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Database: UniProt
Entry: Q14790
LinkDB: Q14790
Original site: Q14790 
ID   CASP8_HUMAN             Reviewed;         479 AA.
AC   Q14790; O14676; Q14791; Q14792; Q14793; Q14794; Q14795; Q14796;
AC   Q15780; Q15806; Q53TT5; Q8TDI1; Q8TDI2; Q8TDI3; Q8TDI4; Q8TDI5;
AC   Q96T22; Q9C0K4; Q9UQ81;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   26-NOV-2014, entry version 184.
DE   RecName: Full=Caspase-8;
DE            Short=CASP-8;
DE            EC=3.4.22.61;
DE   AltName: Full=Apoptotic cysteine protease;
DE   AltName: Full=Apoptotic protease Mch-5;
DE   AltName: Full=CAP4;
DE   AltName: Full=FADD-homologous ICE/ced-3-like protease;
DE   AltName: Full=FADD-like ICE;
DE            Short=FLICE;
DE   AltName: Full=ICE-like apoptotic protease 5;
DE   AltName: Full=MORT1-associated ced-3 homolog;
DE            Short=MACH;
DE   Contains:
DE     RecName: Full=Caspase-8 subunit p18;
DE   Contains:
DE     RecName: Full=Caspase-8 subunit p10;
DE   Flags: Precursor;
GN   Name=CASP8; Synonyms=MCH5;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 5; 6; 7 AND 8).
RC   TISSUE=B-cell, and Thymus;
RX   PubMed=8681376; DOI=10.1016/S0092-8674(00)81265-9;
RA   Boldin M.P., Goncharov T.M., Goltsev Y.V., Wallach D.;
RT   "Involvement of MACH, a novel MORT1/FADD-interacting protease, in
RT   Fas/APO-1- and TNF receptor-induced cell death.";
RL   Cell 85:803-815(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX   PubMed=8681377; DOI=10.1016/S0092-8674(00)81266-0;
RA   Muzio M., Chinnaiyan A.M., Kischkel F.C., O'Rourke K., Shevchenko A.,
RA   Ni J., Scaffidi C., Bretz J.D., Zhang M., Gentz R., Mann M.,
RA   Krammer P.H., Peter M.E., Dixit V.M.;
RT   "FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited
RT   to the CD95 (Fas/APO-1) death-inducing signaling complex.";
RL   Cell 85:817-827(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND VARIANT HIS-285.
RC   TISSUE=T-cell;
RX   PubMed=8755496; DOI=10.1073/pnas.93.15.7464;
RA   Fernandes-Alnemri T., Armstrong R.C., Krebs J.F., Srinivasula S.M.,
RA   Wang L., Bullrich F., Fritz L.C., Trapani J.A., Tomaselli K.J.,
RA   Litwack G., Alnemri E.S.;
RT   "In vitro activation of CPP32 and Mch3 by Mch4, a novel human
RT   apoptotic cysteine protease containing two FADD-like domains.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT HIS-285.
RX   PubMed=9228018; DOI=10.1074/jbc.272.30.18542;
RA   Srinivasula S.M., Ahmad M., Ottilie S., Bullrich F., Banks S.,
RA   Wang Y., Fernandes-Alnemri T., Croce C.M., Litwack G., Tomaselli K.J.,
RA   Armstrong R.C., Alnemri E.S.;
RT   "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates
RT   Fas/TNFR1-induced apoptosis.";
RL   J. Biol. Chem. 272:18542-18545(1997).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=9931493; DOI=10.1016/S0378-1119(98)00565-4;
RA   Grenet J., Teitz T., Wei T., Valentine V., Kidd V.J.;
RT   "Structure and chromosome localization of the human CASP8 gene.";
RL   Gene 226:225-232(1999).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-285.
RX   PubMed=11161814; DOI=10.1006/geno.2000.6392;
RA   Hadano S., Yanagisawa Y., Skaug J., Fichter K., Nasir J.,
RA   Martindale D., Koop B.F., Scherer S.W., Nicholson D.W., Rouleau G.A.,
RA   Ikeda J.-E., Hayden M.R.;
RT   "Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2,
RT   and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2)
RT   critical region at chromosome 2q33-q34: candidate genes for ALS2.";
RL   Genomics 71:200-213(2001).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), AND FUNCTION (ISOFORM 7).
RC   TISSUE=Leukocyte;
RX   PubMed=12010809; DOI=10.1182/blood.V99.11.4070;
RA   Himeji D., Horiuchi T., Tsukamoto H., Hayashi K., Watanabe T.,
RA   Harada M.;
RT   "Characterization of caspase-8L: a novel isoform of caspase-8 that
RT   behaves as an inhibitor of the caspase cascade.";
RL   Blood 99:4070-4078(2002).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 9), AND INTERACTION OF
RP   ISOFORM 9 WITH BCAP31 AT THE ENDOPLASMIC RETICULUM.
RX   PubMed=11917123; DOI=10.1073/pnas.072088099;
RA   Breckenridge D.G., Nguyen M., Kuppig S., Reth M., Shore G.C.;
RT   "The procaspase-8 isoform, procaspase-8L, recruited to the BAP31
RT   complex at the endoplasmic reticulum.";
RL   Proc. Natl. Acad. Sci. U.S.A. 99:4331-4336(2002).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-219 AND HIS-285.
RG   NIEHS SNPs program;
RL   Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA   Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA   Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA   Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA   Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA   Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA   Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA   Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA   Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA   Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA   Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA   Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA   Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA   Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA   Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA   Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA   Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA   Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA   McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA   Waterston R.H., Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2
RT   and 4.";
RL   Nature 434:724-731(2005).
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7).
RC   TISSUE=Leukocyte;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [12]
RP   PARTIAL PROTEIN SEQUENCE, AND PROTEOLYTIC PROCESSING.
RX   PubMed=8962078; DOI=10.1073/pnas.93.25.14486;
RA   Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G.,
RA   Alnemri E.S.;
RT   "Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1
RT   protease Mch5 is a CrmA-inhibitable protease that activates multiple
RT   Ced-3/ICE-like cysteine proteases.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:14486-14491(1996).
