Caspase-2: vestigial remnant or master regulator?

Caspase-2, the second mammalian caspase to be identified and the most evolutionarily conserved caspase, has eluded classification. The lack of a profound phenotype in the caspase-2-deficient mouse resulted in decreased interest in caspase-2 for many years. However, advances in the field, including the identification of a potential activation complex and the development of methods to detect active caspase-2, now illuminate our understanding of the function of this caspase. These studies suggest that caspase-2 induces death through two pathways. First, caspase-2 induces cell death independently of the mitochondrial pathway, in a manner similar to that of ced-3, a caspase in Caenorhabditis elegans. Second, caspase-2 also induces cell death upstream of the mitochondrial pathway. The choice of pathway may depend on the type of death stimulus. The placing of caspase-2 upstream and independent of mitochondrial dysfunction provides a potentially new therapeutic target for aberrant cell death.