3.4.22.61	evolution	caspase-3 is an executioner caspase	717272	
3.4.22.61	evolution	initiator and executioner caspases, the pro-apoptotic members of the caspase family are subdivided in the initiators of apoptosis and the executioners of apoptosis. Caspase-18 and the ancestor of -8 and -10 called caspase-810 in this schematic are still found in fishes. Later on in evolution, caspase-8 and -10 branched off from caspase-810	717282	
3.4.22.61	evolution	initiator and executioner caspases, the pro-apoptotic members of the caspase family are subdivided in the initiators of apoptosis, i.e. caspases-8, -9 and -10 in humans, and the executioners of apoptosis, caspase-3, -6 and -7, phylogenetic tree of all the human caspases, overview. The initiators have a relatively large N-terminal dimerization domain, either a death effector domain, caspases-8 and -10, or a structurally related caspase recruitment domain, caspase-9. Caspase-18 and the ancestor of -8 and -10 called caspase-810 in this schematic are still found in fishes. Later on in evolution, caspase-8 and -10 branched off from caspase-810	717282	
3.4.22.61	malfunction	caspase 8 knockdown stabilizes both cellular inhibitor of apoptosis 1, cIAP-1, and X-linked IAP, XIAP	717576	
3.4.22.61	malfunction	caspase-8 inhibition decreases biofilm cell survival	-, 709486	
3.4.22.61	malfunction	caspase-8 is coupled with the regulation of various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease and dentatorubral pallidoluysian atrophy	731391	
3.4.22.61	malfunction	cells lacking in caspase-8 show reduced adhesion to fibronectin with concomitant reduction in adhesion-induced ERK 1/2 activation, these effects can be restored upon reexpression of either the wild-type or catalytically inactive point mutant protein, implying caspase-8 is involved to promote cell adhesion and adhesion-induced ERK 1/2 activation independently of its catalytical activity	717900	
3.4.22.61	malfunction	depletion of caspase-8 decreases endogenous amyloid beta-protein production	709626	
3.4.22.61	malfunction	developmental abnormalities of caspase-8-deficient mice	717217	
3.4.22.61	malfunction	failure to express caspase-8 has no effect on the life-span of dendritic cells but instead leads to an enhanced intrinsic activation and subsequently more mature and autoreactive lymphocytes. Mice with conditional deletion of caspase-8 in DCs develop a chronic systemic autoimmune disease	732273	
3.4.22.61	malfunction	in p62-deficient cancer cells caspase-8 activity and apoptosis are diminished, yet not abrogated	717276	
3.4.22.61	malfunction	loss of caspase 8 prevents CYLD degradation, resulting in necrotic death. Mutation of the caspase 8 processing site on the substrate converts a pro-survival response to necrotic death without the need for caspase 8 inhibition	718144	
3.4.22.61	malfunction	mice deficient in caspase-8 in basal epidermal keratinocytes suffer from chronic skin inflammation, as an apparent consequence of IRF3 hyper-activation. Catalytically active caspase-8 is required to rescue the lymphocyte development in caspase-8 deficient mice. The developmental phenotype observed in the caspase-8 knockout mouse is shared with both the FLIPL knockout and the FADD knockout	717282	
3.4.22.61	malfunction	no change in A-SMase activity in caspase-8-deficient cells. Retransfection of caspase-8-deficient Jurkat cells with an expression plasmid for caspase-8 restores the ability of the transfected cells to respond to TNF stimulation by increased A-SMase activity. Caspase-8-deficient Jurkat cells are almost completely resistant to TNF/CHX treatment	717539	
3.4.22.61	malfunction	proliferative defects of caspase 8-deficient T cells and B cells. Caspase-8 deficiency causes programmed necrotic cell death	718154	
3.4.22.61	malfunction	silencing of caspase 8 gene is a key factor controlling the outcome of neonatal astrocytes upon Fas engagement, restoration of caspase 8 expression triggers apoptotic cell death in primary neonatal astrocytes	710108	
3.4.22.61	metabolism	activation of caspase 8 is upstream of caspase 3 activation	717470	
3.4.22.61	metabolism	caspase-8 and Bid are the known procurers of the death signal leading from death receptor stimulation to permeabilisation of the outer mitochondrial membrane in the apoptotic pathway, regulation of caspase-8 and Bid function and activation, overview	717276	
3.4.22.61	metabolism	caspase-8 of the extrinsic pathway is able to activate upstream mediators of the intrinsic apoptotic pathway	709367	
3.4.22.61	metabolism	mathematical modeling of CD95 DISC-mediated MAPK activation and apoptosis, overview. Quantitative dynamics of DED proteins, procaspase-8, and c-FLIP, which lead to caspase-8 activation and induction of apoptotic and non-apoptotic signaling pathways	717460	
3.4.22.61	metabolism	model of caspase 8 activation. Upon apoptosis induction triggered by interaction of the death ligand to the trimeric death receptor, adaptor FADD (Fas-associated protein with death domain ) is recruited to the death receptor via a death domain DD-DD interaction. FADD recruited at cell surface can recruit caspase-8 via a DED-DED interaction, leading to procaspase-8 proximity to meet another procaspase-8. Closely located FL motif on DED2 causes domain swapping and dimerization of procaspase-8. The dimerization via tandem DED domain swapping causes the proximity-mediated self-activation of caspase-8	753180	
