Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two novel synthetic tetrapeptides, VEID-CHO and DMQD-CHO, could selectively inhibit caspase-6 and caspase-3, respectively. We used these inhibitors to dissect the pathway of caspase activation in Fas-stimulated Jurkat cells and identify the roles of each active caspase in apoptotic processes. Affinity labeling techniques revealed a branched protease cascade in which caspase-8 activates caspase-3 and -7, and caspase-3, in turn, activates caspase-6. Both caspase-6 and -3 have major roles in nuclear apoptosis. Caspase-6 cleaves nuclear mitotic apparatus protein (NuMA) and mediates the shrinkage and fragmentation of nuclei. Caspase-3 cleaves NuMA at sites distinct from caspase-6, and mediates DNA fragmentation and chromatin condensation. It is also involved in extranuclear apoptotic events: cleavage of PAK2, formation of apoptotic bodies, and exposure of phosphatidylserine on the cell surface. In contrast, a caspase(s) distinct from caspase-3 or -6 mediates the disruption of mitochondrial membrane potential (permeability transition) and the shrinkage of cytoplasm. These findings demonstrate that caspases are organized in a protease cascade, and that each activated caspase plays a distinct role(s) in the execution of Fas-induced cell death.
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PMID:Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. 946 9

Although caspase-8 has an established role as an initiator of death receptor-mediated apoptosis, the function of its closest homolog, caspase-10, is almost completely unknown. To gain a closer insight into the physiological function of caspase-10, we compared the cleavage of known caspase-8 substrates by both initiator caspases. We demonstrate that caspase-10 and -8 have overlapping cleavage preferences for several substrates such as the kinases RIP and PAK2. Interestingly, in other substrates, such as the Bcl-2 protein Bid, we found additional and distinct cleavage sites for both caspases, which might have important consequences for mitochondrial targeting and propagation of the death signal. Caspase-8 and -10 also caused different interchain cleavage patterns of their enzyme precursors. Together, these results suggest that caspase-8 and -10, despite having overlapping functions, also have selective substrate cleavage specificities and might thereby exert nonredundant roles in apoptosis signaling.
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PMID:Unique and overlapping substrate specificities of caspase-8 and caspase-10. 1618 8