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Information on EC 3.4.22.63 - caspase-10 and Organism(s) Homo sapiens and UniProt Accession Q92851
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Word Map
- 3.4.22.63
- caspase-8
- necrosis
- fadd
-
trail
-
apoptosis-inducing
- bid
-
lymphoproliferative
-
factor-related
-
death-inducing
-
fas-associated
-
casp11
-
fas-mediated
-
trail-induced
- c-flips
-
tnf-related
- lymphadenopathy
-
faslg
-
caspase-8-deficient
-
trail-mediated
-
cflar
- apaf-1
-
z-ietd-fmk
-
tnf-r1
-
trail-resistant
-
template-based
- medicine
- pharmacology
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
strict requirement for Asp at position P1 and has a preferred cleavage sequence of Leu-Gln-Thr-Asp-/-Gly
Synonyms
caspase-10, casp10, caspase 10, flice2, caspase-10/b, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
apoptotic protease Mch-4
-
-
-
-
C14.011
-
-
-
-
FAS-associated death domain protein interleukin-1B-converting enzyme 2
-
-
-
-
FLICE2
-
-
-
-
ICE-like apoptotic protease 4
-
-
-
-
Mch4
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
189088-85-5
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Ac-IETD-4-trifluoromethylcoumarin-7-amide + H2O
Ac-IETD + 7-amino-4-trifluoromethylcoumarin
-
-
-
?
BID + H2O
?
cleavage at sites LQTD/G and IEPD/S, for apical caspases
-
-
?
pro-Mch3 + H2O
?
cleaves the propeptide of Mch3 to generate a 33000 Da protein which is further processed to the 20000 Da band and the 12000 Da protein
-
-
?
acetyl-Ala-Glu-Val-Asp-4-trifluoromethylcoumarin-7-amide + H2O
acetyl-Ala-Glu-Val-Asp + 7-amino-4-trifluoromethylcoumarin
-
-
-
-
?
acetyl-VEHD-7-amido-4-methylcoumarin + H2O
acetyl-VEHD + 7-amino-4-methylcoumarin
-
the optimal tetrapeptide recognition motif is LEXD
-
-
?
Hsp90beta + H2O
?
-
Hsp90beta is cleaved by activated caspase-10 under UV-B irradiation at D278, P293, and D294
-
-
?
MDIGAYPHFMPTNLAGDPY + H2O
YPHFMPTNL + AYPHFMPTNL + YPHFMPTNLA + AYPHFMPTNLAG + AYPHFMPTNLAGD + DIGAYPHFMPTNLA + DIGAYPHFMPTNLAG + YPHFMPTNLAGDPY + IGAYPHFMPTNLAGD + MDIG + MDIGA + Met-Asp + Met + Tyr + Pro-Tyr + GDPY + DPY
-
-
quantitative product mass spectrometric analysis, overview
-
?
DEVD-7-amido-4-methylcoumarin + H2O
DEVD + 7-amino-4-methylcoumarin
-
-
-
?
YVAD-7-amido-4-methylcoumarin + H2O
YVAD + 7-amino-4-methylcoumarin
-
-
-
?
YVAD-7-amido-4-methylcoumarin + H2O
YVAD + 7-amino-4-methylcoumarin
less efficient cleavage than DEVD-7-amido-4-methylcoumarin
-
-
?
B cell lymphoma-2-interacting domain + H2O
?
-
caspase-10 can serve as an initiator caspase in Fas signaling leading to Bid processing, caspase cascade activation, and apoptosis
-
-
?
additional information
?
-
FLICE2 is a signaling caspase able to interact with the cell death receptors p55 and CD95 through the adapter molecule FADD
-
-
?
additional information
?
-
caspase-10/c is a truncated protein that is essentially a prodomain-only form of the caspase that lacks proteolytic activity in vitro but efficiently induces the formation of perinuclear filamentous structures and cell death in vivo, potential role of caspase-10/c in amplifying the apoptotic response to extracellular stimuli such as cytokines. Caspase-10/d is proteolytically active in vitro and also induces cell death ion vivo, although it is less active than Mch4. Possible role of caspase-10 family in the fetal development
-
-
?
additional information
?
-
inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II, caspase-10 mutations in Pt 11 and Pt 36 affect TRAIL-induced death of dendritic cells
-
-
?
additional information
?
-
-
inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II, caspase-10 mutations in Pt 11 and Pt 36 affect TRAIL-induced death of dendritic cells
-
-
?
additional information
?
-
the splice variant caspase-10g (comprising five exons including exons 2-5 and a specific exon between exons 5 and 6 of the caspase-10 gene), a prodomain-only isoform of caspase-10, may play a regulatory role preferentially in the NF-kappaB pathway. Caspase-10g induces low level of apoptosis and has no effect on the caspase-10a-mediated cell apoptosis
-
-
?
additional information
?
