ID CASP8_HUMAN Reviewed; 479 AA. AC Q14790; O14676; Q14791; Q14792; Q14793; Q14794; Q14795; Q14796; Q15780; AC Q15806; Q53TT5; Q8TDI1; Q8TDI2; Q8TDI3; Q8TDI4; Q8TDI5; Q96T22; Q9C0K4; AC Q9UQ81; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 258. DE RecName: Full=Caspase-8 {ECO:0000303|PubMed:12010809}; DE Short=CASP-8 {ECO:0000303|PubMed:12010809}; DE EC=3.4.22.61 {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:32929201, ECO:0000269|PubMed:34012073, ECO:0000269|PubMed:8962078}; DE AltName: Full=Apoptotic cysteine protease; DE AltName: Full=Apoptotic protease Mch-5 {ECO:0000303|PubMed:8962078}; DE AltName: Full=CAP4; DE AltName: Full=FADD-homologous ICE/ced-3-like protease {ECO:0000303|PubMed:8681377}; DE AltName: Full=FADD-like ICE {ECO:0000303|PubMed:8681377}; DE Short=FLICE {ECO:0000303|PubMed:8681377}; DE AltName: Full=ICE-like apoptotic protease 5; DE AltName: Full=MORT1-associated ced-3 homolog {ECO:0000303|PubMed:8681376}; DE Short=MACH {ECO:0000303|PubMed:8681376}; DE Contains: DE RecName: Full=Caspase-8 subunit p18 {ECO:0000303|PubMed:8962078}; DE Contains: DE RecName: Full=Caspase-8 subunit p10 {ECO:0000303|PubMed:8962078}; DE Flags: Precursor; GN Name=CASP8 {ECO:0000303|PubMed:9931493, ECO:0000312|HGNC:HGNC:1509}; GN Synonyms=MCH5 {ECO:0000303|PubMed:8962078}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 5; 6; 7 AND 8), FUNCTION, RP INTERACTION WITH FADD, AND TISSUE SPECIFICITY. 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 Fas/APO- RT 1- and TNF receptor-induced cell death."; RL Cell 85:803-815(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, FUNCTION, RP AND IDENTIFICATION IN DISC COMPLEX. 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., Krammer P.H., RA Peter M.E., Dixit V.M.; RT "FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to RT the CD95 (Fas/APO-1) death-inducing signaling complex."; RL Cell 85:817-827(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), FUNCTION, 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., Litwack G., RA Alnemri E.S.; RT "In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic RT 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., Wang Y., RA 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., Martindale D., RA Koop B.F., Scherer S.W., Nicholson D.W., Rouleau G.A., Ikeda J.-E., RA Hayden M.R.; RT "Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and RT ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical RT 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., Harada M.; RT "Characterization of caspase-8L: a novel isoform of caspase-8 that behaves RT 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 complex at RT 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., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., 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., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., 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., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP PARTIAL PROTEIN SEQUENCE, FUNCTION, PROTEOLYTIC PROCESSING, AND SITE. RX PubMed=8962078; DOI=10.1073/pnas.93.25.14486; RA Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G., Alnemri E.S.; RT "Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease RT Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like RT 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 FUNCTION, IDENTIFICATION IN DISC COMPLEX, PROTEOLYTIC PROCESSING, AND RP CLEAVAGE SITES. 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 signaling RT 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., Cromlish J.A., RA 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., Oriente F., RA Miele C., Caruso M., Formisano P., Beguinot F.; RT "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced RT apoptosis."; RL Oncogene 18:4409-4415(1999). RN [18] RP INTERACTION WITH HUMAN CYTOMEGALOVIRUS/HHV-5 PROTEIN UL36 (MICROBIAL RP INFECTION). RX PubMed=11427719; DOI=10.1073/pnas.141108798; RA Skaletskaya A., Bartle L.M., Chittenden T., McCormick A.L., Mocarski E.S., RA Goldmacher V.S.; RT "A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 RT 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 NOL3. RX PubMed=15509781; DOI=10.1128/mcb.24.22.9763-9770.2004; RA Jo D.G., Jun J.I., Chang J.W., Hong Y.M., Song S., Cho D.H., Shim S.M., RA Lee H.J., Cho C., Kim D.H., Jung Y.K.; RT "Calcium binding of ARC mediates regulation of caspase 8 and cell death."; RL Mol. Cell. Biol. 24:9763-9770(2004). RN [21] 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 [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-334, AND IDENTIFICATION BY RP 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 cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [23] 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: dominant- RT negative function of FLASH mutant in NF-kappaB signaling pathway."; RL Oncogene 24:688-696(2005). RN [24] RP PHOSPHORYLATION AT TYR-380, AND MUTAGENESIS OF TYR-380. RX PubMed=16619028; DOI=10.1038/sj.emboj.7601085; RA Cursi S., Rufini A., Stagni V., Condo I., Matafora V., Bachi A., RA Bonifazi A.P., Coppola L., Superti-Furga G., Testi R., Barila D.; RT "Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of RT apoptosis suppression."; RL EMBO J. 25:1895-1905(2006). RN [25] RP INTERACTION WITH MOLLUSCUM CONTAGIOSUM VIRUS PROTEIN MC160 (MICROBIAL RP INFECTION). RX PubMed=16378960; DOI=10.1128/jvi.80.2.578-586.2006; RA Nichols D.B., Shisler J.L.; RT "The MC160 protein expressed by the dermatotropic poxvirus molluscum RT contagiosum virus prevents tumor necrosis factor alpha-induced NF-kappaB RT activation via inhibition of I kappa kinase complex formation."; RL J. Virol. 