent understanding of caspase-9 activation is based, extend this view by insight obtained from recent structural and kinetic studies on caspase-9 signalling, and describe an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This integrated view allows us to postulate and to discuss functional consequences for caspase-9 activation and apoptosis execution that may take centre stage in future experimental cell research on apoptosis signalling.

[Indexed for MEDLINE]

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