-
-
the splice variant caspase-10g (comprising five exons including exons 2-5 and a specific exon between exons 5 and 6 of the caspase-10 gene), a prodomain-only isoform of caspase-10, may play a regulatory role preferentially in the NF-kappaB pathway. Caspase-10g induces low level of apoptosis and has no effect on the caspase-10a-mediated cell apoptosis
-
-
?
additional information
?
-
-
broad specificity towards pro-aspartate-specific cysteine proteases
-
-
?
additional information
?
-
-
caspase-8 has a role in a non-apoptotic or anti-apoptotic signaling pathway leading to NF-kappaB activation through RIP, NIK and IKKalpha
-
-
?
additional information
?
-
-
Mch4 mediates the CrmA-insensitive apoptotic pathways, such as the DNA-damaging agents and staurosporine pathways
-
-
?
additional information
?
-
-
caspase-10 actively contributes to cytotoxic drug-induced apoptosis in leukemic cells. Caspase-10 activation does not occur at the level of a death-inducing signaling complex, nor in a Fas-associated death domain-dependent manner, but requires cytochrome c release from the mitochondria and the adapter molecule Apaf-1. Caspase-10 is activated downstream of caspase-9 and amplifies the caspase cascade by activating caspase-9 and caspase-3 in a feedback loop. Caspase-10 plays a role in cytotoxic drug-induced apoptosis downstream of the mitochondria
-
-
?
additional information
?
-
-
caspase-10 is involved in RIG-I/Mda5-dependent antiviral immune responses, particularly inflammatory responses
-
-
?
additional information
?
-
-
caspase-10 sensitizes breast carcinoma cells to TNF-related apoptosis-inducing ligand-induced but not tumor necrosis factor-induced apoptosis in a caspase-3-dependent manner
-
-
?
additional information
?
-
-
genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome
-
-
?
additional information
?
-
-
spontaneous apoptosis requires the activation of caspase-10/b
-
-
?
additional information
?
-
-
caspase-10 mRNA level is increased by the treatment with sodium butyrate. Sodium butyrate may trigger apoptosis via the induction of the caspase-10 expression
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
B cell lymphoma-2-interacting domain + H2O
?
-
caspase-10 can serve as an initiator caspase in Fas signaling leading to Bid processing, caspase cascade activation, and apoptosis
-
-
?
additional information
?
-
FLICE2 is a signaling caspase able to interact with the cell death receptors p55 and CD95 through the adapter molecule FADD
-
-
?
additional information
?
-
caspase-10/c is a truncated protein that is essentially a prodomain-only form of the caspase that lacks proteolytic activity in vitro but efficiently induces the formation of perinuclear filamentous structures and cell death in vivo, potential role of caspase-10/c in amplifying the apoptotic response to extracellular stimuli such as cytokines. Caspase-10/d is proteolytically active in vitro and also induces cell death ion vivo, although it is less active than Mch4. Possible role of caspase-10 family in the fetal development
-
-
?
additional information
?
-
inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II, caspase-10 mutations in Pt 11 and Pt 36 affect TRAIL-induced death of dendritic cells
-
-
?
additional information
?
-
-
inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II, caspase-10 mutations in Pt 11 and Pt 36 affect TRAIL-induced death of dendritic cells
-
-
?
additional information
?
-
the splice variant caspase-10g (comprising five exons including exons 2-5 and a specific exon between exons 5 and 6 of the caspase-10 gene), a prodomain-only isoform of caspase-10, may play a regulatory role preferentially in the NF-kappaB pathway. Caspase-10g induces low level of apoptosis and has no effect on the caspase-10a-mediated cell apoptosis
-
-
?
additional information
?
-
-
the splice variant caspase-10g (comprising five exons including exons 2-5 and a specific exon between exons 5 and 6 of the caspase-10 gene), a prodomain-only isoform of caspase-10, may play a regulatory role preferentially in the NF-kappaB pathway. Caspase-10g induces low level of apoptosis and has no effect on the caspase-10a-mediated cell apoptosis
-
-
?
additional information
?
-
-
caspase-8 has a role in a non-apoptotic or anti-apoptotic signaling pathway leading to NF-kappaB activation through RIP, NIK and IKKalpha
-
-
?
additional information
?
-
-
Mch4 mediates the CrmA-insensitive apoptotic pathways, such as the DNA-damaging agents and staurosporine pathways
-
-
?
additional information
?
-
-
caspase-10 actively contributes to cytotoxic drug-induced apoptosis in leukemic cells. Caspase-10 activation does not occur at the level of a death-inducing signaling complex, nor in a Fas-associated death domain-dependent manner, but requires cytochrome c release from the mitochondria and the adapter molecule Apaf-1. Caspase-10 is activated downstream of caspase-9 and amplifies the caspase cascade by activating caspase-9 and caspase-3 in a feedback loop. Caspase-10 plays a role in cytotoxic drug-induced apoptosis downstream of the mitochondria
-
-
?
additional information
?
