[1]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 5; 6; 7 AND 8).
TISSUE=B-cell, and Thymus;
DOI=10.1016/S0092-8674(00)81265-9; PubMed=8681376 [NCBI, ExPASy, EBI, Israel, Japan]
Boldin M.P.,
Goncharov T.M.,
Goltsev Y.V.,
Wallach D.;
"Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.";
Cell 85:803-815(1996).
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[2]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
DOI=10.1016/S0092-8674(00)81266-0; PubMed=8681377 [NCBI, ExPASy, EBI, Israel, Japan]
Muzio M.,
Chinnaiyan A.M.,
Kischkel F.C.,
O'Rourke K.,
Shevchenko A.,
Ni J.,
Scaffidi C.,
Bretz J.D.,
Zhang M.,
Gentz R.,
Mann M.,
Krammer P.H.,
Peter M.E.,
Dixit V.M.;
"FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex.";
Cell 85:817-827(1996).
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[3]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND VARIANT HIS-285.
TISSUE=T-cell;
DOI=10.1073/pnas.93.15.7464; PubMed=8755496 [NCBI, ExPASy, EBI, Israel, Japan]
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. U.S.A. 93:7464-7469(1996).
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[4]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT HIS-285.
DOI=10.1074/jbc.272.30.18542; PubMed=9228018 [NCBI, ExPASy, EBI, Israel, Japan]
Srinivasula S.M.,
Ahmad M.,
Ottilie S.,
Bullrich F.,
Banks S.,
Wang Y.,
Fernandes-Alnemri T.,
Croce C.M.,
Litwack G.,
Tomaselli K.J.,
Armstrong R.C.,
Alnemri E.S.;
"FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis.";
J. Biol. Chem. 272:18542-18545(1997).
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[5]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA].
DOI=10.1016/S0378-1119(98)00565-4; PubMed=9931493 [NCBI, ExPASy, EBI, Israel, Japan]
Grenet J.,
Teitz T.,
Wei T.,
Valentine V.,
Kidd V.J.;
"Structure and chromosome localization of the human CASP8 gene.";
Gene 226:225-232(1999).
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[6]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-285.
DOI=10.1006/geno.2000.6392; PubMed=11161814 [NCBI, ExPASy, EBI, Israel, Japan]
Hadano S.,
Yanagisawa Y.,
Skaug J.,
Fichter K.,
Nasir J.,
Martindale D.,
Koop B.F.,
Scherer S.W.,
Nicholson D.W.,
Rouleau G.A.,
Ikeda J.-E.,
Hayden M.R.;
"Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2.";
Genomics 71:200-213(2001).
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[7]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), AND FUNCTION OF ISOFORM 7.
TISSUE=Leukocyte;
DOI=10.1182/blood.V99.11.4070; PubMed=12010809 [NCBI, ExPASy, EBI, Israel, Japan]
Himeji D.,
Horiuchi T.,
Tsukamoto H.,
Hayashi K.,
Watanabe T.,
Harada M.;
"Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade.";
Blood 99:4070-4078(2002).
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[8]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 9), AND INTERACTION OF ISOFORM 9 WITH BCAP31 AT THE ENDOPLASMIC RETICULUM.
DOI=10.1073/pnas.072088099; PubMed=11917123 [NCBI, ExPASy, EBI, Israel, Japan]
Breckenridge D.G.,
Nguyen M.,
Kuppig S.,
Reth M.,
Shore G.C.;
"The procaspase-8 isoform, procaspase-8L, recruited to the BAP31 complex at the endoplasmic reticulum.";
Proc. Natl. Acad. Sci. U.S.A. 99:4331-4336(2002).
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[9]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-219 AND HIS-285.
