ID TNR6_HUMAN Reviewed; 335 AA. AC P25445; A9UJX4; B6VNV4; Q14292; Q14293; Q14294; Q14295; Q16652; Q5T9P1; AC Q5T9P2; Q5T9P3; Q6SSE9; DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1992, sequence version 1. DT 27-MAR-2024, entry version 267. DE RecName: Full=Tumor necrosis factor receptor superfamily member 6; DE AltName: Full=Apo-1 antigen; DE AltName: Full=Apoptosis-mediating surface antigen FAS; DE AltName: Full=FASLG receptor; DE AltName: CD_antigen=CD95; DE Flags: Precursor; GN Name=FAS; Synonyms=APT1, FAS1, TNFRSF6; 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] (ISOFORM 1), AND SUBCELLULAR LOCATION. RX PubMed=1713127; DOI=10.1016/0092-8674(91)90614-5; RA Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., RA Hase A., Seto Y., Nagata S.; RT "The polypeptide encoded by the cDNA for human cell surface antigen Fas can RT mediate apoptosis."; RL Cell 66:233-243(1991). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 226-240; RP 269-291 AND 321-335. RX PubMed=1375228; DOI=10.1016/s0021-9258(19)50076-x; RA Oehm A., Behrmann I., Falk W., Pawlita M., Maier G., Klas C., Li-Weber M., RA Richards S., Dhein J., Trauth B.C., Ponstingl H., Krammer P.H.; RT "Purification and molecular cloning of the APO-1 cell surface antigen, a RT member of the tumor necrosis factor/nerve growth factor receptor RT superfamily. Sequence identity with the Fas antigen."; RL J. Biol. Chem. 267:10709-10715(1992). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4 AND 6), AND TISSUE RP SPECIFICITY. RX PubMed=7575433; DOI=10.1042/bj3100957; RA Liu C., Cheng J., Mountz J.D.; RT "Differential expression of human Fas mRNA species upon peripheral blood RT mononuclear cell activation."; RL Biochem. J. 310:957-963(1995). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 6), AND FUNCTION. RX PubMed=7533181; RA Cascino I., Fiucci G., Papoff G., Ruberti G.; RT "Three functional soluble forms of the human apoptosis-inducing Fas RT molecule are produced by alternative splicing."; RL J. Immunol. 154:2706-2713(1995). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7). RX PubMed=8598453; RA Cascino I., Papoff G., De Maria R., Testi R., Ruberti G.; RT "Fas/Apo-1 (CD95) receptor lacking the intracytoplasmic signaling domain RT protects tumor cells from Fas-mediated apoptosis."; RL J. Immunol. 156:13-17(1996). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 5). RX PubMed=8648105; RA Papoff G., Cascino I., Eramo A., Starace G., Lynch D.H., Ruberti G.; RT "An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents RT cell death in vitro."; RL J. Immunol. 156:4622-4630(1996). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALPS1A SER-262. RX PubMed=17336828; DOI=10.1016/j.imbio.2006.12.003; RA Del-Rey M.J., Manzanares J., Bosque A., Aguilo J.I., Gomez-Rial J., RA Roldan E., Serrano A., Anel A., Paz-Artal E., Allende L.M.; RT "Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new RT germline Fas gene mutation."; RL Immunobiology 212:73-83(2007). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RC TISSUE=Peripheral blood lymphocyte; RA Schaetzlein C.E., Poehlmann R., Philippsen P., Eibel H.; RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA De La Calle-Martin O.; RL Submitted (OCT-2008) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-16; ILE-122 AND RP ILE-305. RG NIEHS SNPs program; RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [14] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Urinary bladder; 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 [15] RP INTERACTION WITH RIPK1. RX PubMed=7538908; DOI=10.1016/0092-8674(95)90072-1; RA Stanger B.Z., Leder P., Lee T.