80:578-586(2006). RN [26] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=16916640; DOI=10.1016/j.molcel.2006.06.020; RA Denault J.B., Bekes M., Scott F.L., Sexton K.M., Bogyo M., Salvesen G.S.; RT "Engineered hybrid dimers: tracking the activation pathway of caspase-7."; RL Mol. Cell 23:523-533(2006). RN [27] 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 nuclear RT bodies."; RL EMBO J. 26:391-401(2007). RN [28] RP INTERACTION WITH TNFRSF10B. RX PubMed=18846110; DOI=10.1038/cdd.2008.124; RA Sun M., Song L., Li Y., Zhou T., Jope R.S.; RT "Identification of an antiapoptotic protein complex at death receptors."; RL Cell Death Differ. 15:1887-1900(2008). RN [29] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, PHOSPHORYLATION AT TYR-380, AND RP MUTAGENESIS OF CYS-360 AND TYR-380. RX PubMed=18216014; DOI=10.1074/jbc.m800549200; RA Barbero S., Barila D., Mielgo A., Stagni V., Clair K., Stupack D.; RT "Identification of a critical tyrosine residue in caspase 8 that promotes RT cell migration."; RL J. Biol. Chem. 283:13031-13034(2008). RN [30] 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-8 RT activity."; RL Mol. Cell. Biol. 30:5726-5740(2010). RN [31] 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., Buerckstuemmer T., RA 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 [32] RP PROTEOLYTIC CLEAVAGE. RX PubMed=22858542; DOI=10.1038/cdd.2012.98; RA van Raam B.J., Ehrnhoefer D.E., Hayden M.R., Salvesen G.S.; RT "Intrinsic cleavage of receptor-interacting protein kinase-1 by RT caspase-6."; RL Cell Death Differ. 20:86-96(2013). RN [33] RP INTERACTION WITH E.COLI NLEF (MICROBIAL INFECTION), CATALYTIC ACTIVITY, RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=23516580; DOI=10.1371/journal.pone.0058937; RA Blasche S., Mortl M., Steuber H., Siszler G., Nisa S., Schwarz F., RA Lavrik I., Gronewold T.M., Maskos K., Donnenberg M.S., Ullmann D., Uetz P., RA Kogl M.; RT "The E. coli effector protein NleF is a caspase inhibitor."; RL PLoS ONE 8:E58937-E58937(2013). RN [34] RP INTERACTION WITH HERPES SIMPLEX VIRUS 1 AND 2 PROTEIN RIR1 (MICROBIAL RP INFECTION). RX PubMed=25674983; DOI=10.1016/j.chom.2015.01.003; RA Guo H., Omoto S., Harris P.A., Finger J.N., Bertin J., Gough P.J., RA Kaiser W.J., Mocarski E.S.; RT "Herpes simplex virus suppresses necroptosis in human cells."; RL Cell Host Microbe 17:243-251(2015). RN [35] RP FUNCTION, INTERACTION WITH PIK3R1, PHOSPHORYLATION AT TYR-380, AND RP MUTAGENESIS OF CYS-360 AND TYR-380. RX PubMed=27109099; DOI=10.1038/onc.2016.99; RA Powley I.R., Hughes M.A., Cain K., MacFarlane M.; RT "Caspase-8 tyrosine-380 phosphorylation inhibits CD95 DISC function by RT preventing procaspase-8 maturation and cycling within the complex."; RL Oncogene 35:5629-5640(2016). RN [36] RP INTERACTION WITH UBR2, AND MUTAGENESIS OF CYS-360. RX PubMed=28602583; DOI=10.1016/j.devcel.2017.05.013; RA Weaver B.P., Weaver Y.M., Mitani S., Han M.; RT "Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and RT Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic RT Development."; RL Dev. Cell 41:665-673(2017). RN [37] RP FUNCTION. RX PubMed=31827281; DOI=10.1038/s41586-019-1828-5; RA Lalaoui N., Boyden S.E., Oda H., Wood G.M., Stone D.L., Chau D., Liu L., RA Stoffels M., Kratina T., Lawlor K.E., Zaal K.J.M., Hoffmann P.M., RA Etemadi N., Shield-Artin K., Biben C., Tsai W.L., Blake M.D., Kuehn H.S., RA Yang D., Anderton H., Silke N., Wachsmuth L., Zheng L., Moura N.S., RA Beck D.B., Gutierrez-Cruz G., Ombrello A.K., Pinto-Patarroyo G.P., RA Kueh A.J., Herold M.J., Hall C., Wang H., Chae J.J., Dmitrieva N.I., RA McKenzie M., Light A., Barham B.K., Jones A., Romeo T.M., Zhou Q., RA Aksentijevich I., Mullikin J.C., Gross A.J., Shum A.K., Hawkins E.D., RA Masters S.L., Lenardo M.J., Boehm M., Rosenzweig S.D., Pasparakis M., RA Voss A.K., Gadina M., Kastner D.L., Silke J.; RT "Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory RT disease."; RL Nature 577:103-108(2020). RN [38] RP FUNCTION. RX PubMed=31827280; DOI=10.1038/s41586-019-1830-y; RA Tao P., Sun J., Wu Z., Wang S., Wang J., Li W., Pan H., Bai R., Zhang J., RA Wang Y., Lee P.Y., Ying W., Zhou Q., Hou J., Wang W., Sun B., Yang M., RA Liu D., Fang R., Han H., Yang Z., Huang X., Li H., Deuitch N., Zhang Y., RA Dissanayake D., Haude K., McWalter K., Roadhouse C., MacKenzie J.J., RA Laxer R.M., Aksentijevich I., Yu X., Wang X., Yuan J., Zhou Q.; RT "A dominant autoinflammatory disease caused by non-cleavable variants of RT RIPK1."; RL Nature 577:109-114(2020). RN [39] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=32929201; DOI=10.1038/s41556-020-0575-z; RA Hou J., Zhao R., Xia W., Chang C.W., You Y., Hsu J.M., Nie L., Chen Y., RA Wang Y.C., Liu C., Wang W.J., Wu Y., Ke B., Hsu J.L., Huang K., Ye Z., RA Yang Y., Xia X., Li Y., Li C.W., Shao B., Tainer J.A., Hung M.C.; RT "PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in RT cancer cells and facilitates tumour necrosis."; RL Nat. Cell Biol. 22:1264-1275(2020). RN [40] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=34012073; DOI=10.1038/s41422-021-00506-9; RA Zhang J.Y., Zhou B., Sun R.Y., Ai Y.L., Cheng K., Li F.N., Wang B.R., RA Liu F.J., Jiang Z.H., Wang W.J., Zhou D., Chen H.Z., Wu Q.; RT "The metabolite alpha-KG induces GSDMC-dependent pyroptosis through death RT receptor 6-activated caspase-8."; RL Cell Res. 31:980-997(2021). RN [41] RP FUNCTION, ADP-RIBOXANATION AT ARG-413 (MICROBIAL INFECTION), AND RP MUTAGENESIS OF ARG-413. RX PubMed=35446120; DOI=10.1128/mbio.00690-22; RA Liu Y., Zeng H., Hou Y., Li Z., Li L., Song X., Ding J., Shao F., Xu Y.; RT "Calmodulin binding activates chromobacterium CopC effector to ADP- RT riboxanate host apoptotic caspases."; RL MBio 0:0-0(2022). RN [42] RP FUNCTION, AND ADP-RIBOXANATION AT ARG-413 (MICROBIAL INFECTION). RX PubMed=35338844; DOI=10.1016/j.molcel.2022.03.010; RA Peng T., Tao X., Xia Z., Hu S., Xue J., Zhu Q., Pan X., Zhang Q., Li S.; RT "Pathogen hijacks programmed