NIEHS SNPs program;
Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
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[10]
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NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
DOI=10.1038/nature03466; PubMed=15815621 [NCBI, ExPASy, EBI, Israel, Japan]
Hillier L.W.,
Graves T.A.,
Fulton R.S.,
Fulton L.A.,
Pepin K.H.,
Minx P.,
Wagner-McPherson C.,
Layman D.,
Wylie K.,
Sekhon M.,
Becker M.C.,
Fewell G.A.,
Delehaunty K.D.,
Miner T.L.,
Nash W.E.,
Kremitzki C.,
Oddy L.,
Du H.,
Sun H., ![]()
Bradshaw-Cordum H.,
Ali J.,
Carter J.,
Cordes M.,
Harris A.,
Isak A.,
van Brunt A.,
Nguyen C.,
Du F.,
Courtney L.,
Kalicki J.,
Ozersky P.,
Abbott S.,
Armstrong J.,
Belter E.A.,
Caruso L.,
Cedroni M.,
Cotton M.,
Davidson T.,
Desai A.,
Elliott G.,
Erb T.,
Fronick C.,
Gaige T.,
Haakenson W.,
Haglund K.,
Holmes A.,
Harkins R.,
Kim K.,
Kruchowski S.S.,
Strong C.M.,
Grewal N.,
Goyea E.,
Hou S.,
Levy A.,
Martinka S.,
Mead K.,
McLellan M.D.,
Meyer R.,
Randall-Maher J.,
Tomlinson C.,
Dauphin-Kohlberg S.,
Kozlowicz-Reilly A.,
Shah N.,
Swearengen-Shahid S.,
Snider J.,
Strong J.T.,
Thompson J.,
Yoakum M.,
Leonard S.,
Pearman C.,
Trani L.,
Radionenko M.,
Waligorski J.E.,
Wang C.,
Rock S.M.,
Tin-Wollam A.-M.,
Maupin R.,
Latreille P.,
Wendl M.C.,
Yang S.-P.,
Pohl C.,
Wallis J.W.,
Spieth J.,
Bieri T.A.,
Berkowicz N.,
Nelson J.O.,
Osborne J.,
Ding L.,
Meyer R.,
Sabo A.,
Shotland Y.,
Sinha P.,
Wohldmann P.E.,
Cook L.L.,
Hickenbotham M.T.,
Eldred J.,
Williams D.,
Jones T.A.,
She X.,
Ciccarelli F.D.,
Izaurralde E.,
Taylor J.,
Schmutz J.,
Myers R.M.,
Cox D.R.,
Huang X.,
McPherson J.D.,
Mardis E.R.,
Clifton S.W.,
Warren W.C.,
Chinwalla A.T.,
Eddy S.R.,
Marra M.A.,
Ovcharenko I.,
Furey T.S.,
Miller W.,
Eichler E.E.,
Bork P.,
Suyama M.,
Torrents D.,
Waterston R.H.,
Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2 and 4.";
Nature 434:724-731(2005).
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[11]
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NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7).
TISSUE=Leukocyte;
DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan]
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
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[12]
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PARTIAL PROTEIN SEQUENCE, AND PROTEOLYTIC PROCESSING.
DOI=10.1073/pnas.93.25.14486; PubMed=8962078 [NCBI, ExPASy, EBI, Israel, Japan]
Srinivasula S.M.,
Ahmad M.,
Fernandes-Alnemri T.,
Litwack 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 cysteine proteases.";
Proc. Natl. Acad. Sci. U.S.A. 93:14486-14491(1996).
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[13]
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FUNCTION.
DOI=10.1074/jbc.272.5.2952; PubMed=9006941 [NCBI, ExPASy, EBI, Israel, Japan]
Muzio M.,
Salvesen G.S.,
Dixit V.M.;
"FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens.";
J. Biol. Chem. 272:2952-2956(1997).
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[14]
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PROTEOLYTIC PROCESSING.
DOI=10.1093/emboj/16.10.2794; PubMed=9184224 [NCBI, ExPASy, EBI, Israel, Japan]
Medema J.P.,
Scaffidi C.,
Kischkel F.C.,
Shevchenko A.,
Mann M.,
Krammer P.H.,
Peter M.E.;
"FLICE is activated by association with the CD95 death-inducing signaling complex (DISC).";
EMBO J. 16:2794-2804(1997).
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[15]
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CHARACTERIZATION OF ISOFORM 7.
DOI=10.1006/bbrc.2000.2841; PubMed=10860845 [NCBI, ExPASy, EBI, Israel, Japan]
Horiuchi T.,
Himeji D.,
Tsukamoto H.,
Harashima S.,
Hashimura C.,
Hayashi K.;
"Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes.";
Biochem. Biophys. Res. Commun. 272:877-881(2000).