-H., Kim E., Seed B.; RT "RIP: a novel protein containing a death domain that interacts with RT Fas/APO-1 (CD95) in yeast and causes cell death."; RL Cell 81:513-523(1995). RN [16] RP FUNCTION, AND IDENTIFICATION IN DISC COMPLEX. 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 [17] RP INTERACTION WITH FEM1B. RX PubMed=10542291; DOI=10.1074/jbc.274.45.32461; RA Chan S.-L., Tan K.-O., Zhang L., Yee K.S.Y., Ronca F., Chan M.-Y., Yu V.C.; RT "F1Aalpha, a death receptor-binding protein homologous to the RT Caenorhabditis elegans sex-determining protein, FEM-1, is a caspase RT substrate that mediates apoptosis."; RL J. Biol. Chem. 274:32461-32468(1999). RN [18] RP INTERACTION WITH FAIM2. RX PubMed=10535980; DOI=10.1073/pnas.96.22.12667; RA Somia N.V., Schmitt M.J., Vetter D.E., Van Antwerp D., Heinemann S.F., RA Verma I.M.; RT "LFG: an anti-apoptotic gene that provides protection from fas-mediated RT cell death."; RL Proc. Natl. Acad. Sci. U.S.A. 96:12667-12672(1999). 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 BABAM2. RX PubMed=15465831; DOI=10.1074/jbc.m408678200; RA Li Q., Ching A.K.-K., Chan B.C.-L., Chow S.K.-Y., Lim P.-L., Ho T.C.-Y., RA Ip W.-K., Wong C.-K., Lam C.W.-K., Lee K.K.-H., Chan J.Y.-H., Chui Y.-L.; RT "A death receptor-associated anti-apoptotic protein, BRE, inhibits RT mitochondrial apoptotic pathway."; RL J. Biol. Chem. 279:52106-52116(2004). RN [21] RP INTERACTION WITH DDX3X; GSK3B AND BIRC2. 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 [22] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-209, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [24] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-118. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [25] RP INTERACTION WITH FADD. RX PubMed=21109225; DOI=10.1016/j.ajhg.2010.10.028; RA Bolze A., Byun M., McDonald D., Morgan N.V., Abhyankar A., Premkumar L., RA Puel A., Bacon C.M., Rieux-Laucat F., Pang K., Britland A., Abel L., RA Cant A., Maher E.R., Riedl S.J., Hambleton S., Casanova J.L.; RT "Whole-exome-sequencing-based discovery of human FADD deficiency."; RL Am. J. Hum. Genet. 87:873-881(2010). RN [26] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [27] 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 [28] RP GLYCOSYLATION AT THR-28, STRUCTURE OF CARBOHYDRATES, AND IDENTIFICATION BY RP MASS SPECTROMETRY. RX PubMed=22171320; DOI=10.1074/mcp.m111.013649; RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.; RT "Human urinary glycoproteomics; attachment site specific analysis of N- and RT O-linked glycosylations by CID and ECD."; RL Mol. Cell. Proteomics 11:1-17(2012). RN [29] RP GLYCOSYLATION AT ARG-250 (MICROBIAL INFECTION). RX PubMed=23955153; DOI=10.1038/nature12436; RA Li S., Zhang L., Yao Q., Li L., Dong N., Rong J., Gao W., Ding X., Sun L., RA Chen X., Chen S., Shao F.; RT "Pathogen blocks host death receptor signalling by arginine GlcNAcylation RT of death domains."; RL Nature 501:242-246(2013). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-225, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [31] RP SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-199, AND MUTAGENESIS OF RP CYS-199. RX PubMed=25301068; DOI=10.1038/cdd.2014.153; RA Rossin A., Durivault J., Chakhtoura-Feghali T., Lounnas N., RA Gagnoux-Palacios L., Hueber A.O.; RT "Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas RT stability."; RL Cell Death Differ. 