cell death signaling by arginine ADPR- RT deacylization of caspases."; RL Mol. Cell 82:1806-1820(2022). RN [43] 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 [44] RP X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 211-479, SUBUNIT, AND ACTIVE SITE. RX PubMed=10508785; DOI=10.1016/s0969-2126(99)80180-4; RA Watt W., Koeplinger K.A., Mildner A.M., Heinrikson R.L., Tomasselli A.G., RA Watenpaugh K.D.; RT "The atomic-resolution structure of human caspase-8, a key activator of RT apoptosis."; RL Structure 7:1135-1143(1999). RN [45] 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., Atkinson T.P., RA Straus S.E., Lenardo M.J.; RT "Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations RT lead to human immunodeficiency."; RL Nature 419:395-399(2002). RN [46] 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., Reed M.W.R., RA Pharoah P.D., Ponder B.A.J., Meuth M., Bhattacharyya N.P., Cox A.; RT "Association of a common variant of the CASP8 gene with reduced risk of RT breast cancer."; RL J. Natl. Cancer Inst. 96:1866-1869(2004). RN [47] 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., Reed M.W.R., RA Pooley K.A., Scollen S., Baynes C., Ponder B.A.J., Chanock S., RA Lissowska J., Brinton L., Peplonska B., Southey M.C., Hopper J.L., RA McCredie M.R.E., Giles G.G., Fletcher O., Johnson N., dos Santos Silva I., RA Gibson L., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Torres D., RA Hamann U., Justenhoven C., Brauch H., Chang-Claude J., Kropp S., Risch A., RA Wang-Gohrke S., Schuermann P., Bogdanova N., Doerk T., Fagerholm R., RA Aaltonen K., Blomqvist C., Nevanlinna H., Seal S., Renwick A., RA Stratton M.R., Rahman N., Sangrajrang S., Hughes D., Odefrey F., RA Brennan P., Spurdle A.B., Chenevix-Trench G., Beesley J., Mannermaa A., RA Hartikainen J., Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., RA Broeks A., Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., RA Yoo K.-Y., 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 risk."; RL Nat. Genet. 39:352-358(2007). RN [48] RP ERRATUM OF PUBMED:17293864. 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., Reed M.W.R., RA Pooley K.A., Scollen S., Baynes C., Ponder B.A.J., Chanock S., RA Lissowska J., Brinton L., Peplonska B., Southey M.C., Hopper J.L., RA McCredie M.R.E., Giles G.G., Fletcher O., Johnson N., dos Santos Silva I., RA Gibson L., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Torres D., RA Hamann U., Justenhoven C., Brauch H., Chang-Claude J., Kropp S., Risch A., RA Wang-Gohrke S., Schuermann P., Bogdanova N., Doerk T., Fagerholm R., RA Aaltonen K., Blomqvist C., Nevanlinna H., Seal S., Renwick A., RA Stratton M.R., Rahman N., Sangrajrang S., Hughes D., Odefrey F., RA Brennan P., Spurdle A.B., Chenevix-Trench G., Beesley J., Mannermaa A., RA Hartikainen J., Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., RA Broeks A., Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., RA Yoo K.-Y., 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 [49] 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., Zhang X., RA Zhang Q., Zeng C., Lin D.; RT "A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is RT associated with susceptibility to multiple cancers."; RL Nat. Genet. 39:605-613(2007). RN [50] 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., Prieto V.G., RA 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: Thiol protease that plays a key role in programmed cell death CC by acting as a molecular switch for apoptosis, necroptosis and CC pyroptosis, and is required to prevent tissue damage during embryonic CC development and adulthood (PubMed:23516580, PubMed:8681376, CC PubMed:8681377, PubMed:9006941, PubMed:9184224, PubMed:8962078, CC PubMed:35446120, PubMed:35338844). Initiator protease that induces CC extrinsic apoptosis by mediating cleavage and activation of effector CC caspases responsible for FAS/CD95-mediated and TNFRSF1A-induced cell CC death (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, CC PubMed:9184224, PubMed:8962078, PubMed:35446120, PubMed:35338844). CC Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CC CASP9 and CASP10 (PubMed:8962078, PubMed:9006941, PubMed:16916640). CC Binding to the adapter molecule FADD recruits it to either receptor CC FAS/TNFRSF6 or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting CC aggregate called the death-inducing signaling complex (DISC) performs CC CASP8 proteolytic activation (PubMed:9184224). The active dimeric CC enzyme is then liberated from the DISC and free to activate downstream CC apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N- CC terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in CC the DISC (PubMed:9184224). In addition to extrinsic apoptosis, also CC acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at CC 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting CC TNF-induced apoptosis, necroptosis and inflammatory response CC (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by CC mediating cleavage and activation of gasdermin-C and -D (GSDMC and CC GSDMD, respectively): gasdermin cleavage promotes release of the N- CC terminal moiety that binds to membranes and forms pores, triggering CC pyroptosis (PubMed:32929201, PubMed:34012073). Initiates pyroptosis CC following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a CC regulator of innate immunity by mediating cleavage and inactivation of CC N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production CC (By similarity). May participate in the Granzyme B (GZMB) cell death CC pathways (PubMed:8755496). Cleaves PARP1 and PARP2 (PubMed:8681376). CC Independent of its protease activity, promotes cell migration following CC phosphorylation at Tyr-380 (PubMed:18216014, PubMed:27109099). CC {ECO:0000250|UniProtKB:O89110, ECO:0000269|PubMed:16916640, CC ECO:0000269|PubMed:18216014, ECO:0000269|PubMed:23516580, CC ECO:0000269|PubMed:27109099, ECO:0000269|PubMed:31827280, CC ECO:0000269|PubMed:31827281, ECO:0000269|PubMed:32929201, CC ECO:0000269|PubMed:34012073, ECO:0000269|PubMed:35338844, CC ECO:0000269|PubMed:35446120, ECO:0000269|PubMed:8681376, CC ECO:0000269|PubMed:8681377, ECO:0000269|PubMed:8755496, CC ECO:0000269|PubMed:8962078, ECO:0000269|PubMed:9006941, CC ECO:0000269|PubMed:9184224}. CC -!