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J. Cell Biol. 159 (5): 739-745

Copyright © 2002 by the Rockefeller University Press.


A novel Apaf-1–independent putative caspase-2 activation complex

Stuart H. Read1, Belinda C. Baliga1, Paul G. Ekert2, David L. Vaux2, and Sharad Kumar1,3

1 Hanson Institute, e Road, Adelaide, Australia 5000
2 Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia 3050
3 Department of Medicine, Adelaide University, Adelaide, Australia 5005

Address correspondence to Sharad Kumar, Hanson Institute, P.O. Box 14, Rundle Mall, Adelaide, Australia 5000. Tel.: 61-8-8222-3738. Fax: 61-8-8222-3139. E-mail: sharad.kumar{at}

Abstract: CVaspase activation is a key event in apoptosis execution. In stress-induced apoptosis, the mitochondrial pathway of caspase activation is believed to be of central importance. In this pathway, cytochrome c released from mitochondria facilitates the formation of an Apaf-1 apoptosome that recruits and activates caspase-9. Recent data indicate that in some cells caspase-9 may not be the initiator caspase in stress-mediated apoptosis because caspase-2 is required upstream of mitochondria for the release of cytochrome c and other apoptogenic factors. To determine how caspase-2 is activated, we have studied the formation of a complex that mediates caspase-2 activation. Using gel filtration analysis of cell lysates, we show that caspase-2 is spontaneously recruited to a large protein complex independent of cytochrome c and Apaf-1 and that recruitment of caspase-2 to this complex is sufficient to mediate its activation. Using substrate-binding assays, we also provide the first evidence that caspase-2 activation may occur without processing of the precursor molecule. Our data are consistent with a model where caspase-2 activation occurs by oligomerization, independent of the Apaf-1 apoptosome.

Key Words: apoptosis; caspase activation; apoptosome; caspase-9; initiator caspase

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