RN   [13]
RP   FUNCTION.
RX   PubMed=9006941; DOI=10.1074/jbc.272.5.2952;
RA   Muzio M., Salvesen G.S., Dixit V.M.;
RT   "FLICE induced apoptosis in a cell-free system. Cleavage of caspase
RT   zymogens.";
RL   J. Biol. Chem. 272:2952-2956(1997).
RN   [14]
RP   PROTEOLYTIC PROCESSING.
RX   PubMed=9184224; DOI=10.1093/emboj/16.10.2794;
RA   Medema J.P., Scaffidi C., Kischkel F.C., Shevchenko A., Mann M.,
RA   Krammer P.H., Peter M.E.;
RT   "FLICE is activated by association with the CD95 death-inducing
RT   signaling complex (DISC).";
RL   EMBO J. 16:2794-2804(1997).
RN   [15]
RP   CHARACTERIZATION (ISOFORM 7).
RX   PubMed=10860845; DOI=10.1006/bbrc.2000.2841;
RA   Horiuchi T., Himeji D., Tsukamoto H., Harashima S., Hashimura C.,
RA   Hayashi K.;
RT   "Dominant expression of a novel splice variant of caspase-8 in human
RT   peripheral blood lymphocytes.";
RL   Biochem. Biophys. Res. Commun. 272:877-881(2000).
RN   [16]
RP   INTERACTION WITH BCL2; BCL2L1 AND BCAP31.
RX   PubMed=9334338; DOI=10.1083/jcb.139.2.327;
RA   Ng F.W.H., Nguyen M., Kwan T., Branton P.E., Nicholson D.W.,
RA   Cromlish J.A., Shore G.C.;
RT   "p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the
RT   endoplasmic reticulum.";
RL   J. Cell Biol. 139:327-338(1997).
RN   [17]
RP   INTERACTION WITH PEA15.
RX   PubMed=10442631; DOI=10.1038/sj.onc.1202831;
RA   Condorelli G., Vigliotta G., Cafieri A., Trencia A., Andalo P.,
RA   Oriente F., Miele C., Caruso M., Formisano P., Beguinot F.;
RT   "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-
RT   induced apoptosis.";
RL   Oncogene 18:4409-4415(1999).
RN   [18]
RP   INTERACTION WITH HHV-5 PROTEIN UL36.
RX   PubMed=11427719; DOI=10.1073/pnas.141108798;
RA   Skaletskaya A., Bartle L.M., Chittenden T., McCormick A.L.,
RA   Mocarski E.S., Goldmacher V.S.;
RT   "A cytomegalovirus-encoded inhibitor of apoptosis that suppresses
RT   caspase-8 activation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 98:7829-7834(2001).
RN   [19]
RP   SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX   PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA   Hillman R.T., Green R.E., Brenner S.E.;
RT   "An unappreciated role for RNA surveillance.";
RL   Genome Biol. 5:R8.1-R8.16(2004).
RN   [20]
RP   INTERACTION WITH RFFL AND RNF34.
RX   PubMed=15069192; DOI=10.1073/pnas.0307459101;
RA   McDonald E.R. III, El-Deiry W.S.;
RT   "Suppression of caspase-8- and -10-associated RING proteins results in
RT   sensitization to death ligands and inhibition of tumor cell growth.";
RL   Proc. Natl. Acad. Sci. U.S.A. 101:6170-6175(2004).
RN   [21]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-334, AND IDENTIFICATION
RP   BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=15592455; DOI=10.1038/nbt1046;
RA   Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA   Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT   "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT   cells.";
RL   Nat. Biotechnol. 23:94-101(2005).
RN   [22]
RP   MUTAGENESIS OF ASP-73.
RX   PubMed=15592525; DOI=10.1038/sj.onc.1208186;
RA   Jun J.-I., Chung C.-W., Lee H.-J., Pyo J.-O., Lee K.N., Kim N.-S.,
RA   Kim Y.S., Yoo H.-S., Lee T.-H., Kim E., Jung Y.-K.;
RT   "Role of FLASH in caspase-8-mediated activation of NF-kappaB:
RT   dominant-negative function of FLASH mutant in NF-kappaB signaling
RT   pathway.";
RL   Oncogene 24:688-696(2005).
RN   [23]
RP   INTERACTION WITH CASP8P2.
RX   PubMed=17245429; DOI=10.1038/sj.emboj.7601504;
RA   Milovic-Holm K., Krieghoff E., Jensen K., Will H., Hofmann T.G.;
RT   "FLASH links the CD95 signaling pathway to the cell nucleus and
RT   nuclear bodies.";
RL   EMBO J. 26:391-401(2007).
RN   [24]
RP   PHOSPHORYLATION AT SER-387 BY CDK1.
RX   PubMed=20937773; DOI=10.1128/MCB.00731-10;
RA   Matthess Y., Raab M., Sanhaji M., Lavrik I.N., Strebhardt K.;
RT   "Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-
RT   8 activity.";
RL   Mol. Cell. Biol. 30:5726-5740(2010).
RN   [25]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA   Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [26]
RP   INTERACTION WITH E.COLI NLEF, CATALYTIC ACTIVITY, FUNCTION, AND ENZYME
RP   REGULATION.
RA   Blasche S., Moertl M., Steuber H., Siszler G., Nisa S., Schwarz F.,
RA   Lavrik I., Gronewold T.M.A., Maskos K., Donnenberg M.S., Ullmann D.,
RA   Uetz P., Koegl M.;
RT   "The E.coli effector protein NleF is a caspase inhibitor.";
RL   PLoS ONE 0:0-0(2013).
RN   [27]
RP   X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
RX   PubMed=10508784; DOI=10.1016/S0969-2126(99)80179-8;
RA   Blanchard H., Kodandapani L., Mittl P.R.E., Di Marco S., Krebs J.F.,
RA   Wu J.C., Tomaselli K.J., Gruetter M.G.;
RT   "The three-dimensional structure of caspase-8: an initiator enzyme in
RT   apoptosis.";
RL   Structure 7:1125-1133(1999).
