From procaspase‐8 to caspase‐8: Revisiting structural functions of caspase‐8

Abstract Caspase‐8 is well‐characterized to initiate an apoptotic pathway triggered by the external stimuli. The proximity‐driven model recently has been proposed to interpret the activation mechanism of caspase‐8 in so‐far unprecedent detail, in which dimerization, autocleavage, and inhibitor of caspase‐8 are indispensable. Intriguingly, death effector domains (DEDs) and ubiquitination after active caspase‐8 is released into cytosol can also promote cell apoptosis indirectly. In addition to the proapoptotic role of caspase‐8, there is emerging evidence to indicate that the precursor of caspase‐8, procaspase‐8, has an important function in cell adhesion and migration. Phosphorylation of caspase‐8 by c‐src controls these functions by preventing the conversion of procaspase‐8 to caspase‐8. This provides a mechanism to switch these opposing functions. In the migratory role, procaspase‐8 interacts with the phosphatidylinositol‐3‐OH kinase (PI3K) regulatory subunit p85α and c‐src to modulate signaling by Rac and extracellular signal‐regulated kinase (ERK) 1/2, and promotes calpain2 activation. Here, the focus of this review is to highlight three respective aspects of caspase‐8, including precursor functions, activation mechanism and maintenance of activity. J. Cell. Physiol. 225: 316–320, 2010. © 2010 Wiley‐Liss, Inc.