3.4.22.61	metabolism	recruitment of caspase 8 and FLIP to a RIPK1-containing complex determines cell fate, overview	718154	
3.4.22.61	metabolism	the interaction of phosphorylated caspase-8 with regulatory subunit, p85alpha, of phosphatidylinositol-3-OH kinase enhances Rac activation to promote cell migration, requiring Tyr380 and phosphorylation by c-src	717900	
3.4.22.61	additional information	active caspase-8 colocalizes with internalized TNF-R1 receptosomes	717539	
3.4.22.61	additional information	FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. Caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis	717282	
3.4.22.61	additional information	following caspase-8 recruitment to the DISC, the E3 ligase cullin-3 is able to ubiquitinate caspase-8 which in turn recruits the ubiquitin-binding protein p62, caspase-8 polyubiquitination by cullin-3 and its subsequent p62-dependent aggregation stabilises active caspase-8 and thereby positively regulates apoptosis. The caspase-8/cullin-3/p62 complex is translocates to the cytosol from where it induces apoptosis in a p62-dependent manner	717276	
3.4.22.61	physiological function	activation of caspase 8 is involved in Fas-induced apoptosis in neonatal astrocytes	710108	
3.4.22.61	physiological function	apoptosis is mediated with caspase-8 activation	710618	
3.4.22.61	physiological function	caspase 8 can initiate apoptosis in response to cell surface receptor activation, but it is also required for embryonic development and immune cell proliferation, defined by suppression of receptor-interacting protein kinase 3, a kinase that triggers an alternative form of cell death called programmed necrosis. The extrinsic apoptosis, is mediated by a group of receptors of the tumour necrosis factor, TNF, superfamily called the death receptors. Caspase 8 is further implicated in cell motility, metastasis, and suppression of inflammation. The non-apoptotic roles of FADD and caspase 8 are involved the sup­pression of RIPK3-dependent programmed necrosis, the caspase 8–FLIP heterodimer is implicated in carrying out the suppression of RIPK3 signalling. Mechanism of caspase 8 activation, detailed overview	718154	
3.4.22.61	physiological function	caspase 8 inhibits programmed necrosis by processing CYLD. Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis. CYLD is cleaved by caspase 8 to promote survival	718144	
3.4.22.61	physiological function	caspase 8 inhibits programmed necrosis by processing CYLD. Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis. CYLD is cleaved by caspase 8 to promote survival. TNF-treated caspase-8-sufficient Jurkat T cells dying by apoptosis but remain unchanged in the caspase-8-deficient cells dying by necrosis	718144	
3.4.22.61	physiological function	caspase 8 is a key molecule of apoptosis in hepatocellular carcinoma. Methylation of caspase 8 and positive expression of its gene product is significantly correlated with high apoptotic indices	710203	
3.4.22.61	physiological function	caspase 8 is an initiator caspase for caspase 3 during H2O2-induced apoptosis	717470	
3.4.22.61	physiological function	caspase 8 is involved in apoptosis, trophoblast differentiation process, regulation of inflammatory processes, lymphocyte proliferation, cell migration, and cell differentiation with or without enucleation	710260	
3.4.22.61	physiological function	caspase-10 negatively regulates caspase-8-mediated cell death. Caspase-10 reduces death-inducing signaling complex DISC association and activation of caspase-8. Caspase-10 does not compete with caspase-8 for binding to adaptor protein FADD. Caspase-8 is required upstream of both regulator cFLIP and caspase-10 and DISC formation critically depends on the scaffold function of caspase-8. Caspase-10 rewires DISC signaling to NF-kappaB activation/cell survival and the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction	753197	
3.4.22.61	physiological function	caspase-8 activity has an essential role in CD95/Fas-mediated MAPK activation. Stimulation of CD95/Fas/APO-1 results in the induction of both apoptotic and non-apoptotic signaling pathways. CD95 DISC-induced caspase-8 activity is important for the initiation of ERK1/2 and p38 MAPK activation, caspase-8 activation mechanism, overview. The long c-FLIP isoform, c-FLIPL, and the short c-FLIP isoform, c-FLIPR, inhibit MAPK induction by blocking caspase-8 processing at the DISC. Caspase-8 activity is also essential to MAPK activation in response to anti-APO-1 stimulation	717460	
3.4.22.61	physiological function	caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation	732273	
3.4.22.61	physiological function	caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes. TNF-induced A-SMase activation strictly depends on functional caspase-8 and caspase-7 expression	717539	
3.4.22.61	physiological function	caspase-8 cleavage of the interleukin-21, IL-21, receptor is a negative feedback regulation of IL-21 signaling. Caspase-3 and the BH3 interacting domain death agonist, Bid, are cleaved by CASP8 as part of the apoptotic pathway	717605	
3.4.22.61	physiological function	caspase-8 is involved in the presenilin1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis	709626	
3.4.22.61	physiological function	caspase-8 is not essential in goniothalamin-induced apoptosis	710625	