RN   [28]
RP   X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 211-479, AND SUBUNIT.
RX   PubMed=10508785; DOI=10.1016/S0969-2126(99)80180-4;
RA   Watt W., Koeplinger K.A., Mildner A.M., Heinrikson R.L.,
RA   Tomasselli A.G., Watenpaugh K.D.;
RT   "The atomic-resolution structure of human caspase-8, a key activator
RT   of apoptosis.";
RL   Structure 7:1135-1143(1999).
RN   [29]
RP   VARIANT CASP8D TRP-248.
RX   PubMed=12353035; DOI=10.1038/nature01063;
RA   Chun H.J., Zheng L., Ahmad M., Wang J., Speirs C.K., Siegel R.M.,
RA   Dale J.K., Puck J., Davis J., Hall C.G., Skoda-Smith S.,
RA   Atkinson T.P., Straus S.E., Lenardo M.J.;
RT   "Pleiotropic defects in lymphocyte activation caused by caspase-8
RT   mutations lead to human immunodeficiency.";
RL   Nature 419:395-399(2002).
RN   [30]
RP   VARIANT HIS-285, AND PROTECTION AGAINST BREAST CANCER.
RX   PubMed=15601643; DOI=10.1093/jnci/dji001;
RA   MacPherson G., Healey C.S., Teare M.D., Balasubramanian S.P.,
RA   Reed M.W.R., Pharoah P.D., Ponder B.A.J., Meuth M.,
RA   Bhattacharyya N.P., Cox A.;
RT   "Association of a common variant of the CASP8 gene with reduced risk
RT   of breast cancer.";
RL   J. Natl. Cancer Inst. 96:1866-1869(2004).
RN   [31]
RP   VARIANT HIS-285, AND PROTECTION AGAINST BREAST CANCER.
RX   PubMed=17293864; DOI=10.1038/ng1981;
RG   The Kathleen Cunningham foundation consortium for research into familial breast cancer;
RG   Breast cancer association consortium;
RA   Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S.,
RA   Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J.,
RA   Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C.,
RA   Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O., Johnson N.,
RA   dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G.,
RA   Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H.,
RA   Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P.,
RA   Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C.,
RA   Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N.,
RA   Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B.,
RA   Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J.,
RA   Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A.,
RA   Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y.,
RA   Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J.,
RA   Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J.,
RA   Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P.,
RA   Easton D.F.;
RT   "A common coding variant in CASP8 is associated with breast cancer
RT   risk.";
RL   Nat. Genet. 39:352-358(2007).
RN   [32]
RP   ERRATUM.
RG   The Kathleen Cunningham foundation consortium for research into familial breast cancer;
RG   Breast cancer association consortium;
RA   Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S.,
RA   Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J.,
RA   Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C.,
RA   Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O., Johnson N.,
RA   dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G.,
RA   Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H.,
RA   Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P.,
RA   Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C.,
RA   Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N.,
RA   Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B.,
RA   Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J.,
RA   Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A.,
RA   Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y.,
RA   Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J.,
RA   Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J.,
RA   Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P.,
RA   Easton D.F.;
RL   Nat. Genet. 39:688-688(2007).
RN   [33]
RP   INVOLVEMENT IN PROTECTION AGAINST LUNG CANCER.
RX   PubMed=17450141; DOI=10.1038/ng2030;
RA   Sun T., Gao Y., Tan W., Ma S., Shi Y., Yao J., Guo Y., Yang M.,
RA   Zhang X., Zhang Q., Zeng C., Lin D.;
RT   "A six-nucleotide insertion-deletion polymorphism in the CASP8
RT   promoter is associated with susceptibility to multiple cancers.";
RL   Nat. Genet. 39:605-613(2007).
RN   [34]
RP   VARIANT HIS-285, AND RISK FACTOR FOR CUTANEOUS MELANOMA.
RX   PubMed=18563783; DOI=10.1002/humu.20803;
RA   Li C., Zhao H., Hu Z., Liu Z., Wang L.-E., Gershenwald J.E.,
RA   Prieto V.G., Lee J.E., Duvic M., Grimm E.A., Wei Q.;
RT   "Genetic variants and haplotypes of the caspase-8 and caspase-10 genes
RT   contribute to susceptibility to cutaneous melanoma.";
RL   Hum. Mutat. 29:1443-1451(2008).
CC   -!- FUNCTION: Most upstream protease of the activation cascade of
CC       caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A
CC       induced cell death. Binding to the adapter molecule FADD recruits
CC       it to either receptor. The resulting aggregate called death-
CC       inducing signaling complex (DISC) performs CASP8 proteolytic
CC       activation. The active dimeric enzyme is then liberated from the
CC       DISC and free to activate downstream apoptotic proteases.
CC       Proteolytic fragments of the N-terminal propeptide (termed CAP3,
CC       CAP5 and CAP6) are likely retained in the DISC. Cleaves and
CC       activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May
CC       participate in the GZMB apoptotic pathways. Cleaves ADPRT.
CC       Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC.
CC       Likely target for the cowpox virus CRMA death inhibitory protein.
CC       Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic
CC       site and may interfere with the pro-apoptotic activity of the
CC       complex. {ECO:0000269|PubMed:9006941, ECO:0000269|Ref.26}.
CC   -!- CATALYTIC ACTIVITY: Strict requirement for Asp at position P1 and
CC       has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-
CC       (Gly/Ser/Ala). {ECO:0000269|Ref.26}.
CC   -!- ENZYME REGULATION: Inhibited by the effector protein NleF that is
CC       produced by pathogenic E.coli; this inhibits apoptosis.
CC       {ECO:0000269|Ref.26}.
CC   -!- SUBUNIT: Heterotetramer that consists of two anti-parallel
CC       arranged heterodimers, each one formed by a 18 kDa (p18) and a 10
CC       kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9
CC       interacts at the endoplasmic reticulum with a complex containing
CC       BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 (By
CC       similarity). Interacts with CASP8AP2. Interacts with RFFL and
CC       RNF34; negatively regulate CASP8 through proteasomal degradation.
