Caspase 10b, Active (CASP8) Active Protein

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

CASP8: Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2. Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation. Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle. Belongs to the peptidase C14A family. 9 isoforms of the human protein are produced by alternative splicing.

Protein type: Apoptosis; Protease; EC 3.4.22.61

Chromosomal Location of Human Ortholog: 2q33-q34

Cellular Component: nucleoplasm; mitochondrial outer membrane; neuron projection; cytoskeleton; mitochondrion; Noc1p-Noc2p complex; cytoplasm; CD95 death-inducing signaling complex; microtubule organizing center; cytosol; lipid raft

Molecular Function: peptidase activity; protein binding; protein heterodimerization activity; ubiquitin protein ligase binding; cysteine-type endopeptidase activity; death receptor binding; protein complex binding; tumor necrosis factor receptor binding; cysteine-type peptidase activity

Biological Process: macrophage differentiation; viral reproduction; T cell activation; positive regulation of proteolysis; apoptosis; protein heterooligomerization; heart development; natural killer cell activation; response to lipopolysaccharide; toll-like receptor 3 signaling pathway; proteolysis; response to estradiol stimulus; response to antibiotic; proteolysis involved in cellular protein catabolic process; angiogenesis; positive regulation of macrophage differentiation; toll-like receptor 4 signaling pathway; cell structure disassembly during apoptosis; caspase activation; positive regulation of I-kappaB kinase/NF-kappaB cascade; B cell activation; MyD88-independent toll-like receptor signaling pathway; negative regulation of I-kappaB kinase/NF-kappaB cascade; response to ethanol; induction of apoptosis via death domain receptors; response to cobalt ion; toll-like receptor signaling pathway; innate immune response; response to cold; neural tube formation

Disease: Caspase 8 Deficiency; Breast Cancer; Lung Cancer; Hepatocellular Carcinoma