- FUNCTION: [Isoform 5]: Lacks the catalytic site and may interfere with CC the pro-apoptotic activity of the complex. CC {ECO:0000305|PubMed:8681376}. CC -!- FUNCTION: [Isoform 6]: Lacks the catalytic site and may interfere with CC the pro-apoptotic activity of the complex. CC {ECO:0000305|PubMed:8681376}. CC -!- FUNCTION: [Isoform 7]: Lacks the catalytic site and may interfere with CC the pro-apoptotic activity of the complex (Probable). Acts as an CC inhibitor of the caspase cascade (PubMed:12010809). CC {ECO:0000269|PubMed:12010809, ECO:0000305|PubMed:8681376}. CC -!- FUNCTION: [Isoform 8]: Lacks the catalytic site and may interfere with CC the pro-apoptotic activity of the complex. CC {ECO:0000305|PubMed:8681376}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Strict requirement for Asp at position P1 and has a preferred CC cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).; CC EC=3.4.22.61; Evidence={ECO:0000269|PubMed:16916640, CC ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:32929201, CC ECO:0000269|PubMed:34012073, ECO:0000269|PubMed:8962078}; CC -!- ACTIVITY REGULATION: CASP8 activity is restricted by RIPK1 (By CC similarity). Inhibited by the effector protein NleF that is produced by CC pathogenic E.coli; this inhibits apoptosis (PubMed:23516580). CC {ECO:0000250|UniProtKB:O89110, ECO:0000269|PubMed:23516580}. CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged CC heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) CC subunit (PubMed:10508784). Component of the death-induced signaling CC complex (DISC) composed of cell surface receptor FAS/CD95 or TNFRSF1A, CC adapter protein FADD and the CASP8 protease; recruitment of CASP8 to CC the complex is required for processing of CASP8 into the p18 and p10 CC subunits (PubMed:9184224, PubMed:8681376, PubMed:8681377). Component of CC the AIM2 PANoptosome complex, a multiprotein complex that drives CC inflammatory cell death (PANoptosis) (By similarity). Interacts with CC CFLAR and PEA15 (PubMed:10442631). Interacts with TNFAIP8L2 (By CC similarity). Interacts with CASP8AP2 (PubMed:16378960). Interacts with CC RFFL and RNF34; negatively regulate CASP8 through proteasomal CC degradation (PubMed:15069192). Interacts with NOL3; decreases CASP8 CC activity in a mitochondria localization- and phosphorylation-dependent CC manner and this interaction is dissociated by calcium CC (PubMed:15509781). Interacts with UBR2ca (PubMed:28602583). Interacts CC with RIPK1 (By similarity). Interacts with stimulated TNFRSF10B; this CC interaction is followed by CASP8 proteolytic cleavage and activation CC (PubMed:18846110). Interacts (phosphorylated on Tyr-380) with PIK3R1 CC (PubMed:27109099). {ECO:0000250|UniProtKB:O89110, CC ECO:0000250|UniProtKB:Q9JHX4, ECO:0000269|PubMed:10442631, CC ECO:0000269|PubMed:10508784, ECO:0000269|PubMed:15069192, CC ECO:0000269|PubMed:15509781, ECO:0000269|PubMed:16378960, CC ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:27109099, CC ECO:0000269|PubMed:28602583, ECO:0000269|PubMed:8681376, CC ECO:0000269|PubMed:8681377, ECO:0000269|PubMed:9184224}. CC -!- SUBUNIT: [Isoform 9]: Interacts at the endoplasmic reticulum with a CC complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. CC {ECO:0000269|PubMed:11917123, ECO:0000269|PubMed:9334338}. CC -!- SUBUNIT: (Microbial infection) Interacts with human CC cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CC CASP8 activation. {ECO:0000269|PubMed:11427719}. CC -!- SUBUNIT: (Microbial infection) Interacts with NleF from pathogenic CC E.coli. {ECO:0000269|PubMed:23516580}. CC -!- SUBUNIT: (Microbial infection) Interacts with molluscum contagiosum CC virus protein MC160. {ECO:0000269|PubMed:16378960}. CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction CC motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP CC homotypic interaction motif); this interaction prevents necroptosis CC activation. {ECO:0000269|PubMed:25674983}. CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction CC motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP CC homotypic interaction motif); this interaction prevents necroptosis CC activation. {ECO:0000269|PubMed:25674983}. CC -!- INTERACTION: CC Q14790; P05067: APP; NbExp=3; IntAct=EBI-78060, EBI-77613; CC Q14790; P10275: AR; NbExp=3; IntAct=EBI-78060, EBI-608057; CC Q14790; P51572: BCAP31; NbExp=3; IntAct=EBI-78060, EBI-77683; CC Q14790; Q92851: CASP10; NbExp=3; IntAct=EBI-78060, EBI-495095; CC Q14790; Q14790: CASP8; NbExp=2; IntAct=EBI-78060, EBI-78060; CC Q14790; Q9UKL3: CASP8AP2; NbExp=3; IntAct=EBI-78060, EBI-2339650; CC Q14790; O15519: CFLAR; NbExp=9; IntAct=EBI-78060, EBI-514941; CC Q14790; O15519-1: CFLAR; NbExp=2; IntAct=EBI-78060, EBI-4567563; CC Q14790; Q13618: CUL3; NbExp=6; IntAct=EBI-78060, EBI-456129; CC Q14790; Q13158: FADD; NbExp=45; IntAct=EBI-78060, EBI-494804; CC Q14790; P25445: FAS; NbExp=14; IntAct=EBI-78060, EBI-494743; CC Q14790; P25445-1: FAS; NbExp=3; IntAct=EBI-78060, EBI-15749113; CC Q14790; P48023: FASLG; NbExp=5; IntAct=EBI-78060, EBI-495538; CC Q14790; Q06787-7: FMR1; NbExp=3; IntAct=EBI-78060, EBI-25856644; CC Q14790; Q13418: ILK; NbExp=2; IntAct=EBI-78060, EBI-747644; CC Q14790; Q9UDY8: MALT1; NbExp=10; IntAct=EBI-78060, EBI-1047372; CC Q14790; O60936: NOL3; NbExp=3; IntAct=EBI-78060, EBI-740992; CC Q14790; P53350: PLK1; NbExp=3; IntAct=EBI-78060, EBI-476768; CC