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[16]
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INTERACTION WITH BCL2; BCL2L1 AND BCAP31.
DOI=10.1083/jcb.139.2.327; PubMed=9334338 [NCBI, ExPASy, EBI, Israel, Japan]
Ng F.W.H.,
Nguyen M.,
Kwan T.,
Branton P.E.,
Nicholson D.W.,
Cromlish J.A.,
Shore G.C.;
"p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum.";
J. Cell Biol. 139:327-338(1997).
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[17]
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INTERACTION WITH PEA15.
DOI=10.1038/sj.onc.1202831; PubMed=10442631 [NCBI, ExPASy, EBI, Israel, Japan]
Condorelli G.,
Vigliotta G.,
Cafieri A.,
Trencia A.,
Andalo P.,
Oriente F.,
Miele C.,
Caruso M.,
Formisano P.,
Beguinot F.;
"PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.";
Oncogene 18:4409-4415(1999).
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[18]
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SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
DOI=10.1186/gb-2004-5-2-r8; PubMed=14759258 [NCBI, ExPASy, EBI, Israel, Japan]
Hillman R.T.,
Green R.E.,
Brenner S.E.;
"An unappreciated role for RNA surveillance.";
Genome Biol. 5:RESEARCH008.1-RESEARCH008.16(2004).
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[19]
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PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-334, AND MASS SPECTROMETRY.
DOI=10.1038/nbt1046; PubMed=15592455 [NCBI, ExPASy, EBI, Israel, Japan]
Rush J.,
Moritz A.,
Lee K.A.,
Guo A.,
Goss V.L.,
Spek E.J.,
Zhang H.,
Zha X.-M.,
Polakiewicz R.D.,
Comb M.J.;
"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
Nat. Biotechnol. 23:94-101(2005).
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[20]
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MUTAGENESIS OF ASP-73.
DOI=10.1038/sj.onc.1208186; PubMed=15592525 [NCBI, ExPASy, EBI, Israel, Japan]
Jun J.-I.,
Chung C.-W.,
Lee H.-J.,
Pyo J.-O.,
Lee K.N.,
Kim N.-S.,
Kim Y.S.,
Yoo H.-S.,
Lee T.-H.,
Kim E.,
Jung Y.-K.;
"Role of FLASH in caspase-8-mediated activation of NF-kappaB: dominant-negative function of FLASH mutant in NF-kappaB signaling pathway.";
Oncogene 24:688-696(2005).
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[21]
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PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219, AND MASS SPECTROMETRY.
DOI=10.1126/science.1140321; PubMed=17525332 [NCBI, ExPASy, EBI, Israel, Japan]
Matsuoka S.,
Ballif B.A.,
Smogorzewska A.,
McDonald E.R. III,
Hurov K.E.,
Luo J.,
Bakalarski C.E.,
Zhao Z.,
Solimini N.,
Lerenthal Y.,
Shiloh Y.,
Gygi S.P.,
Elledge S.J.;
"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.";
Science 316:1160-1166(2007).
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[22]
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X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
DOI=10.1016/S0969-2126(99)80179-8; PubMed=10508784 [NCBI, ExPASy, EBI, Israel, Japan]
Blanchard H.,
Kodandapani L.,
Mittl P.R.E.,
Di Marco S.,
Krebs J.F.,
Wu J.C.,
Tomaselli K.J.,
Gruetter M.G.;
"The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.";
Structure 7:1125-1133(1999).
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[23]
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X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 211-479, AND SUBUNIT.
DOI=10.1016/S0969-2126(99)80180-4; PubMed=10508785 [NCBI, ExPASy, EBI, Israel, Japan]
Watt W.,
Koeplinger K.A.,
Mildner A.M.,
Heinrikson R.L.,
Tomasselli A.G.,
Watenpaugh K.D.;
"The atomic-resolution structure of human caspase-8, a key activator of apoptosis.";
Structure 7:1135-1143(1999).
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[24]
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VARIANT CASP8D TRP-248.
DOI=10.1038/nature01063; PubMed=12353035 [NCBI, ExPASy, EBI, Israel, Japan]
Chun H.J.,
Zheng L.,
Ahmad M.,
Wang J.,
Speirs C.K.,
Siegel R.M.,
Dale J.K.,
Puck J.,
Davis J.,
Hall C.G.,
Skoda-Smith S.,
Atkinson T.P.,
Straus S.E.,
Lenardo M.J.;
"Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.";
Nature 419:395-399(2002).