3.4.22.61	physiological function	caspase-8 of fish may play an essential role in ammonia induced apoptosis. Caspase-8 transcripts are detected in liver after exposure to ammonia. Caspase-8 cleaved fragment is detected and significant alteration of procaspase-8 level is found with the same ammonia treatment condition. Remarkable changes of immunopositive staining are observed after ammonia treatment	753599	
3.4.22.61	physiological function	caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. The heterodimer of caspase-8 with the long isoform of cellular FLIP, FLIPL, fulfills these pro-survival functions of caspase-8. Caspase-8 has important functions in survival and development, caspase-8 activation not only triggers apoptosis but is also essential for embryonic development. Tissue specific knockout of caspase-8 revealed an essential role for this caspase in the development of a variety of tissues,most notably the endothelial cells of the heart and vascular system, lymphocytes and monocytes. Caspase-8 in programmed necrosis, detailed overview	717282	
3.4.22.61	physiological function	caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. The heterodimer of caspase-8 with the long isoform of cellular FLIP, FLIPL, fulfills these pro-survival functions of caspase-8. Caspase-8 has important functions in survival and development. Caspase-8 in programmed necrosis, detailed overview	717282	
3.4.22.61	physiological function	caspase-8-dependent apoptosis is demonstrated by cleavage of caspase-8 after recombinant eosinophil cationic protein treatment	707876	
3.4.22.61	physiological function	cell death is associated with caspase-8 activation	708496	
3.4.22.61	physiological function	cleavage by caspase 8 and the subsequent association with the outer mitochondrial membrane are two critical events that activate BH3-only protein Bid during death receptor-mediated apoptosis	754133	
3.4.22.61	physiological function	cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death	731153	
3.4.22.61	physiological function	DISC-activated caspase-8 and -10 trigger a caspase cascade by cleavage of caspase-3. Caspase-8 and Bid are the known procurers of the death signal leading from death receptor stimulation to permeabilisation of the outer mitochondrial membrane in the apoptotic pathway, regulation of caspase-8 and Bid function and activation, overview. In type II cells activation of the mitochondrial arm of the apoptosis pathway is required for the induction of apoptosis following a death receptor stimulus. The bridging element between the two arms of the apoptosis pathway is the caspase-8-mediated cleavage of the pro-apoptotic Bcl-2 family member Bid. The anionic mitochondria-specific phospho-lipid cardiolipin acts as a mitochondria-associated platform that is actually required for caspase-8 translocation, oligomerisation and activation after CD95 stimulation, and hence CD95-induced death in type II cells. In type I cells caspase-8 activation at the DISC is very efficient, resulting in direct activation of caspase-3 and the caspase cascade	717276	
3.4.22.61	physiological function	FADD-dependent formation of heterodimers between caspase-8 and FLIPL mediates the developmental role of caspase-8. The catalytic domain of caspase-8 is crucial for its activity in the context of activation by homodimerization. Mechanism of caspase-8 functional divergence in apoptotic and non-apoptotic pathways, overview	717217	
3.4.22.61	physiological function	infection by Trypanosoma cruzi induces caspase-8 activity and caspase-8 inhibition increases trophoblast cells infection while decreases parasite-induced cellular differentiation and apoptotic cell death, but not cellular proliferation	753517	
3.4.22.61	physiological function	interleukin-1beta production after hypoxia might be associated with caspase-8 rather than caspase-1	754897	
3.4.22.61	physiological function	mature caspase-8 cleaves a huge number of different cellular substrates in the cytosol. Under apoptotic stimuli, caspase-8 undergoes catalytic autocleavage to generate the proapoptotic mature tetramer to induce apoptosis	717900	
3.4.22.61	physiological function	neuronal death in Tg(DELTACR) mice is not accompanied by activation of caspase-8	707052	
3.4.22.61	physiological function	NPI-0052 plus lenalidomide-triggered apoptosis is primarily dependent on caspase-8 signaling	707857	
3.4.22.61	physiological function	programmed cell death involves the caspase-8-dependent extrinsic pathway	703032	
3.4.22.61	physiological function	targeting of caspase-8 substrates to the plasma membrane accelerates apoptosis	731601	
3.4.22.61	physiological function	the enzyme is a key mediator of neuronal apoptosis	731391	
3.4.22.61	physiological function	the Fas-associated protein with a death domain and subsequent activated caspase-8 are responsible for double-stranded RNA-dependent protein kinase-induced apoptosis in recombinant virus-infected cells	709094	
3.4.22.61	physiological function	Tumor necrosis factor–related apoptosis-inducing ligand, TRAIL, induces degradation of cellular inhibitor of apoptosis 1, cIAP-1, requiring caspase 8 activity, for, at least in part, direct cleavage of cIAP-1 by caspase 8. Cellular depletion of cIAP-1 enhances the efficiency of TRAIL-mediated apoptosis. cIAP-1 and cIAP-2 are responsible for Lys-63 polyubiquitination of RIP1 in cancer cells, which, in turn, results in activation of NF-kappaBmediated survival signals	717576