22:643-653(2015). RN [32] RP GLYCOSYLATION AT ARG-250 (MICROBIAL INFECTION), AND MUTAGENESIS OF ARG-250. RX PubMed=30979585; DOI=10.1016/j.molcel.2019.03.028; RA Ding J., Pan X., Du L., Yao Q., Xue J., Yao H., Wang D.C., Li S., Shao F.; RT "Structural and functional insights into host death domains inactivation by RT the bacterial arginine GlcNAcyltransferase effector."; RL Mol. Cell 74:922-935(2019). RN [33] RP STRUCTURE BY NMR OF 218-335. RX PubMed=8967952; DOI=10.1038/384638a0; RA Huang B., Eberstadt M., Olejniczak E.T., Meadows R.P., Fesik S.W.; RT "NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain."; RL Nature 384:638-641(1996). RN [34] RP X-RAY CRYSTALLOGRAPHY (2.73 ANGSTROMS) OF 223-335 IN COMPLEX WITH FADD, RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-291 AND RP ILE-313. RX PubMed=19118384; DOI=10.1038/nature07606; RA Scott F.L., Stec B., Pop C., Dobaczewska M.K., Lee J.J., Monosov E., RA Robinson H., Salvesen G.S., Schwarzenbacher R., Riedl S.J.; RT "The Fas-FADD death domain complex structure unravels signalling by RT receptor clustering."; RL Nature 457:1019-1022(2009). RN [35] RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 230-254 IN COMPLEX WITH CALM, AND RP CALMODULIN-BINDING. RX PubMed=24914971; DOI=10.1107/s1399004714006919; RA Jiang T., Cao P., Gong Y., Yu H.J., Gui W.J., Zhang W.T.; RT "Structural insights into the mechanism of calmodulin binding to death RT receptors."; RL Acta Crystallogr. D 70:1604-1613(2014). RN [36] RP VARIANT ALPS1A PRO-241. RX PubMed=7540117; DOI=10.1016/0092-8674(95)90013-6; RA Fisher G.H., Rosenberg F.J., Straus S.E., Dale J.K., Middleton L.A., RA Lin A.Y., Strober W., Lenardo M.J., Puck J.M.; RT "Dominant interfering Fas gene mutations impair apoptosis in a human RT autoimmune lymphoproliferative syndrome."; RL Cell 81:935-946(1995). RN [37] RP VARIANT ALPS1A TYR-260. RX PubMed=8929361; DOI=10.1056/nejm199611283352204; RA Drappa J., Vaishnaw A.K., Sullivan K.E., Chu J.-L., Elkon K.B.; RT "Fas gene mutations in the Canale-Smith syndrome, an inherited RT lymphoproliferative disorder associated with autoimmunity."; RL N. Engl. J. Med. 335:1643-1649(1996). RN [38] RP VARIANTS ALPS1A TRP-121 AND CYS-232. RX PubMed=9028321; RA Bettinardi A., Brugnoni D., Quiros-Roldan E., Malagoli A., La Grutta S., RA Correra A., Notarangelo L.D.; RT "Missense mutations in the Fas gene resulting in autoimmune RT lymphoproliferative syndrome: a molecular and immunological analysis."; RL Blood 89:902-909(1997). RN [39] RP VARIANTS ALPS1A ASP-257 AND SER-310. RX PubMed=9028957; RA Sneller M.C., Wang J., Dale J.K., Strober W., Middelton L.A., Choi Y., RA Fleisher T.A., Lim M.S., Jaffe E.S., Puck J.M., Lenardo M.J., Straus S.E.; RT "Clinical, immunologic, and genetic features of an autoimmune RT lymphoproliferative syndrome associated with abnormal lymphocyte RT apoptosis."; RL Blood 89:1341-1348(1997). RN [40] RP VARIANT ALPS1A ALA-28. RX PubMed=9322534; DOI=10.1053/gast.1997.v113.pm9322534; RA Pensati L., Costanzo A., Ianni A., Accapezzato D., Iorio R., Natoli G., RA Nisini R., Almerighi C., Balsano C., Vajro P., Vegnente A., Levrero M.; RT "Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a RT patient with type 2 autoimmune hepatitis."; RL Gastroenterology 113:1384-1389(1997). RN [41] RP VARIANTS NON-HODGKIN LYMPHOMA THR-25; PHE-180; LEU-183; ILE-198; VAL-260; RP LYS-264; LYS-272; PHE-278 AND ASN-299. RX PubMed=9787134; RA Groenbaek K., Straten P.T., Ralfkiaer E., Ahrenkiel V., Andersen M.K., RA Hansen N.E., Zeuthen J., Hou-Jensen K., Guldberg P.; RT "Somatic Fas mutations in non-Hodgkin's lymphoma: association with RT extranodal disease and autoimmunity."; RL Blood 92:3018-3024(1998). RN [42] RP VARIANT ALPS1A VAL-260. RX PubMed=9821419; DOI=10.1016/s0022-3476(98)70102-7; RA Infante A.J., Britton H.A., DeNapoli T., Middelton L.A., Lenardo M.J., RA Jackson C.E., Wang J., Fleisher T., Straus S.E., Puck J.M.; RT "The clinical spectrum in a large kindred with autoimmune RT lymphoproliferative syndrome caused by a Fas mutation that impairs RT lymphocyte apoptosis."; RL J. Pediatr. 