CC       Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this
CC       interaction inhibits CASP8 activation. Interacts with NleF from
CC       pathogenic E.coli. {ECO:0000250|UniProtKB:O89110,
CC       ECO:0000269|PubMed:10442631, ECO:0000269|PubMed:10508785,
CC       ECO:0000269|PubMed:11427719, ECO:0000269|PubMed:11917123,
CC       ECO:0000269|PubMed:15069192, ECO:0000269|PubMed:17245429,
CC       ECO:0000269|PubMed:9334338, ECO:0000269|Ref.26}.
CC   -!- INTERACTION:
CC       P51572:BCAP31; NbExp=3; IntAct=EBI-78060, EBI-77683;
CC       Q92851:CASP10; NbExp=3; IntAct=EBI-78060, EBI-495095;
CC       Q9UKL3:CASP8AP2; NbExp=3; IntAct=EBI-78060, EBI-2339650;
CC       O15519:CFLAR; NbExp=9; IntAct=EBI-78060, EBI-514941;
CC       O15519-1:CFLAR; NbExp=2; IntAct=EBI-78060, EBI-4567563;
CC       Q13618:CUL3; NbExp=6; IntAct=EBI-78060, EBI-456129;
CC       Q13158:FADD; NbExp=36; IntAct=EBI-78060, EBI-494804;
CC       P25445:FAS; NbExp=14; IntAct=EBI-78060, EBI-494743;
CC       P48023:FASLG; NbExp=4; IntAct=EBI-78060, EBI-495538;
CC       Q13418:ILK; NbExp=2; IntAct=EBI-78060, EBI-747644;
CC       Q9UDY8:MALT1; NbExp=10; IntAct=EBI-78060, EBI-1047372;
CC       O60936:NOL3; NbExp=3; IntAct=EBI-78060, EBI-740992;
CC       P29350:PTPN6; NbExp=3; IntAct=EBI-78060, EBI-78260;
CC       Q13546:RIPK1; NbExp=23; IntAct=EBI-78060, EBI-358507;
CC       Q969K3:RNF34; NbExp=3; IntAct=EBI-78060, EBI-2340642;
CC       O00220:TNFRSF10A; NbExp=9; IntAct=EBI-78060, EBI-518861;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=9;
CC       Name=1; Synonyms=Alpha-1;
CC         IsoId=Q14790-1; Sequence=Displayed;
CC       Name=2; Synonyms=Alpha-2, MCH5-beta;
CC         IsoId=Q14790-2; Sequence=VSP_000810;
CC       Name=3; Synonyms=Alpha-3;
CC         IsoId=Q14790-3; Sequence=VSP_000813;
CC       Name=4; Synonyms=Alpha-4;
CC         IsoId=Q14790-4; Sequence=VSP_000809, VSP_000810;
CC       Name=5; Synonyms=Beta-1;
CC         IsoId=Q14790-5; Sequence=VSP_000814, VSP_000815;
CC       Name=6; Synonyms=Beta-2;
CC         IsoId=Q14790-6; Sequence=VSP_000811, VSP_000812;
CC       Name=7; Synonyms=Beta-3, 8L;
CC         IsoId=Q14790-7; Sequence=VSP_000816, VSP_000817;
CC         Note=May be produced at very low levels due to a premature stop
CC         codon in the mRNA, leading to nonsense-mediated mRNA decay.;
CC       Name=8; Synonyms=Beta-4;
CC         IsoId=Q14790-8; Sequence=VSP_000810, VSP_000816, VSP_000817;
CC       Name=9; Synonyms=8L;
CC         IsoId=Q14790-9; Sequence=VSP_000808;
CC         Note=Ref.8 (AAL87628) sequence is in conflict in position:
CC         14:K->R. {ECO:0000305};
CC   -!- TISSUE SPECIFICITY: Isoform 1, isoform 5 and isoform 7 are
CC       expressed in a wide variety of tissues. Highest expression in
CC       peripheral blood leukocytes, spleen, thymus and liver. Barely
CC       detectable in brain, testis and skeletal muscle.
CC   -!- DOMAIN: Isoform 9 contains a N-terminal extension that is required
CC       for interaction with the BCAP31 complex.
CC   -!- PTM: Generation of the subunits requires association with the
CC       death-inducing signaling complex (DISC), whereas additional
CC       processing is likely due to the autocatalytic activity of the
CC       activated protease. GZMB and CASP10 can be involved in these
CC       processing events. {ECO:0000269|PubMed:8962078,
CC       ECO:0000269|PubMed:9184224}.
CC   -!- PTM: Phosphorylation on Ser-387 during mitosis by CDK1 inhibits
CC       activation by proteolysis and prevents apoptosis. This
CC       phosphorylation occurs in cancer cell lines, as well as in primary
CC       breast tissues and lymphocytes. {ECO:0000269|PubMed:15592455,
CC       ECO:0000269|PubMed:20937773}.
CC   -!- POLYMORPHISM: Genetic variations in CASP8 are associated with
CC       reduced risk of lung cancer [MIM:211980] in a population of Han
CC       Chinese subjects. Genetic variations are also associated with
CC       decreased risk of cancer of various other forms including
CC       esophageal, gastric, colorectal, cervical, and breast, acting in
CC       an allele dose-dependent manner.
CC   -!- DISEASE: Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder
CC       resembling autoimmune lymphoproliferative syndrome (ALPS). It is
CC       characterized by lymphadenopathy, splenomegaly, and defective
CC       CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It
CC       leads to defects in activation of T-lymphocytes, B-lymphocytes,
CC       and natural killer cells leading to immunodeficiency characterized
CC       by recurrent sinopulmonary and herpes simplex virus infections and
CC       poor responses to immunization. {ECO:0000269|PubMed:12353035}.
CC       Note=The disease is caused by mutations affecting the gene
CC       represented in this entry.