Q14790; P29350: PTPN6; NbExp=3; IntAct=EBI-78060, EBI-78260; CC Q14790; P04049: RAF1; NbExp=3; IntAct=EBI-78060, EBI-365996; CC Q14790; Q13546: RIPK1; NbExp=28; IntAct=EBI-78060, EBI-358507; CC Q14790; Q969K3: RNF34; NbExp=3; IntAct=EBI-78060, EBI-2340642; CC Q14790; P21580: TNFAIP3; NbExp=3; IntAct=EBI-78060, EBI-527670; CC Q14790; O00220: TNFRSF10A; NbExp=9; IntAct=EBI-78060, EBI-518861; CC Q14790; P13051-2: UNG; NbExp=3; IntAct=EBI-78060, EBI-25834258; CC Q14790; Q96AX1: VPS33A; NbExp=3; IntAct=EBI-78060, EBI-2527283; CC Q14790-1; Q13158: FADD; NbExp=5; IntAct=EBI-288309, EBI-494804; CC Q14790-2; O15519-1: CFLAR; NbExp=3; IntAct=EBI-15777741, EBI-4567563; CC Q14790-5; Q13158: FADD; NbExp=4; IntAct=EBI-288326, EBI-494804; CC PRO_0000004629; PRO_0000004631 [Q14790]: CASP8; NbExp=2; IntAct=EBI-4478080, EBI-12736099; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9JHX4}. Nucleus CC {ECO:0000250|UniProtKB:Q9JHX4}. Cell projection, lamellipodium CC {ECO:0000269|PubMed:18216014}. Note=Recruitment to lamellipodia of CC migrating cells is enhanced by phosphorylation at Tyr-380. CC {ECO:0000269|PubMed:18216014}. 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 {ECO:0000303|PubMed:12010809}; CC IsoId=Q14790-7; Sequence=VSP_000816, VSP_000817; 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 -!- TISSUE SPECIFICITY: Isoform 1, isoform 5 and isoform 7 are expressed in CC a wide variety of tissues. Highest expression in peripheral blood CC leukocytes, spleen, thymus and liver. Barely detectable in brain, CC testis and skeletal muscle. CC -!- DOMAIN: The catalytic domain is sufficient for recruitment to CC lamellipodia but catalytic activity is not necessary. CC {ECO:0000269|PubMed:18216014}. CC -!- DOMAIN: [Isoform 9]: Contains a N-terminal extension that is required CC for interaction with the BCAP31 complex. {ECO:0000269|PubMed:11917123}. CC -!- PTM: Generation of the p10 and p18 subunits requires association with CC the death-inducing signaling complex (DISC), whereas additional CC processing is likely due to the autocatalytic activity of the activated CC protease. GZMB and CASP10 can be involved in these processing events. CC {ECO:0000269|PubMed:8962078, ECO:0000269|PubMed:9184224}. CC -!- PTM: Phosphorylation on Ser-387 during mitosis by CDK1 inhibits CC activation by proteolysis and prevents apoptosis (PubMed:20937773). CC Phosphorylation on Tyr-380 by SRC is mediated by interaction with the CC SRC SH2 domain and does not affect dimerization or recruitment to the CC death-inducing signaling complex (DISC) but negatively regulates DISC- CC mediated processing and activation of CASP8, down-regulating its CC proapoptotic function (PubMed:16619028, PubMed:27109099). CC Phosphorylation on Tyr-380 also enhances localization to lamellipodia CC in migrating cells (PubMed:18216014). {ECO:0000269|PubMed:16619028, CC ECO:0000269|PubMed:18216014, ECO:0000269|PubMed:20937773, CC ECO:0000269|PubMed:27109099}. CC -!- PTM: (Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CC CASP8 processing, preventing CASP8 activation and ability to mediate CC extrinsic apoptosis. {ECO:0000269|PubMed:35338844, CC ECO:0000269|PubMed:35446120}. CC -!- PTM: (Microbial infection) Proteolytically cleaved by the cowpox virus CC CRMA death inhibitory protein. {ECO:0000269|PubMed:8962078}. CC -!- POLYMORPHISM: Genetic variations in CASP8 are associated with reduced CC risk of lung cancer [MIM:211980] in a population of Han Chinese CC subjects. Genetic variations are also associated with decreased risk of CC cancer of various other forms including esophageal, gastric, CC colorectal, cervical, and breast, acting in an allele dose-dependent CC manner. {ECO:0000269|PubMed:17450141}. CC -!- DISEASE: Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder CC resembling autoimmune lymphoproliferative syndrome (ALPS). It is CC characterized by lymphadenopathy, splenomegaly, and defective CD95- CC induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to CC defects in activation of T-lymphocytes, B-lymphocytes, and natural CC killer cells leading to immunodeficiency characterized by recurrent CC sinopulmonary and herpes simplex virus infections and poor responses to CC immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 7]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}. 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://structure.bmc.lu.se/idbase/CASP8base/"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/casp8/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 CCDS; CCDS92923.1; -. [Q14790-3] 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. DR RefSeq; XP_005246943.1; XM_005246886.1. DR RefSeq; XP_005246944.1; XM_005246887.1. DR RefSeq; XP_005246945.1; XM_005246888.1. DR RefSeq; XP_005246946.1; XM_005246889.1. DR RefSeq; XP_005246947.1; XM_005246890.3. DR RefSeq; XP_005246948.1; XM_005246891.4. DR RefSeq; XP_005246949.1; XM_005246892.1. DR RefSeq; XP_006712852.1; XM_006712789.1. DR RefSeq; XP_006712853.1; XM_006712790.3. DR RefSeq; XP_006712856.1; XM_006712793.2. 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 PDB; 4PRZ; X-ray; 2.12 A; A=217-479. DR PDB; 4PS1; X-ray; 1.73 A; A/B/C/D=217-479. DR PDB; 4ZBW; X-ray; 2.20 A; A/B=2-188. DR PDB; 5H31; X-ray; 3.17 A; A/B/C/D=1-188. DR PDB; 5H33; X-ray; 3.60 A; A/B=1-188. DR PDB; 5JQE; X-ray; 3.16 A; A=1-186. DR PDB; 5L08; EM; 4.60 A; A/B/C/D/E/F/G/H/I=1-184. DR PDB; 6AGW; X-ray; 2.09 A; A=1-180. DR PDB; 6PX9; X-ray; 2.88 A; A/B/C/D/E/F=217-479. DR PDB; 7DEE; NMR; -; B=2-9. DR PDB; 7LVJ; X-ray; 1.50 A; A=1-188. DR PDB; 7LVM; X-ray; 1.47 A; A=2-188. 