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[25]
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INVOLVEMENT IN PROTECTION AGAINST LUNG CANCER.
DOI=10.1038/ng2030; PubMed=17450141 [NCBI, ExPASy, EBI, Israel, Japan]
Sun T.,
Gao Y.,
Tan W.,
Ma S.,
Shi Y.,
Yao J.,
Guo Y.,
Yang M.,
Zhang X.,
Zhang Q.,
Zeng C.,
Lin D.;
"A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers.";
Nat. Genet. 39:605-613(2007).
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- FUNCTION: 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. Isoforms 5, 6, 7 and 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.
- CATALYTIC ACTIVITY: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).
- SUBUNIT: 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 (By similarity).
- INTERACTION:
Self; NbExp=2; IntAct=EBI-78060, EBI-78060;
P51572:BCAP31; NbExp=1; IntAct=EBI-288343, EBI-77683;
P51572:BCAP31; NbExp=1; IntAct=EBI-78060, EBI-77683;
Q9JJV8:BCL2 (xeno); NbExp=1; IntAct=EBI-78060, EBI-1749099;
Q92851:CASP10; NbExp=2; IntAct=EBI-78060, EBI-495095;
P30429:ced-4 (xeno); NbExp=1; IntAct=EBI-78060, EBI-494118;
Q9HAV5:EDA2R; NbExp=1; IntAct=EBI-288343, EBI-526033;
Q13158:FADD; NbExp=1; IntAct=EBI-288326, EBI-494804;
Q13158:FADD; NbExp=3; IntAct=EBI-78060, EBI-494804;
P25445:FAS; NbExp=3; IntAct=EBI-78060, EBI-494743;
Q13418:ILK; NbExp=1; IntAct=EBI-78060, EBI-747644;
O60936:NOL3; NbExp=3; IntAct=EBI-78060, EBI-740992;
P08160:P35 (xeno); NbExp=1; IntAct=EBI-78060, EBI-1030934;
Q13546:RIPK1; NbExp=1; IntAct=EBI-78060, EBI-358507;
Q9D8Y7:Tnfaip8l2 (xeno); NbExp=1; IntAct=EBI-78060, EBI-1781612;
- SUBCELLULAR LOCATION: Cytoplasm.
- ALTERNATIVE PRODUCTS:
9 named isoforms [FASTA] produced by alternative splicing.
|
| Name | 2 |
| Synonyms | Alpha-2, MCH5-beta |
| Isoform ID | Q14790-2 |
| Features which should be applied to build the isoform sequence: VSP_000810. |
|
|
| Name | 3 |
| Synonyms | Alpha-3 |
| Isoform ID | Q14790-3 |
| Features which should be applied to build the isoform sequence: VSP_000813. |
|
| | | |
| Name | 7 |
| Synonyms | Beta-3, 8L |
| Isoform ID | Q14790-7 |
| Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. |
| Features which should be applied to build the isoform sequence: VSP_000816, VSP_000817. |
|
| |
| Name | 9 |
| Synonyms | 8L |
| Isoform ID | Q14790-9 |
| Features which should be applied to build the isoform sequence: VSP_000808. |
|
|
- TISSUE SPECIFICITY: Isoforms 1, 5 and 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.
- DOMAIN: Isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex.
- PTM: Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events.
- PTM: Phosphorylated upon DNA damage, probably by ATM or ATR.
- POLYMORPHISM: Genetic vaiations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic vaiations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.
- DISEASE: Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.
- SIMILARITY: Belongs to the peptidase C14A family [view classification].
- SIMILARITY: Contains 2 DED (death effector) domains.
- SEQUENCE CAUTION:
- Sequence=CAA66858.1; Type=Miscellaneous discrepancy;
- Sequence=CAA66859.1; Type=Miscellaneous discrepancy;
- WEB RESOURCE: Name=CASP8base; Note=CASP8 mutation db; URL="http://bioinf.uta.fi/CASP8base/";.
- WEB RESOURCE: Name=GeneReviews; URL="http://www.genetests.org/query?gene=CASP8";.
- WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/casp8/";.
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