CC   -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
CC   -!- SIMILARITY: Contains 2 DED (death effector) domains.
CC       {ECO:0000255|PROSITE-ProRule:PRU00065}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAA66858.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305};
CC       Sequence=CAA66859.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=CASP8base; Note=CASP8 mutation db;
CC       URL="http://bioinf.uta.fi/CASP8base/";
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/casp8/";
CC   -----------------------------------------------------------------------
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DR   EMBL; X98172; CAA66853.1; -; mRNA.
DR   EMBL; X98173; CAA66854.1; -; mRNA.
DR   EMBL; X98174; CAA66855.1; -; mRNA.
DR   EMBL; X98175; CAA66856.1; -; mRNA.
DR   EMBL; X98176; CAA66857.1; -; mRNA.
DR   EMBL; X98177; CAA66858.1; ALT_SEQ; mRNA.
DR   EMBL; X98178; CAA66859.1; ALT_SEQ; mRNA.
DR   EMBL; U58143; AAC50602.1; -; mRNA.
DR   EMBL; U60520; AAC50645.1; -; mRNA.
DR   EMBL; AF009620; AAB70913.1; -; mRNA.
DR   EMBL; AF102146; AAD24962.1; -; Genomic_DNA.
DR   EMBL; AF102139; AAD24962.1; JOINED; Genomic_DNA.
DR   EMBL; AF102140; AAD24962.1; JOINED; Genomic_DNA.
DR   EMBL; AF102141; AAD24962.1; JOINED; Genomic_DNA.
DR   EMBL; AF102142; AAD24962.1; JOINED; Genomic_DNA.
DR   EMBL; AF102143; AAD24962.1; JOINED; Genomic_DNA.
DR   EMBL; AF102144; AAD24962.1; JOINED; Genomic_DNA.
DR   EMBL; AF102145; AAD24962.1; JOINED; Genomic_DNA.
DR   EMBL; AB038985; BAB32555.1; -; Genomic_DNA.
DR   EMBL; AF380342; AAK57437.1; -; mRNA.
DR   EMBL; AF422925; AAL87628.1; -; mRNA.
DR   EMBL; AF422926; AAL87629.1; -; mRNA.
DR   EMBL; AF422927; AAL87630.1; -; mRNA.
DR   EMBL; AF422928; AAL87631.1; -; mRNA.
DR   EMBL; AF422929; AAL87632.1; -; mRNA.
DR   EMBL; DQ355026; ABC67468.1; -; Genomic_DNA.
DR   EMBL; AC007256; AAY24225.1; -; Genomic_DNA.
DR   EMBL; BC028223; -; NOT_ANNOTATED_CDS; mRNA.
DR   CCDS; CCDS2342.1; -. [Q14790-1]
DR   CCDS; CCDS2343.1; -. [Q14790-2]
DR   CCDS; CCDS2345.1; -. [Q14790-5]
DR   CCDS; CCDS42798.1; -. [Q14790-9]
DR   CCDS; CCDS42799.1; -. [Q14790-4]
DR   RefSeq; NP_001073593.1; NM_001080124.1. [Q14790-2]
DR   RefSeq; NP_001073594.1; NM_001080125.1. [Q14790-9]
DR   RefSeq; NP_001219.2; NM_001228.4. [Q14790-4]
DR   RefSeq; NP_203519.1; NM_033355.3. [Q14790-1]
DR   RefSeq; NP_203520.1; NM_033356.3. [Q14790-2]
DR   RefSeq; NP_203522.1; NM_033358.3. [Q14790-5]
DR   RefSeq; XP_005246943.1; XM_005246886.1. [Q14790-1]
DR   RefSeq; XP_005246944.1; XM_005246887.1. [Q14790-1]
DR   RefSeq; XP_005246945.1; XM_005246888.1. [Q14790-1]
DR   RefSeq; XP_005246946.1; XM_005246889.1. [Q14790-1]
DR   RefSeq; XP_005246947.1; XM_005246890.1. [Q14790-1]
DR   RefSeq; XP_005246948.1; XM_005246891.2. [Q14790-1]
DR   RefSeq; XP_005246949.1; XM_005246892.1. [Q14790-2]
DR   RefSeq; XP_006712852.1; XM_006712789.1. [Q14790-1]
DR   RefSeq; XP_006712853.1; XM_006712790.1. [Q14790-1]
DR   RefSeq; XP_006712856.1; XM_006712793.1. [Q14790-5]
DR   UniGene; Hs.599762; -.
DR   PDB; 1F9E; X-ray; 2.90 A; A/C/E/G/I/K=222-374, B/D/F/H/J/L=390-478.
DR   PDB; 1I4E; X-ray; 3.00 A; B=222-479.
DR   PDB; 1QDU; X-ray; 2.80 A; A/C/E/G/I/K=222-374, B/D/F/H/J/L=390-477.
DR   PDB; 1QTN; X-ray; 1.20 A; A=211-374, B=385-479.
DR   PDB; 2C2Z; X-ray; 1.95 A; A=218-374, B=376-479.
DR   PDB; 2FUN; X-ray; 3.00 A; B/D=222-479.
DR   PDB; 2K7Z; NMR; -; A=217-479.
DR   PDB; 2Y1L; X-ray; 1.80 A; A/C=218-374, B/D=376-479.
DR   PDB; 3H11; X-ray; 1.90 A; B=217-479.
DR   PDB; 3KJN; X-ray; 1.80 A; A=211-374, B=385-479.
DR   PDB; 3KJQ; X-ray; 1.80 A; A=211-374, B=385-479.
DR   PDB; 4JJ7; X-ray; 1.18 A; A=217-479.
DR   PDBsum; 1F9E; -.
DR   PDBsum; 1I4E; -.
DR   PDBsum; 1QDU; -.
DR   PDBsum; 1QTN; -.
DR   PDBsum; 2C2Z; -.
DR   PDBsum; 2FUN; -.
DR   PDBsum; 2K7Z; -.