-
-
caspase-10 is involved in RIG-I/Mda5-dependent antiviral immune responses, particularly inflammatory responses
-
-
?
additional information
?
-
-
caspase-10 sensitizes breast carcinoma cells to TNF-related apoptosis-inducing ligand-induced but not tumor necrosis factor-induced apoptosis in a caspase-3-dependent manner
-
-
?
additional information
?
-
-
genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome
-
-
?
additional information
?
-
-
spontaneous apoptosis requires the activation of caspase-10/b
-
-
?
additional information
?
-
-
caspase-10 mRNA level is increased by the treatment with sodium butyrate. Sodium butyrate may trigger apoptosis via the induction of the caspase-10 expression
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
CrmA
-
caspase-10 is more resistant than caspase-8, EC 3.4.22.61, to the caspase inhibitor
-
Z-VAD-fluoromethylketone
-
caspase-10 is more resistant than caspase-8, EC 3.4.22.61, to the caspase inhibitor
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Sodium citrate
activates the wild-type enzyme up to 500fold and the D297A mutant 100fold at up to 1.0 M, is inhibitory above probably due to precipitation
2-(acetyloxy)benzoic acid 4-(nitrooxymethyl)-phenyl ester
-
i.e. para-NO-ASA, activates proteolytic enzyme activation. The compund inhibits the proliferation and induces cell death in acute lymphoblastic leukemia cell lines and patient samples
FLICE-like inhibitory protein
-
i.e. FLIPL, activation occurs independently of cleavage of either the caspase or FLIPL
-
FLIPL protein
-
heterodimerization with the long isoform of cFLIP, FLIPL, leads to activation of caspase-10. The heterodimer of caspase-10 with FLIPL still can cleave Bid and induce intrinsic apoptosis
-
additional information
procaspase-10 is proteolytically activated to caspase-10, mechanism of activation and the role of the inter-subunit cleavage, overview. Caspase-10 follows the proximity-induced dimerization model for apical caspases. Chemically inducible dimerization fusions activate the wild-type but not the cleavage site mutant caspase-10
-
additional information
-
procaspase-10 is proteolytically activated to caspase-10, mechanism of activation and the role of the inter-subunit cleavage, overview. Caspase-10 follows the proximity-induced dimerization model for apical caspases. Chemically inducible dimerization fusions activate the wild-type but not the cleavage site mutant caspase-10
-
additional information
-
caspase-10 is activated at the DISC, downstream of death-receptor signaling
-
additional information
-
proteolytic activation of caspase-10 is induced in apoptosis
-
additional information
-
in head and neck squamous cancer cell lines with low caspase-8 levels, Smac mimetics treatment induced caspase-10 activation
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
nine different cell lines, caspase-10 fragments are specifically detected in Smac mimetic-sensitive HSC3 cells
additional information
the expression levels of caspase-10-related mRNAs are generally higher in fetal than in adult tissues
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
caspase-10/c is insoluble and localizes to filamentous perinuclear structures
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
human caspase-10 and caspase-8, EC 3.4.22.61, are highly homologous in their protein sequence, 46% identical in the catalytic domain, and their genes are on the same region of human chromosome 2q33-34 suggesting that they have a common ancestor
metabolism
apoptosis is a form of programmed cell death that requires members of a family of aspartate-specific cysteine proteases, called caspases, to both initiate and execute the apoptotic phenotype
physiological function
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
malfunction
physiological function
additional information
physiological function
prodeath role for both cleaved and uncleaved caspase-10
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
physiological function
the apoptosis-inducing complex FADDosome is driven by ATR-dependent caspase-10 upregulation. During FADDosome-induced apoptosis, FLICE-inhibitory protein cFLIPL is ubiquitinated by TRAF2, leading to its degradation and subsequent adaptor protein FADD-dependent caspase-8 activation. Cancer cells lacking caspase-10, TRAF2 or ATR switch from this cell-autonomous suicide to a more effective, autocrine/paracrine mode of apoptosis initiated by a different complex, the FLIPosome. It leads to processing of cFLIPL to cFLIPp43, TNF-alpha production and consequently, contrary to the FADDosome, p53-independent apoptosis
malfunction
-
addition of a caspase-10 inhibitor totally blocks PTK7-knockdown-induced apoptosis
malfunction
-
caspase-10 silencing in neuroblastoma is cell-type related. Downregulation of individual or all caspase-10 isoforms in SH-EP cells does not affect TRAIL sensitivity
malfunction
-
mutations or deficiencies in caspase-10 are associated with autoimmune lymphoproliferative syndrome
malfunction