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 PDBsum; 4PRZ; -. DR PDBsum; 4PS1; -. DR PDBsum; 4ZBW; -. DR PDBsum; 5H31; -. DR PDBsum; 5H33; -. DR PDBsum; 5JQE; -. DR PDBsum; 5L08; -. DR PDBsum; 6AGW; -. DR PDBsum; 6PX9; -. DR PDBsum; 7DEE; -. DR PDBsum; 7LVJ; -. DR PDBsum; 7LVM; -. DR AlphaFoldDB; Q14790; -. DR BMRB; Q14790; -. DR EMDB; EMD-8300; -. DR SMR; Q14790; -. DR BioGRID; 107291; 183. DR ComplexPortal; CPX-1907; Ripoptosome. DR ComplexPortal; CPX-975; Caspase-8 complex. DR CORUM; Q14790; -. DR DIP; DIP-30915N; -. DR ELM; Q14790; -. DR IntAct; Q14790; 181. DR MINT; Q14790; -. DR STRING; 9606.ENSP00000351273; -. DR BindingDB; Q14790; -. DR ChEMBL; CHEMBL3776; -. DR DrugBank; DB05103; AN-9. DR DrugBank; DB12651; Bardoxolone. DR DrugBank; DB11752; Bryostatin 1. DR DrugBank; DB12843; Oleandrin. DR DrugBank; DB04297; Trichostatin A. DR GuidetoPHARMACOLOGY; 1624; -. DR MEROPS; C14.009; -. DR iPTMnet; Q14790; -. DR PhosphoSitePlus; Q14790; -. DR SwissPalm; Q14790; -. DR BioMuta; CASP8; -. DR DMDM; 2493531; -. DR CPTAC; CPTAC-794; -. DR CPTAC; CPTAC-795; -. DR EPD; Q14790; -. DR jPOST; Q14790; -. DR MassIVE; Q14790; -. DR MaxQB; Q14790; -. DR PaxDb; 9606-ENSP00000351273; -. DR PeptideAtlas; Q14790; -. DR ProteomicsDB; 60172; -. [Q14790-1] DR ProteomicsDB; 60173; -. [Q14790-2] DR ProteomicsDB; 60174; -. [Q14790-3] DR ProteomicsDB; 60175; -. [Q14790-4] DR ProteomicsDB; 60176; -. [Q14790-5] DR ProteomicsDB; 60177; -. [Q14790-6] DR ProteomicsDB; 60178; -. [Q14790-7] DR ProteomicsDB; 60179; -. [Q14790-8] DR ProteomicsDB; 60180; -. [Q14790-9] DR Pumba; Q14790; -. DR Antibodypedia; 697; 1645 antibodies from 51 providers. DR DNASU; 841; -. DR Ensembl; ENST00000264275.9; ENSP00000264275.5; ENSG00000064012.24. [Q14790-4] DR Ensembl; ENST00000323492.11; ENSP00000325722.7; ENSG00000064012.24. [Q14790-2] DR Ensembl; ENST00000358485.8; ENSP00000351273.4; ENSG00000064012.24. [Q14790-9] DR Ensembl; ENST00000392258.7; ENSP00000376087.3; ENSG00000064012.24. [Q14790-5] DR Ensembl; ENST00000392263.6; ENSP00000376091.2; ENSG00000064012.24. [Q14790-2] DR Ensembl; ENST00000413726.6; ENSP00000397528.2; ENSG00000064012.24. [Q14790-1] DR Ensembl; ENST00000432109.6; ENSP00000412523.2; ENSG00000064012.24. [Q14790-1] DR Ensembl; ENST00000440732.6; ENSP00000396869.2; ENSG00000064012.24. [Q14790-1] DR Ensembl; ENST00000444430.3; ENSP00000394434.3; ENSG00000064012.24. [Q14790-3] DR Ensembl; ENST00000447616.6; ENSP00000388306.2; ENSG00000064012.24. [Q14790-6] DR Ensembl; ENST00000673742.1; ENSP00000501268.1; ENSG00000064012.24. [Q14790-1] DR Ensembl; ENST00000696067.1; ENSP00000512369.1; ENSG00000064012.24. [Q14790-1] DR Ensembl; ENST00000696068.1; ENSP00000512370.1; ENSG00000064012.24. [Q14790-6] DR Ensembl; ENST00000696087.1; ENSP00000512382.1; ENSG00000064012.24. [Q14790-2] DR GeneID; 841; -. DR KEGG; hsa:841; -. DR MANE-Select; ENST00000673742.1; ENSP00000501268.1; NM_001372051.1; NP_001358980.1. DR UCSC; uc002uxo.2; human. [Q14790-1] DR AGR; HGNC:1509; -. DR CTD; 841; -. DR DisGeNET; 841; -. DR GeneCards; CASP8; -. DR HGNC; HGNC:1509; CASP8. DR HPA; ENSG00000064012; Tissue enhanced (bone). DR MalaCards; CASP8; -. DR MIM; 211980; phenotype. DR MIM; 601763; gene. DR MIM; 607271; phenotype. DR neXtProt; NX_Q14790; -. DR OpenTargets; ENSG00000064012; -. DR Orphanet; 210159; Adult hepatocellular carcinoma. DR Orphanet; 275517; Autoimmune lymphoproliferative syndrome with recurrent viral infections. DR PharmGKB; PA26092; -. DR VEuPathDB; HostDB:ENSG00000064012; -. DR eggNOG; KOG3573; Eukaryota. DR GeneTree; ENSGT00940000160319; -. DR HOGENOM; CLU_036904_4_2_1; -. DR InParanoid; Q14790; -. DR OMA; WNRIEDG; -. DR OrthoDB; 2873736at2759; -. DR PhylomeDB; Q14790; -. DR TreeFam; TF102023; -. DR BioCyc; MetaCyc:HS00790-MONOMER; -. DR BRENDA; 3.4.22.61; 2681. DR PathwayCommons; Q14790; -. DR Reactome; R-HSA-111465; Apoptotic cleavage of cellular proteins. DR Reactome; R-HSA-140534; Caspase activation via Death Receptors in the presence of ligand. DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway. DR Reactome; R-HSA-2562578; TRIF-mediated programmed cell death. DR Reactome; R-HSA-264870; Caspase-mediated cleavage of cytoskeletal proteins. DR Reactome; R-HSA-3371378; Regulation by c-FLIP. DR Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis. DR Reactome; R-HSA-5218900; CASP8 activity is inhibited. DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling. DR Reactome; R-HSA-5660668; CLEC7A/inflammasome pathway. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-69416; Dimerization of procaspase-8. DR Reactome; R-HSA-75108; Activation, myristolyation of BID and translocation to mitochondria. DR Reactome; R-HSA-75153; Apoptotic execution phase. DR Reactome; R-HSA-75157; FasL/ CD95L signaling. DR Reactome; R-HSA-75158; TRAIL signaling. DR Reactome; R-HSA-9013957; TLR3-mediated TICAM1-dependent programmed cell death. DR Reactome; R-HSA-933543; NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10. DR Reactome; R-HSA-9686347; Microbial modulation of RIPK1-mediated regulated necrosis. DR Reactome; R-HSA-9693928; Defective RIPK1-mediated regulated necrosis. DR Reactome; R-HSA-9758274; Regulation of NF-kappa B signaling. DR SignaLink; Q14790; -. DR SIGNOR; Q14790; -. DR BioGRID-ORCS; 841; 22 hits in 1176 CRISPR screens. DR ChiTaRS; CASP8; human. DR EvolutionaryTrace; Q14790; -. DR GeneWiki; Caspase_8; -. DR GenomeRNAi; 841; -. DR Pharos; Q14790; Tchem. DR PRO; PR:Q14790; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q14790; Protein. DR Bgee; ENSG00000064012; Expressed in monocyte and 171 other cell types or tissues. DR ExpressionAtlas; Q14790; baseline and differential. 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:UniProt. DR GO; GO:0005856; C:cytoskeleton; TAS:ProtInc. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0031264; C:death-inducing signaling complex; IDA:UniProtKB. DR GO; GO:0030027; C:lamellipodium; IDA:UniProtKB. DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; TAS:ProtInc. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0032991; C:protein-containing complex; IDA:ARUK-UCL. 