DR   PDBsum; 2Y1L; -.
DR   PDBsum; 3H11; -.
DR   PDBsum; 3KJN; -.
DR   PDBsum; 3KJQ; -.
DR   PDBsum; 4JJ7; -.
DR   ProteinModelPortal; Q14790; -.
DR   SMR; Q14790; 223-479.
DR   BioGrid; 107291; 93.
DR   DIP; DIP-30915N; -.
DR   IntAct; Q14790; 68.
DR   MINT; MINT-91645; -.
DR   BindingDB; Q14790; -.
DR   ChEMBL; CHEMBL3776; -.
DR   GuidetoPHARMACOLOGY; 1624; -.
DR   MEROPS; C14.009; -.
DR   PhosphoSite; Q14790; -.
DR   DMDM; 2493531; -.
DR   MaxQB; Q14790; -.
DR   PaxDb; Q14790; -.
DR   PRIDE; Q14790; -.
DR   DNASU; 841; -.
DR   Ensembl; ENST00000264274; ENSP00000264274; ENSG00000064012. [Q14790-3]
DR   Ensembl; ENST00000264275; ENSP00000264275; ENSG00000064012. [Q14790-4]
DR   Ensembl; ENST00000323492; ENSP00000325722; ENSG00000064012. [Q14790-2]
DR   Ensembl; ENST00000358485; ENSP00000351273; ENSG00000064012. [Q14790-9]
DR   Ensembl; ENST00000392258; ENSP00000376087; ENSG00000064012. [Q14790-5]
DR   Ensembl; ENST00000392263; ENSP00000376091; ENSG00000064012. [Q14790-2]
DR   Ensembl; ENST00000432109; ENSP00000412523; ENSG00000064012. [Q14790-1]
DR   GeneID; 841; -.
DR   KEGG; hsa:841; -.
DR   UCSC; uc002uxo.1; human. [Q14790-5]
DR   UCSC; uc002uxp.1; human. [Q14790-4]
DR   UCSC; uc002uxq.1; human. [Q14790-2]
DR   UCSC; uc002uxr.1; human. [Q14790-1]
DR   UCSC; uc002uxt.1; human. [Q14790-9]
DR   UCSC; uc002uxv.1; human. [Q14790-8]
DR   UCSC; uc010fte.1; human. [Q14790-6]
DR   UCSC; uc010ftf.2; human. [Q14790-3]
DR   CTD; 841; -.
DR   GeneCards; GC02P202062; -.
DR   HGNC; HGNC:1509; CASP8.
DR   HPA; CAB002047; -.
DR   HPA; HPA001302; -.
DR   HPA; HPA005688; -.
DR   HPA; HPA006191; -.
DR   MIM; 211980; phenotype.
DR   MIM; 601763; gene.
DR   MIM; 607271; phenotype.
DR   neXtProt; NX_Q14790; -.
DR   Orphanet; 275517; Autoimmune lymphoproliferative syndrome with recurrent viral infections.
DR   PharmGKB; PA26092; -.
DR   eggNOG; NOG303276; -.
DR   GeneTree; ENSGT00760000118912; -.
DR   HOVERGEN; HBG050803; -.
DR   InParanoid; Q14790; -.
DR   KO; K04398; -.
DR   OMA; IFIEMEK; -.
DR   OrthoDB; EOG7CRTQM; -.
DR   PhylomeDB; Q14790; -.
DR   TreeFam; TF102023; -.
DR   BRENDA; 3.4.22.61; 2681.
DR   Reactome; REACT_107; Apoptotic cleavage of cellular proteins.
DR   Reactome; REACT_13541; Caspase-mediated cleavage of cytoskeletal proteins.
DR   Reactome; REACT_1503; Caspase-8 activation by cleavage.
DR   Reactome; REACT_150361; TRIF-mediated programmed cell death.
DR   Reactome; REACT_164011; Regulation by c-FLIP.
DR   Reactome; REACT_25039; NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
DR   Reactome; REACT_402; TRAIL signaling.
DR   Reactome; REACT_701; Activation, myristolyation of BID and translocation to mitochondria.
DR   Reactome; REACT_75776; NOD1/2 Signaling Pathway.
DR   Reactome; REACT_832; Dimerization of procaspase-8.
DR   Reactome; REACT_900; FasL/ CD95L signaling.
DR   Reactome; REACT_995; Apoptotic execution phase.
DR   SignaLink; Q14790; -.
DR   ChiTaRS; CASP8; human.
DR   EvolutionaryTrace; Q14790; -.
DR   GeneWiki; Caspase_8; -.
DR   GenomeRNAi; 841; -.
DR   NextBio; 3510; -.
DR   PMAP-CutDB; Q14790; -.
DR   PRO; PR:Q14790; -.
DR   Bgee; Q14790; -.
DR   ExpressionAtlas; Q14790; baseline and differential.
DR   Genevestigator; Q14790; -.
DR   GO; GO:0031265; C:CD95 death-inducing signaling complex; IDA:UniProtKB.
DR   GO; GO:0044297; C:cell body; IEA:Ensembl.
DR   GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR   GO; GO:0005856; C:cytoskeleton; TAS:ProtInc.
DR   GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR   GO; GO:0031264; C:death-inducing signaling complex; IDA:UniProtKB.
DR   GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR   GO; GO:0005815; C:microtubule organizing center; IDA:HPA.
DR   GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR   GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR   GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR   GO; GO:0030690; C:Noc1p-Noc2p complex; IEA:Ensembl.
DR   GO; GO:0005634; C:nucleus; IDA:HPA.
DR   GO; GO:0097342; C:ripoptosome; IDA:UniProtKB.
DR   GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
DR   GO; GO:0097199; F:cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IMP:UniProtKB.
DR   GO; GO:0008234; F:cysteine-type peptidase activity; TAS:ProtInc.
DR   GO; GO:0035877; F:death effector domain binding; IPI:UniProtKB.
DR   GO; GO:0008233; F:peptidase activity; IMP:UniProtKB.