-
apoptosis is totally prevented when caspase-10 is specifically inhibited in the cells
physiological function
-
caspase-10 activation is important in the initiation phase of apoptosis
physiological function
-
flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10
physiological function
-
activation of caspase-10 in apoptosis is induced by PTK7 knockdown. Caspase-10 may play a critical role in PTK7-knockdown-induced apoptosis, downstream of mitochondria. The intrinsic pathway, i.e. mitochondria pathway, involves a decrease in mitochondrial membrane potential and release of cytochrome, overview
physiological function
-
caspase-10 is an initiator caspase of proinflammatory and apoptotic pathways induced by vaccinia infection. The processing of a short vaccinia virus-encoded antigen can take place by a proteasome-independent pathway involving initiator caspase-5 and -10, which generate antigenic peptides recognized by CD8+ T lymphocytes. Each enzyme can use the degradation products of the other as substrate for new cleavages, indicating concerted endoproteolytic activity of caspase-5 and -10, EC 3.4.22.58 and EC 3.4.22.63
physiological function
-
individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis in several tumour cell types. Distinct caspase-10 isoforms induce opposed apoptotic signals in NB cells. Isozymes caspase-10A and -10D strongly increase tumour necrosis factor-related apoptosis-inducing ligand, i.e. TRAIL, and FasL sensitivity, whereas caspase-10B or -10G have no effect or are weakly anti-apoptotic. The unique C-terminal end of caspase-10B is responsible for its degradation by the ubiquitin-proteasome pathway and for its lack of pro-apoptotic activity compared with caspase-10A and -10D. Functional comparison to caspase-8, EC 3.4.22.61, overview. Caspase-10A or -10D isoforms can substitute for caspase-8 in the initiation extrinsic apoptosis
physiological function
-
apoptosis is dependent on caspase-10 in association with the formation of the death-inducing signaling complex (DISC) incorporating pro-caspase-10 and tumor necrosis factor receptor 1 (TNF-R1), the process is ligand-independent
physiological function
-
caspase-10 is the key initiator caspase involved in tributyltin-mediated apoptosis in immune cells. Caspase-10 is recruited by the TRAIL-R2 receptor
physiological function
-
Smac mimetic-induced cell death is associated with caspase-10 activation and is Bid-independent, suggesting that in the absence of caspase-8, caspase-10 mediates response to Smac mimetics, overview
additional information
residue D297 is essential for autocleavage, while even though the sequence surrounding D319 is compatible for cleavage by caspase-10, its location close to the compact core makes it unavailable for cleavage
additional information
-
residue D297 is essential for autocleavage, while even though the sequence surrounding D319 is compatible for cleavage by caspase-10, its location close to the compact core makes it unavailable for cleavage
additional information
-
isozymes caspase-10B and -10A/B are protected from CHX-mediated degradation by lactacystin treatment
additional information
-
the heterodimer of caspase-10 with FLIPL still can cleave Bid and induce intrinsic apoptosis
additional information
-
autophagy is associated to human caspase-10-induced cell death in yeast, a specific process that depends on an intact MAPK pathway, the Factor-arrest (Far) protein family, and the autophagy machinery, overview. Far11 coordinates a death-promoting signal and regulates both autophagy and the DNA damage response. The expression of human caspase-10 in Saccharomyces cerevisiae activates an intracellular death signal that depends on the Far protein complex. Expression of initiator caspase-10 is toxic in yeast and induces a lethal phenotype with most of the principal hallmarks of apoptosis and autophagy, which include the production of ROS, chromatin condensation, phosphatidylserine externalization, and increased vacuolization. The MAP kinases Fus3, Kss1, and Slt2 are activated after the expression of caspase-10 in yeast cells
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CASPA_HUMAN
521
0
58951
Swiss-Prot
other Location (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
caspase-10 follows the proximity-induced dimerization model for apical caspases. Chemically inducible dimerization fusions activate the wild-type but not the cleavage site mutant caspase-10
dimer
-
caspases can only be active as dimers, since neither the active site dyad nor the substrate pocket can be formed in the monomeric form
additional information
additional information
homology modelling of caspase-10, structural modeling based on the structure of procaspase-8, PDB ID 2K7Z
additional information
-
homology modelling of caspase-10, structural modeling based on the structure of procaspase-8, PDB ID 2K7Z
additional information
-
proMch4 can autoprocess after Asp-219 and Asp-372 to generate the two subunits of the mature enzyme: P17, the large subunit and p12, the small subunit