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; IDA:UniProtKB. DR GO; GO:0097199; F:cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IDA:UniProt. 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:0005123; F:death receptor binding; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0008233; F:peptidase activity; IDA:BHF-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0097110; F:scaffold protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:Ensembl. 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:0001525; P:angiogenesis; ISS:UniProtKB. 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: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:GO_Central. DR GO; GO:0007507; P:heart development; ISS:UniProtKB. DR GO; GO:0030225; P:macrophage differentiation; IBA:GO_Central. DR GO; GO:0030101; P:natural killer cell activation; TAS:UniProtKB. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0060546; P:negative regulation of necroptotic process; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IMP:ARUK-UCL. DR GO; GO:0045651; P:positive regulation of macrophage differentiation; IMP:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0045862; P:positive regulation of proteolysis; IDA:BHF-UCL. DR GO; GO:0051604; P:protein maturation; IDA:UniProt. DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB. DR GO; GO:0051603; P:proteolysis involved in protein catabolic process; IMP:BHF-UCL. DR GO; GO:0070269; P:pyroptosis; ISS:UniProtKB. DR GO; GO:0001817; P:regulation of cytokine production; ISS:UniProtKB. DR GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB. DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; TAS:Reactome. DR GO; GO:0032025; P:response to cobalt ion; 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:0097264; P:self proteolysis; ISS:UniProtKB. 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:0036462; P:TRAIL-activated apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR CDD; cd00032; CASc; 1. DR CDD; cd08333; DED_Caspase_8_r1; 1. DR Gene3D; 3.40.50.1460; -; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 2. DR InterPro; IPR033170; Caspase-8_DED1. DR InterPro; IPR029030; Caspase-like_dom_sf. DR InterPro; IPR033139; Caspase_cys_AS. DR InterPro; IPR016129; Caspase_his_AS. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR001875; DED_dom. DR InterPro; IPR011600; Pept_C14_caspase. DR InterPro; IPR002138; Pept_C14_p10. DR InterPro; IPR001309; Pept_C14_p20. DR InterPro; IPR015917; Pept_C14A. DR PANTHER; PTHR48169:SF3; CASP8 AND FADD-LIKE APOPTOSIS REGULATOR A-RELATED; 1. DR PANTHER; PTHR48169; DED DOMAIN-CONTAINING PROTEIN; 1. 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; SSF52129; Caspase-like; 1. DR SUPFAM; SSF47986; DEATH domain; 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. DR Genevisible; Q14790; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Apoptosis; KW Cell projection; Cytoplasm; Direct protein sequencing; Disease variant; KW Host-virus interaction; Hydrolase; Nucleus; Phosphoprotein; Protease; KW Reference proteome; Repeat; Thiol protease; Zymogen. FT PROPEP 1..216 FT /evidence="ECO:0000269|PubMed:8962078, FT ECO:0000269|PubMed:9184224" FT /id="PRO_0000004628" FT CHAIN 217..374 FT /note="Caspase-8 subunit p18" FT /id="PRO_0000004629" FT PROPEP 375..384 FT /evidence="ECO:0000269|PubMed:8962078, FT ECO:0000269|PubMed:9184224" FT /id="PRO_0000004630" FT CHAIN 385..479 FT /note="Caspase-8 subunit p10" FT /id="PRO_0000004631" FT DOMAIN 2..80 FT /note="DED 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065" FT DOMAIN 100..177 FT /note="DED 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065" FT ACT_SITE 317 FT /evidence="ECO:0000269|PubMed:10508785" FT ACT_SITE 360 FT /evidence="ECO:0000269|PubMed:10508785" FT SITE 216..217 FT /note="Cleavage; by autocatalytic cleavage" FT /evidence="ECO:0000269|PubMed:8962078, FT ECO:0000269|PubMed:9184224" FT SITE 374..375 FT /note="Cleavage; by CASP6" FT /evidence="ECO:0000269|PubMed:22858542" FT SITE 384..385 FT /note="Cleavage; by autocatalytic cleavage" FT /evidence="ECO:0000269|PubMed:8962078, FT ECO:0000269|PubMed:9184224" FT MOD_RES 188 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O89110" FT MOD_RES 211 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O89110" FT MOD_RES 224 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:O89110" FT MOD_RES 334 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 380 FT /note="Phosphotyrosine; by SRC" FT /evidence="ECO:0000269|PubMed:16619028, FT ECO:0000269|PubMed:27109099" FT MOD_RES 387 FT /note="Phosphoserine; by CDK1" FT /evidence="ECO:0000269|PubMed:20937773" FT MOD_RES 413 FT /note="(Microbial infection) ADP-riboxanated arginine" FT /evidence="ECO:0000269|PubMed:35338844, FT ECO:0000269|PubMed:35446120" FT VAR_SEQ 1 FT /note="M -> MEGGRRARVVIESKRNFFLGAFPTPFPAEHVELGRLGDSETAMVPGK FT GGADYILLPFKKM (in isoform 9)" FT /evidence="ECO:0000303|PubMed:11917123" FT /id="VSP_000808" FT VAR_SEQ 102 FT /note="R -> RFHFCRMSWAEANSQCQTQSVPFWRRVDHLLIR (in isoform FT 4)" FT /evidence="ECO:0000303|PubMed:8755496" FT /id="VSP_000809" FT VAR_SEQ 184..267 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8681376" FT /id="VSP_000813" FT VAR_SEQ 184..220 FT /note="ERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQ -> DFGQSLPNEKQ FT TSGILSDHQQSQFCKSTGESAQTSQH (in isoform 6)" FT /evidence="ECO:0000303|PubMed:8681376" FT /id="VSP_000811" FT VAR_SEQ 184..198 FT /note="Missing (in isoform 2, isoform 4 and isoform 8)" FT /evidence="ECO:0000303|PubMed:11917123, FT ECO:0000303|PubMed:8681376, ECO:0000303|PubMed:8755496, FT ECO:0000303|PubMed:9228018" FT /id="VSP_000810" FT VAR_SEQ 199..235 FT /note="GEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGY -> DFGQSLPNEKQ FT TSGILSDHQQSQFCKSTGESAQTSQH (in isoform 5)" FT /evidence="ECO:0000303|PubMed:8681376" FT /id="VSP_000814" FT VAR_SEQ 221..479 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:8681376" FT /id="VSP_000812" FT VAR_SEQ 236..479 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:8681376" FT /id="VSP_000815" FT VAR_SEQ 269..276 FT /note="ALTTTFEE -> TVEPKREK (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|PubMed:12010809, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:8681376" FT /id="VSP_000816" FT VAR_SEQ 277..479 FT /note="Missing (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|PubMed:12010809, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:8681376" FT /id="VSP_000817" FT VARIANT 219 FT /note="S -> T (in dbSNP:rs35976359)" FT /evidence="ECO:0000269|Ref.9" FT /id="VAR_025816" FT VARIANT 248 FT /note="R -> W (in CASP8D; dbSNP:rs17860424)" FT /evidence="ECO:0000269|PubMed:12353035" FT /id="VAR_014204" FT VARIANT 285 FT /note="D -> H (associated with protection against breast FT cancer; also associated with a lower risk of cutaneous FT melanoma; dbSNP:rs1045485)" FT /evidence="ECO:0000269|PubMed:11161814, FT ECO:0000269|PubMed:15601643, ECO:0000269|PubMed:17293864, FT ECO:0000269|PubMed:18563783, ECO:0000269|PubMed:8755496, FT ECO:0000269|PubMed:9228018, ECO:0000269|Ref.9" FT /id="VAR_020127" FT MUTAGEN 73 FT /note="D->A: Abolishes binding to FLASH. Induces NF-kappa-B FT activation." FT /evidence="ECO:0000269|PubMed:15592525" FT MUTAGEN 360 FT /note="C->A: Does not affect localization to lamellipodia FT of migrating cells. Prevents DISC-mediated processing of FT CASP8." FT /evidence="ECO:0000269|PubMed:18216014, FT ECO:0000269|PubMed:27109099" FT MUTAGEN 360 FT /note="C->S: Abolishes interaction with UBR2." FT /evidence="ECO:0000269|PubMed:28602583" FT MUTAGEN 380 FT /note="Y->E: Phosphomimetic mutant which does not affect FT interaction with PIK3R1 or DISC-mediated processing." FT /evidence="ECO:0000269|PubMed:27109099" FT MUTAGEN 380 FT /note="Y->F: Abolishes phosphorylation at this site. Lack FT of efficient localization to lamellipodia and lack of FT promotion of cell migration. Lack of interaction with the FT SH2 domain of SRC. Lack of interaction with PIK3R1. FT Impaired DISC-mediated processing." FT /evidence="ECO:0000269|PubMed:16619028, FT ECO:0000269|PubMed:18216014, ECO:0000269|PubMed:27109099" FT MUTAGEN 387 FT /note="S->A: Impaired CDK1-mediated phosphorylation and FT enhanced apoptosis." FT MUTAGEN 413 FT /note="R->A: Abolished ADP-riboxanation by C.violaceum FT CopC." FT /evidence="ECO:0000269|PubMed:35446120" FT CONFLICT 294 FT /note="E -> D (in Ref. 5; AAD24962)" FT /evidence="ECO:0000305" FT CONFLICT 331 FT /note="A -> P (in Ref. 2; AAC50602 and 5; AAD24962)" FT /evidence="ECO:0000305" FT CONFLICT 343..344 FT /note="LK -> FG (in Ref. 8; AAL87631)" FT /evidence="ECO:0000305" FT HELIX 3..13 FT /evidence="ECO:0007829|PDB:7LVM" FT HELIX 16..25 FT /evidence="ECO:0007829|PDB:7LVM" FT TURN 26..29 FT /evidence="ECO:0007829|PDB:7LVM" FT HELIX 32..34 FT /evidence="ECO:0007829|PDB:7LVM" FT TURN 35..37 FT /evidence="ECO:0007829|PDB:5H31" FT HELIX 41..50 FT /evidence="ECO:0007829|PDB:7LVM" FT STRAND 53..55 FT /evidence="ECO:0007829|PDB:7LVM" FT HELIX 60..68 FT /evidence="ECO:0007829|PDB:7LVM" FT HELIX 72..79 FT /evidence="ECO:0007829|PDB:7LVM" FT HELIX 83..90 FT /evidence="ECO:0007829|PDB:7LVM" FT TURN 93..95 FT /evidence="ECO:0007829|PDB:4ZBW" FT HELIX 100..111 FT /evidence="ECO:0007829|PDB:7LVM" FT HELIX 114..127 FT /evidence="ECO:0007829|PDB:7LVM" FT STRAND 129..131 FT /evidence="ECO:0007829|PDB:7LVJ" FT HELIX 139..148 FT /evidence="ECO:0007829|PDB:7LVM" FT STRAND 151..153 FT /evidence="ECO:0007829|PDB:7LVJ" FT HELIX 158..165 FT /evidence="ECO:0007829|PDB:7LVM" FT HELIX 169..184 FT /evidence="ECO:0007829|PDB:7LVM" FT STRAND 230..232 FT /evidence="ECO:0007829|PDB:3H11" FT STRAND 235..240 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 245..250 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 252..254 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 255..257 FT /evidence="ECO:0007829|PDB:2K7Z" FT HELIX 263..276 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 280..286 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 289..301 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 304..306 FT /evidence="ECO:0007829|PDB:1QDU" FT STRAND 310..316 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 322..324 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 326..328 FT /evidence="ECO:0007829|PDB:1I4E" FT STRAND 330..332 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 333..337 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 338..340 FT /evidence="ECO:0007829|PDB:4JJ7" FT TURN 342..344 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 346..348 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 349..351 FT /evidence="ECO:0007829|PDB:6PX9" FT STRAND 353..359 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 361..364 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 369..371 FT /evidence="ECO:0007829|PDB:1QDU" FT STRAND 377..379 FT /evidence="ECO:0007829|PDB:2K7Z" FT STRAND 392..394 FT /evidence="ECO:0007829|PDB:1QDU" FT TURN 395..398 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 399..405 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 412..414 FT /evidence="ECO:0007829|PDB:3H11" FT TURN 415..417 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 420..432 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 433..435 FT /evidence="ECO:0007829|PDB:4JJ7" FT HELIX 439..450 FT /evidence="ECO:0007829|PDB:4JJ7" FT TURN 456..459 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 465..468 FT /evidence="ECO:0007829|PDB:4JJ7" FT STRAND 471..473 FT /evidence="ECO:0007829|PDB:1QDU" FT CONFLICT Q14790-9:14 FT /note="K -> R (in Ref. 8; AAL87628)" FT /evidence="ECO:0000305" 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 //