DR   GO; GO:0097110; F:scaffold protein binding; IPI:ParkinsonsUK-UCL.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR   GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; IDA:BHF-UCL.
DR   GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR   GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR   GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR   GO; GO:0097190; P:apoptotic signaling pathway; IMP:BHF-UCL.
DR   GO; GO:0042113; P:B cell activation; TAS:UniProtKB.
DR   GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR   GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR   GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl.
DR   GO; GO:0097194; P:execution phase of apoptosis; IMP:UniProtKB.
DR   GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR   GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IBA:RefGenome.
DR   GO; GO:0007507; P:heart development; IEA:Ensembl.
DR   GO; GO:0097284; P:hepatocyte apoptotic process; IEA:Ensembl.
DR   GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR   GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:Reactome.
DR   GO; GO:0030225; P:macrophage differentiation; TAS:UniProtKB.
DR   GO; GO:0002756; P:MyD88-independent toll-like receptor signaling pathway; TAS:Reactome.
DR   GO; GO:0030101; P:natural killer cell activation; TAS:UniProtKB.
DR   GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR   GO; GO:0060546; P:negative regulation of necroptotic process; IEA:Ensembl.
DR   GO; GO:0001841; P:neural tube formation; IEA:Ensembl.
DR   GO; GO:0035872; P:nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway; TAS:Reactome.
DR   GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR   GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IEA:Ensembl.
DR   GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR   GO; GO:0045651; P:positive regulation of macrophage differentiation; IMP:UniProtKB.
DR   GO; GO:1900740; P:positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; TAS:Reactome.
DR   GO; GO:0045862; P:positive regulation of proteolysis; IDA:BHF-UCL.
DR   GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR   GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR   GO; GO:0051603; P:proteolysis involved in cellular protein catabolic process; IMP:BHF-UCL.
DR   GO; GO:2001239; P:regulation of extrinsic apoptotic signaling pathway in absence of ligand; TAS:Reactome.
DR   GO; GO:0070243; P:regulation of thymocyte apoptotic process; IEA:Ensembl.
DR   GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
DR   GO; GO:0032025; P:response to cobalt ion; IEA:Ensembl.
DR   GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR   GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR   GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR   GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR   GO; GO:0034612; P:response to tumor necrosis factor; IMP:BHF-UCL.
DR   GO; GO:0060715; P:syncytiotrophoblast cell differentiation involved in labyrinthine layer development; TAS:UniProtKB.
DR   GO; GO:0042110; P:T cell activation; TAS:UniProtKB.
DR   GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR   GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR   GO; GO:0002224; P:toll-like receptor signaling pathway; TAS:Reactome.
DR   GO; GO:0036462; P:TRAIL-activated apoptotic signaling pathway; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR   GO; GO:0016032; P:viral process; IEA:UniProtKB-KW.
DR   Gene3D; 1.10.533.10; -; 2.
DR   Gene3D; 3.40.50.1460; -; 1.
DR   InterPro; IPR029030; Caspase-like_dom.
DR   InterPro; IPR011029; DEATH-like_dom.
DR   InterPro; IPR001875; DED.
DR   InterPro; IPR011600; Pept_C14_caspase.
DR   InterPro; IPR001309; Pept_C14_ICE_p20.
DR   InterPro; IPR016129; Pept_C14_ICE_p20_AS.
DR   InterPro; IPR002138; Pept_C14_p10.
DR   InterPro; IPR015917; Pept_C14A_p45_core.
DR   Pfam; PF01335; DED; 2.
DR   Pfam; PF00656; Peptidase_C14; 1.
DR   PRINTS; PR00376; IL1BCENZYME.
DR   SMART; SM00115; CASc; 1.
DR   SMART; SM00031; DED; 2.
DR   SUPFAM; SSF47986; SSF47986; 2.
DR   PROSITE; PS01122; CASPASE_CYS; 1.
DR   PROSITE; PS01121; CASPASE_HIS; 1.
DR   PROSITE; PS50207; CASPASE_P10; 1.
DR   PROSITE; PS50208; CASPASE_P20; 1.
DR   PROSITE; PS50168; DED; 2.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Apoptosis;
KW   Complete proteome; Cytoplasm; Direct protein sequencing;
KW   Disease mutation; Host-virus interaction; Hydrolase; Phosphoprotein;
KW   Polymorphism; Protease; Reference proteome; Repeat; Thiol protease;
KW   Zymogen.
FT   PROPEP        1    216
FT                                /FTId=PRO_0000004628.
FT   CHAIN       217    374       Caspase-8 subunit p18.
FT                                /FTId=PRO_0000004629.
FT   PROPEP      375    384
FT                                /FTId=PRO_0000004630.
FT   CHAIN       385    479       Caspase-8 subunit p10.
FT                                /FTId=PRO_0000004631.
FT   DOMAIN        2     80       DED 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00065}.
FT   DOMAIN      100    177       DED 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00065}.
FT   ACT_SITE    317    317
FT   ACT_SITE    360    360
FT   MOD_RES     188    188       Phosphoserine. {ECO:0000250}.
FT   MOD_RES     211    211       Phosphoserine. {ECO:0000250}.
FT   MOD_RES     224    224       N6-acetyllysine. {ECO:0000250}.
FT   MOD_RES     334    334       Phosphotyrosine.
FT                                {ECO:0000269|PubMed:15592455}.
FT   MOD_RES     387    387       Phosphoserine; by CDK1.
FT                                {ECO:0000269|PubMed:20937773}.
FT   VAR_SEQ       1      1       M -> MEGGRRARVVIESKRNFFLGAFPTPFPAEHVELGRL
FT                                GDSETAMVPGKGGADYILLPFKKM (in isoform 9).
FT                                {ECO:0000303|PubMed:11917123}.
FT                                /FTId=VSP_000808.
FT   VAR_SEQ     102    102       R -> RFHFCRMSWAEANSQCQTQSVPFWRRVDHLLIR
FT                                (in isoform 4).