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
proteolytic modification
proteolytic modification
Mch4 is derived from a single chain proenzym, granzyme B cleaves proMch4 at a IXXD-A processing sequence to produce mature Mch4
proteolytic modification
autoprocessing, the wild-type 55000 Da GST fusion protein is cleaved to the 43000 Da active form
proteolytic modification
caspase-10/c and caspase-10/d are splice isoforms. Caspase-10/c is a truncated protein that is essentially a prodomain-only form of the caspase. Caspase-10/d is a hybrid of caspase-10/a (Mch4) and caspase-10/b (FLICE2), as it is identical to FLICE2 except for the small p12 catalytic subunit, which is identical to Mch4
proteolytic modification
procaspase-10 is activated to caspase-10, mechanism of activation and the role of the inter-subunit cleavage, overview. Caspase-10 follows the proximity-induced dimerization model for apical caspases
proteolytic modification
-
proMch4 can autoprocess after Asp-219 and Asp-372 to generate the two subunits of the mature enzyme : P17, the large subunit and p12, the small subunit
proteolytic modification
-
caspase-10 is activated at the DISC, downstream of death-receptor signaling. Caspases-8 and -10 are recruited to the DISC as intact monomers and recruitment of the caspases to the DISC subsequently leads to their dimerization and activation through induced proximity, mechanism, overview
proteolytic modification
-
procaspase-10 is activated to caspase-10. Activation of caspase-10 is induced in apoptosis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D219A
involved in proteolytic activation, essential for CASP10-induced cell death
D297A
site-directed mutagenesis, the single mutation D297A completely abrogates autocleavage between the subunits, the purified mutant is a single chain of 35 kDa. The cleavage site mutant has restricted specificity and highly reduced activity on protein substrates, overview
D416A
involved in proteolytic activation, essential for CASP10-induced cell death
I406L
-
impairs apoptosis when transfected alone and dominantly inhibits apoptosis mediated by wild-type caspase-10 in a co-transfection assay
L285F
-
impairs apoptosis when transfected alone and dominantly inhibits apoptosis mediated by wild-type caspase-10 in a co-transfection assay
L285P
-
the mutation may contribute to the pathogenesis of factions of T-acute lymphoblastic leukemia and multiple myeloma
R21C
-
the mutation may contribute to the pathogenesis of factions of T-acute lymphoblastic leukemia and multiple myeloma
V410I
Y446C
-
no dominant negative effect in co-transfection assay into H9 lymphocytic cell line
additional information
V410I
-
no dominant negative effect in co-transfection assay into H9 lymphocytic cell line. Protection from severe disease by caspase-10 V410I in 63 families with autoimmune lymphoproliferative syndrome Ia due to dominant Fas mutation
V410I
-
the mutation in caspase-10, that is associated with autoimmune lymphoproliferative syndrome, ALPS, is a common polymorphism in the healthy Danish population
additional information
construction of a truncated mutant lacking the first 202 residues, and of the truncation mutant with a substitution D297A in the catalytic site, cloning into a vector with chimeric protein with an N-terminal His-tag followed by the Fv-domain. Chemically inducible dimerization fusions activate the wild-type but not the cleavage site mutant caspase-10
additional information
-
construction of a truncated mutant lacking the first 202 residues, and of the truncation mutant with a substitution D297A in the catalytic site, cloning into a vector with chimeric protein with an N-terminal His-tag followed by the Fv-domain. Chemically inducible dimerization fusions activate the wild-type but not the cleavage site mutant caspase-10
additional information
-
somatic mutation of caspase-10 is rare in colon, breast, lung, and hepatocellular carcinomas, caspase-10 mutation may contribute to the pathogenesis of some colon carcinomas
additional information
-
caspase-10 isoforms are transiently downregulated using siRNAs targeting all caspase-10 isoforms, or siRNAs specific for individual caspase-10 isoforms. Downregulation of individual or all caspase-10 isoforms in SH-EP cells does not affect TRAIL sensitivity
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
caspase-10B is a highly unstable caspase-10 isoform, while isozymes caspase-10A, -D and and -G are remarkably stable
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged truncated mutant, with and without the D279A mutation, from Escherichia coli strain BL21 (DE3) by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of both the long and short isoforms of the wild-type or the caspase-10 mutants are transfected into Hela or MCF-7 cells together with a bet-gal reporter construct
splice variant caspase-10g (comprising five exons including exons 2-5 and a specific exon between exons 5 and 6 of the caspase-10 gene), expression in HeLa and JURKAT cells
