Activation of the c-Jun N-terminal Kinase/Stress-activated Protein Kinase Pathway by Overexpression of Caspase-8 and Its Homologs

• Published in: The Journal of biological chemistry Vol. 274; no. 27; pp. 19211 - 19219
• Main Authors: Chaudhary, P M, Eby, M T, Jasmin, A, Hood, L
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 02-07-1999
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Caspase 8; Caspase 9; Caspases - metabolism; CD40 Antigens - metabolism; Cell Line; DNA - metabolism; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinases; Protein Binding; Serpins - metabolism; Viral Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.27.19211

Caspase-8 is the most proximal caspase in the caspase cascade and possesses a prodomain consisting of two homologous death
effector domains (DEDs). We have discovered that caspase-8 and its homologs can physically interact with tumor necrosis factor
receptor-associated factor family members and activate the c-Jun N-terminal kinase (JNK, or stress-activated protein kinase)
pathway. This ability resides in the DED-containing prodomain of these proteins and is independent of their role as cell death
proteases. A point mutant in the first DED of caspase-8 can block JNK activation induced by several death domain receptors.
Inhibition of JNK activation blocks apoptosis mediated by caspase-10, Mach-related inducer of toxicity/cFLIP, and Fas/CD95,
thereby suggesting a cooperative role of this pathway in the mediation of caspase-induced apoptosis.