FT                                {ECO:0000303|PubMed:8755496}.
FT                                /FTId=VSP_000809.
FT   VAR_SEQ     184    267       Missing (in isoform 3).
FT                                {ECO:0000303|PubMed:8681376}.
FT                                /FTId=VSP_000813.
FT   VAR_SEQ     184    220       ERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQ ->
FT                                DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH (in
FT                                isoform 6). {ECO:0000303|PubMed:8681376}.
FT                                /FTId=VSP_000811.
FT   VAR_SEQ     184    198       Missing (in isoform 2, isoform 4 and
FT                                isoform 8). {ECO:0000303|PubMed:11917123,
FT                                ECO:0000303|PubMed:8681376,
FT                                ECO:0000303|PubMed:8755496,
FT                                ECO:0000303|PubMed:9228018}.
FT                                /FTId=VSP_000810.
FT   VAR_SEQ     199    235       GEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGY ->
FT                                DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH (in
FT                                isoform 5). {ECO:0000303|PubMed:8681376}.
FT                                /FTId=VSP_000814.
FT   VAR_SEQ     221    479       Missing (in isoform 6).
FT                                {ECO:0000303|PubMed:8681376}.
FT                                /FTId=VSP_000812.
FT   VAR_SEQ     236    479       Missing (in isoform 5).
FT                                {ECO:0000303|PubMed:8681376}.
FT                                /FTId=VSP_000815.
FT   VAR_SEQ     269    276       ALTTTFEE -> TVEPKREK (in isoform 7 and
FT                                isoform 8). {ECO:0000303|PubMed:12010809,
FT                                ECO:0000303|PubMed:15489334,
FT                                ECO:0000303|PubMed:8681376}.
FT                                /FTId=VSP_000816.
FT   VAR_SEQ     277    479       Missing (in isoform 7 and isoform 8).
FT                                {ECO:0000303|PubMed:12010809,
FT                                ECO:0000303|PubMed:15489334,
FT                                ECO:0000303|PubMed:8681376}.
FT                                /FTId=VSP_000817.
FT   VARIANT     219    219       S -> T (in dbSNP:rs35976359).
FT                                {ECO:0000269|Ref.9}.
FT                                /FTId=VAR_025816.
FT   VARIANT     248    248       R -> W (in CASP8D; dbSNP:rs17860424).
FT                                {ECO:0000269|PubMed:12353035}.
FT                                /FTId=VAR_014204.
FT   VARIANT     285    285       D -> H (associated with protection
FT                                against breast cancer; also associated
FT                                with a lower risk of cutaneous melanoma;
FT                                dbSNP:rs1045485).
FT                                {ECO:0000269|PubMed:11161814,
FT                                ECO:0000269|PubMed:15601643,
FT                                ECO:0000269|PubMed:17293864,
FT                                ECO:0000269|PubMed:18563783,
FT                                ECO:0000269|PubMed:8755496,
FT                                ECO:0000269|PubMed:9228018,
FT                                ECO:0000269|Ref.9}.
FT                                /FTId=VAR_020127.
FT   MUTAGEN      73     73       D->A: Abolishes binding to FLASH. Induces
FT                                NF-kappa-B activation.
FT                                {ECO:0000269|PubMed:15592525}.
FT   MUTAGEN     387    387       S->A: Impaired CDK1-mediated
FT                                phosphorylation and enhanced apoptosis.
FT   CONFLICT    294    294       E -> D (in Ref. 5; AAD24962).
FT                                {ECO:0000305}.
FT   CONFLICT    331    331       A -> P (in Ref. 2; AAC50602 and 5;
FT                                AAD24962). {ECO:0000305}.
FT   CONFLICT    343    344       LK -> FG (in Ref. 8; AAL87631).
FT                                {ECO:0000305}.
FT   STRAND      230    232       {ECO:0000244|PDB:3H11}.
FT   STRAND      235    240       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       245    250       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       252    254       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      255    257       {ECO:0000244|PDB:2K7Z}.
FT   HELIX       263    276       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      280    286       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       289    301       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       304    306       {ECO:0000244|PDB:1QDU}.
FT   STRAND      310    316       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      322    324       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      326    328       {ECO:0000244|PDB:1I4E}.
FT   STRAND      330    332       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       333    337       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       338    340       {ECO:0000244|PDB:4JJ7}.
FT   TURN        342    344       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       346    348       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      353    359       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      361    364       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      369    371       {ECO:0000244|PDB:1QDU}.
FT   STRAND      377    379       {ECO:0000244|PDB:2K7Z}.
FT   STRAND      392    394       {ECO:0000244|PDB:1QDU}.
FT   TURN        395    398       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      399    405       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      412    414       {ECO:0000244|PDB:3H11}.
FT   TURN        415    417       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       420    432       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       433    435       {ECO:0000244|PDB:4JJ7}.
FT   HELIX       439    450       {ECO:0000244|PDB:4JJ7}.
FT   TURN        456    459       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      465    468       {ECO:0000244|PDB:4JJ7}.
FT   STRAND      471    473       {ECO:0000244|PDB:1QDU}.
SQ   SEQUENCE   479 AA;  55391 MW;  7A5FEAA6B39B582F CRC64;
     MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS
     FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF
     KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE
     FSKERSSSLE GSPDEFSNGE ELCGVMTISD SPREQDSESQ TLDKVYQMKS KPRGYCLIIN
     NHNFAKAREK VPKLHSIRDR NGTHLDAGAL TTTFEELHFE IKPHDDCTVE QIYEILKIYQ
     LMDHSNMDCF ICCILSHGDK GIIYGTDGQE APIYELTSQF TGLKCPSLAG KPKVFFIQAC
     QGDNYQKGIP VETDSEEQPY LEMDLSSPQT RYIPDEADFL LGMATVNNCV SYRNPAEGTW
     YIQSLCQSLR ERCPRGDDIL TILTEVNYEV SNKDDKKNMG KQMPQPTFTL RKKLVFPSD
//
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