the caspase-10 gene is linked to the caspase-8 gene, EC 3.4.22.61, at the human chromosome locus 2q33-34. Expression of His-tagged truncated mutant, with and without the D279A mutation, in Escherichia coli strain BL21 (DE3)
gene CASP10, recombinant expression of human caspase-10 in Saccharomyces cerevisiae strain strain BY4741 and derivatives, phenotypes, overview. Identification of 46 suppressors whose coexpression abolishes caspase-10 function and leads to cell curvaival and growth
-
proMch4 lacking the two N-terminal FADD-like domains is subcloned in the bacterial expression vector pET21b
-
the caspase-10 gene is linked to the caspase-8 gene, EC 3.4.22.61, at the human chromosome locus 2q33-34
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
pharmacology
-
tumour necrosis factor-related apoptosis-inducing ligand and SMs effectively kill head and neck squamous cancer cell lines and therefore represent potential targeted therapeutics for head and neck cancer. Distinct molecular mechanisms determine the sensitivity to each agent, with levels of TNF-alpha, caspase-8, Bid and caspase-10 providing important predictive biomarkers of response to these agents
medicine
in HL-60 cells that are treated with chemotherapy drugs combined with a caspase-10 inhibitor, the rate of survival decreases significantly compared with HL?60 cells treated with chemotherapy drugs alone. The rate of survival of Jurkat cells treated with chemotherapy drugs combined with the caspase-10 inhibitor increases significantly compared with Jurkat cells treated with chemotherapy drugs alone. Caspase-10 may be associated with autophagy in acute myeloid leukemia cells, but not in acute lymphatic leukemia cells
medicine
the apoptosis-inducing complex FADDosome is driven by ATR-dependent caspase-10 upregulation. During FADDosome-induced apoptosis, FLICE-inhibitory protein cFLIPL is ubiquitinated by TRAF2, leading to its degradation and subsequent adaptor protein FADD-dependent caspase-8 activation. Cancer cells lacking caspase-10, TRAF2 or ATR switch from this cell-autonomous suicide to a more effective, autocrine/paracrine mode of apoptosis initiated by a different complex, the FLIPosome. It leads to processing of cFLIPL to cFLIPp43, TNF-alpha production and consequently, contrary to the FADDosome, p53-independent apoptosis
medicine
-
two patients that are combined heterozygous for single nucleotide substitutions in the Fas and caspase-10 genes. The first patient carries a splice site defect suppressing allele expression in the Fas gene and the P501L substitution in caspase-10. The second has a mutation causing a premature stop codon (Q47X) in the Fas gene and the Y446C substitution in caspase-10. Fas expression is reduced and caspase-10 activity is decreased in both patients. In both patients, the mutations are inherited from distinct healthy parents. Co-transmission of these mutation is responsible for autoimmune lymphoproliferative syndrome
medicine
-
silencer of death domain and caspase-10 are frequently over-expressed in ALL. Interfering with these proteins may provide another strategy for the treatment of this and potentially other cancers
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Garcia-Calvo, M.; Peterson, E.P.; Leiting, B.; Ruel, R.; Nicholson, D.W.; Thornberry, N.A.
Inhibition of human caspases by peptide-based and macromolecular inhibitors
J. Biol. Chem.
273
32608-32613
1998
Homo sapiens
Garcia-Calvo, M.; Peterson, E.P.; Rasper, D.M.; Vaillancourt, J.P.; Zamboni, R.; Nicholson, D.W.; Thornberry, N.A.
Purification and catalytic properties of human caspase family members
Cell Death Differ.
6
362-369
1999
Homo sapiens
Chang, H.Y.; Yang, X.
Proteases from cell suicide: functions and regulation of caspases
Microbiol. Mol. Biol. Rev.
64
821-846
2000
Homo sapiens
Fernandes-Alnemri, T.; Armstrong, R.C.; Krebs, J.F.; Srinivasula, S.M.; Wang, L.; Bullrich, F.; Fritz, L.C.; Trapani, J.A.; Tomaselli, K.J.; Litwack, G.; Alnemri, E.S.
In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains
Proc. Natl. Acad. Sci. USA
93
7464-7469
1996
Homo sapiens (Q92851)
Srinivasula, S.M.; Ahmad, M.; Fernandes-Almeri, T.; Liwack, G.; Alnemri, E.S.
Molecular ordering of the Fas-apoptotic pathway: the fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteien proteases
Proc. Natl. Acad. Sci. USA
93
14486-14491
1996
Homo sapiens
Vincenz, C.; Dixit, V.M.
Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling
J. Biol. Chem.
272
6578-6583
1997
Homo sapiens (Q92851)
Ng P.W.; Porter A.G.; Janicke R.U.
Molecular cloning and characterization of two novel pro-apoptotic isoforms of caspase-10
J. Biol. Chem.
274
10301-10308
1999
Homo sapiens (Q92851)
Shikama, Y.; Yamada, M.; Miyashita, T.
Caspase-8 and caspase-10 activate NF-kappaB through RIP, NIK and IKKalpha kinases
Eur. J. Immunol.
33
1998-2006
2003
Homo sapiens
Wang J.; Zheng L.; Lobito A.; Chan F.K.; Dale J.; Sneller M.; Yao X.; Puck J.M.; Straus S.E.; Lenardo M.J.
Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II
Cell
98
47-58
1999
Homo sapiens (Q92851), Homo sapiens
Boatright, K.M.; Deis, C.; Denault, J.B.; Sutherlin, D.P.; Salvesen, G.S.
Activiation of caspases-8 and -10 by FLIP L
Biochem. J.
382
651-657
2004
Homo sapiens
Zhu, S.; Hsu, A.P.; Vacek, M.M.; Zheng, L.; Schaeffer, A.A.; Dale, J.K.; Davis, J.; Fischer, R.E.; Straus, S.E.; Boruchov, D.; Saulsbury, F.T.; Lenardo, M.J.; Puck, J.M.
Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome
Hum. Genet.
119
284-294
2006
Homo sapiens
Milhas, D.; Cuvillier, O.; Therville, N.; Clave, P.; Thomsen, M.; Levade, T.; Benoist, H.; Segui, B.
Caspase-10 triggers Bid cleavage and caspase cascade activation in FasL-induced apoptosis
J. Biol. Chem.
280
19836-19842
2005
Homo sapiens
Takahashi, K.; Kawai, T.; Kumar, H.; Sato, S.; Yonehara, S.; Akira, S.
Roles of caspase-8 and caspase-10 in innate immune responses to double-stranded RNA
J. Immunol.
176
4520-4524
2006
Homo sapiens
Goepel, F.; Weinmann, P.; Schymeinsky, J.; Walzog, B.
Identification of caspase-10 in human neutrophils and its role in spontaneous apoptosis
J. Leukocyte Biol.
75
836-843
2004
Homo sapiens
Engels, I.H.; Totzke, G.; Fischer, U.; Schulze-Osthoff, K.; Jaenicke, R.U.
Caspase-10 sensitizes breast carcinoma cells to TRAIL-induced but not tumor necrosis factor-induced apoptosis in a caspase-3-dependent manner
Mol. Cell. Biol.
25
2808-2818
2005
Homo sapiens
Filomenko, R.; Prevotat, L.; Rebe, C.; Cortier, M.; Jeannin, J.F.; Solary, E.; Bettaieb, A.
Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells
Oncogene
25
7635-7645
2006
Homo sapiens
Wang, H.; Wang, P.; Sun, X.; Luo, Y.; Wang, X.; Ma, D.; Wu, J.
Cloning and characterization of a novel caspase-10 isoform that activates NF-kB activity
Biochim. Biophys. Acta
1770
1528-1537
2007
Homo sapiens (Q92851), Homo sapiens
Cerutti, E.; Campagnoli, M.F.; Ferretti, M.; Garelli, E.; Crescenzio, N.; Rosolen, A.; Chiocchetti, A.; Lenardo, M.J.; Ramenghi, U.; Dianzani, U.
Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome
BMC Immunol.
8
28
2007
Homo sapiens
Nohara, K.; Yokoyama, Y.; Kano, K.
The important role of caspase-10 in sodium butyrate-induced apoptosis
Kobe J. Med. Sci.
53
265-273
2007
Homo sapiens
Lisa-Santamaria, P.; Neiman, A.M.; Cuesta-Marban, A.; Mollinedo, F.; Revuelta, J.L.; Jimenez, A.
Human initiator caspases trigger apoptotic and autophagic phenotypes in Saccharomyces cerevisiae
Biochim. Biophys. Acta
1793
561-571
2009
Homo sapiens (Q92851), Homo sapiens
Hyer, M.L.; Shi, R.; Krajewska, M.; Meyer, C.; Lebedeva, I.V.; Fisher, P.B.; Reed, J.C.
Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid and related synthetic triterpenoids in prostate cancer
Cancer Res.
68
2927-2933
2008
Homo sapiens
Pawar, P.; Ma, L.; Byon, C.H.; Liu, H.; Ahn, E.Y.; Jhala, N.; Arnoletti, J.P.; McDonald, J.M.; Chen, Y.
Molecular mechanisms of tamoxifen therapy for cholangiocarcinoma: role of calmodulin
Clin. Cancer Res.
15
1288-1296
2009
Homo sapiens
Li, C.; Zhao, H.; Hu, Z.; Liu, Z.; Wang, L.E.; Gershenwald, J.E.; Prieto, V.G.; Lee, J.E.; Duvic, M.; Grimm, E.A.; Wei, Q.
Genetic variants and haplotypes of the caspase-8 and caspase-10 genes contribute to susceptibility to cutaneous melanoma
Hum. Mutat.
29
1443-1451
2008
Homo sapiens
Su, H.C.
The technological transformation of patient-driven human immunology research
Immunol. Res.
43
167-171
2009
Homo sapiens, no activity in Mus musculus
Xu, B.; Zhou, Z.G.; Li, Y.; Wang, L.; Yang, L.; Zhou, B.; Liu, H.Y.; Song, J.M.; Zeng, Y.J.; Wang, R.; Shen, X.G.; Sun, X.F.
