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Caspase 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.

Original publication

DOI

10.1083/jcb.200209004

Type

Journal article

Journal

J Cell Biol

Publication Date

09/12/2002

Volume

159

Pages

739 - 745

Keywords

Animals, Apoptosis, Apoptotic Protease-Activating Factor 1, Caspase 2, Caspases, Cell Extracts, Cell Line, Cytochrome c Group, Enzyme Activation, Green Fluorescent Proteins, HeLa Cells, Humans, Kinetics, Luminescent Proteins, Macromolecular Substances, Mice, Mice, Knockout, Models, Biological, Molecular Weight, Myeloid Cells, Potassium Chloride, Proteins, Recombinant Fusion Proteins, Sodium Chloride, Time Factors, Tumor Cells, Cultured