Clinicopathological significance of caspase-8 and caspase-10 expression in rectal cancer
Oncology
74
229-236
2008
Homo sapiens
Conrad, D.M.; Furlong, S.J.; Doucette, C.D.; West, K.A.; Hoskin, D.W.
The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells
Apoptosis
15
597-607
2010
Homo sapiens
Chen, H.; Xia, Y.; Fang, D.; Hawke, D.; Lu, Z.
Caspase-10-mediated heat shock protein 90beta cleavage promotes UVB irradiation-induced cell apoptosis
Mol. Cell. Biol.
29
3657-3664
2009
Homo sapiens
Kim, M.S.; Oh, J.E.; Min, C.K.; Lee, S.; Chung, N.G.; Yoo, N.J.; Lee, S.H.
Mutational analysis of CASP10 gene in acute leukaemias and multiple myelomas
Pathology
41
484-487
2009
Homo sapiens
Oh, J.E.; Kim, M.S.; Ahn, C.H.; Kim, S.S.; Han, J.Y.; Lee, S.H.; Yoo, N.J.
Mutational analysis of CASP10 gene in colon, breast, lung and hepatocellular carcinomas
Pathology
42
73-76
2010
Homo sapiens
Wachmann, K.; Pop, C.; van Raam, B.J.; Drag, M.; Mace, P.D.; Snipas, S.J.; Zmasek, C.; Schwarzenbacher, R.; Salvesen, G.S.; Riedl, S.J.
Activation and specificity of human caspase-10
Biochemistry
49
8307-8315
2010
Homo sapiens (Q92851), Homo sapiens
van Raam, B.J.; Salvesen, G.S.
Proliferative versus apoptotic functions of caspase-8 hetero or homo: the caspase-8 dimer controls cell fate
Biochim. Biophys. Acta
1824
113-122
2012
Homo sapiens, no activity in Mus musculus
Muehlethaler-Mottet, A.; Flahaut, M.; Bourloud, K.B.; Nardou, K.; Coulon, A.; Liberman, J.; Thome, M.; Gross, N.
Individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis
Cell Death Dis.
2
e125
2011
Homo sapiens
Lopez, D.; Jimenez, M.; Garcia-Calvo, M.; Del Val, M.
Concerted antigen processing of a short viral antigen by human caspase-5 and -10
J. Biol. Chem.
286
16910-16913
2011
Homo sapiens
Meng, L.; Sefah, K.; ODonoghue, M.B.; Zhu, G.; Shangguan, D.; Noorali, A.; Chen, Y.; Zhou, L.; Tan, W.
Silencing of PTK7 in colon cancer cells: caspase-10-dependent apoptosis via mitochondrial pathway
PLoS ONE
5
e14018
2010
Homo sapiens
Raulf, N.; El-Attar, R.; Kulms, D.; Lecis, D.; Delia, D.; Walczak, H.; Papenfuss, K.; Odell, E.; Tavassoli, M.
Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10
Br. J. Cancer
111
1955-1964
2014
Homo sapiens
Lisa-Santamaria, P.; Jimenez, A.; Revuelta, J.L.
The protein factor-arrest 11 (Far11) is essential for the toxicity of human caspase-10 in yeast and participates in the regulation of autophagy and the DNA damage signaling
J. Biol. Chem.
287
29636-29647
2012
Homo sapiens
Krug, H.F.
Caspase-10 is the key initiator caspase involved in tributyltin-mediated apoptosis in human immune cells
J. Toxicol.
2012
395482
2012
Homo sapiens
Cisterne, A.; Baraz, R.; Khan, N.I.; Welschinger, R.; Basnett, J.; Fung, C.; Rizos, H.; Bradstock, K.F.; Bendall, L.J.
Silencer of death domains controls cell death through tumour necrosis factor-receptor 1 and caspase-10 in acute lymphoblastic leukemia
PLoS ONE
9
e103383
2014
Homo sapiens
Mohr, A.; Deedigan, L.; Jencz, S.; Mehrabadi, Y.; Houlden, L.; Albarenque, S.M.; Zwacka, R.M.
Caspase-10 a molecular switch from cell-autonomous apoptosis to communal cell death in response to chemotherapeutic drug treatment
Cell Death Differ.
25
340-352
2018
Homo sapiens (Q92851)
Horn, S.; Hughes, M.A.; Schilling, R.; Sticht, C.; Tenev, T.; Ploesser, M.; Meier, P.; Sprick, M.R.; MacFarlane, M.; Leverkus, M.
Caspase-10 negatively regulates caspase-8-mediated cell death, switching the response to CD95L in favor of NF-kappaB activation and cell survival
Cell Rep.
19
785-797
2017
Homo sapiens (Q92851)
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