133:629-633(1998). RN [43] RP VARIANTS ALPS1A LYS-241 AND GLN-250. RX PubMed=10090885; DOI=10.1086/302333; RA Jackson C.E., Fischer R.E., Hsu A.P., Anderson S.M., Choi Y., Wang J., RA Dale J.K., Fleisher T.A., Middelton L.A., Sneller M.C., Lenardo M.J., RA Straus S.E., Puck J.M.; RT "Autoimmune lymphoproliferative syndrome with defective Fas: genotype RT influences penetrance."; RL Am. J. Hum. Genet. 64:1002-1014(1999). RN [44] RP VARIANTS ALPS1A LEU-249; PRO-250; ASP-253; SER-253; ARG-259; LYS-270 AND RP LYS-272. RX PubMed=10515860; RA Rieux-Laucat F., Blachere S., Danielan S., De Villartay J.P., Oleastro M., RA Solary E., Bader-Meunier B., Arkwright P., Pondare C., Bernaudin F., RA Chapel H., Nielsen S., Berrah M., Fischer A., Le Deist F.; RT "Lymphoproliferative syndrome with autoimmunity: A possible genetic basis RT for dominant expression of the clinical manifestations."; RL Blood 94:2575-2582(1999). RN [45] RP VARIANT ALPS1A GLY-272. RX PubMed=10340403; DOI=10.1016/s0301-472x(99)00033-8; RA Peters A.M., Kohfink B., Martin H., Griesinger F., Wormann B., Gahr M., RA Roesler J.; RT "Defective apoptosis due to a point mutation in the death domain of CD95 RT associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, RT and Hodgkin's disease."; RL Exp. Hematol. 27:868-874(1999). RN [46] RP VARIANTS ALPS1A ARG-82; PRO-250; GLY-260 AND ILE-270. RX PubMed=9927496; DOI=10.1172/jci5121; RA Vaishnaw A.K., Orlinick J.R., Chu J.-L., Krammer P.H., Chao M.V., RA Elkon K.B.; RT "The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo- RT 1) mutations."; RL J. Clin. Invest. 103:355-363(1999). RN [47] RP VARIANTS SQUAMOUS CELL CARCINOMA SER-118; ARG-178 AND ASP-255. RX PubMed=10620127; DOI=10.1046/j.1523-1747.2000.00819.x; RA Lee S.H., Shin M.S., Kim H.S., Park W.S., Kim S.Y., Jang J.J., Rhim K.J., RA Jang J., Lee H.K., Park J.Y., Oh R.R., Han S.Y., Lee J.H., Lee J.Y., RA Yoo N.J.; RT "Somatic mutations of Fas (Apo-1/CD95) gene in cutaneous squamous cell RT carcinoma arising from a burn scar."; RL J. Invest. Dermatol. 114:122-126(2000). RN [48] RP VARIANTS ALPS1A PRO-241; VAL-260; ILE-270 AND GLY-272. RX PubMed=11418480; DOI=10.1182/blood.v98.1.194; RA Straus S.E., Jaffe E.S., Puck J.M., Dale J.K., Elkon K.B., Roesen-Wolff A., RA Peters A.M.J., Sneller M.C., Hallahan C.W., Wang J., Fischer R.E., RA Jackson C.M., Lin A.Y., Baeumler C., Siegert E., Marx A., Vaishnaw A.K., RA Grodzicky T., Fleisher T.A., Lenardo M.J.; RT "The development of lymphomas in families with autoimmune RT lymphoproliferative syndrome with germline Fas mutations and defective RT lymphocyte apoptosis."; RL Blood 98:194-200(2001). RN [49] RP CHARACTERIZATION OF VARIANTS ALPS1A CYS-232; GLN-250; ASP-257; TYR-260; RP VAL-260; LYS-270 AND LYS-272, AND MUTAGENESIS OF ARG-250; GLU-261; GLN-283 RP AND LYS-287. RX PubMed=20935634; DOI=10.1038/nsmb.1920; RA Wang L., Yang J.K., Kabaleeswaran V., Rice A.J., Cruz A.C., Park A.Y., RA Yin Q., Damko E., Jang S.B., Raunser S., Robinson C.V., Siegel R.M., RA Walz T., Wu H.; RT "The Fas-FADD death domain complex structure reveals the basis of DISC RT assembly and disease mutations."; RL Nat. Struct. Mol. Biol. 17:1324-1329(2010). CC -!- FUNCTION: Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits CC caspase CASP8 to the activated receptor. The resulting death-inducing CC signaling complex (DISC) performs CASP8 proteolytic activation which CC initiates the subsequent cascade of caspases (aspartate-specific CC cysteine proteases) mediating apoptosis. FAS-mediated apoptosis may CC have a role in the induction of peripheral tolerance, in the antigen- CC stimulated suicide of mature T-cells, or both. The secreted isoforms 2 CC to 6 block apoptosis (in vitro). {ECO:0000269|PubMed:19118384, CC ECO:0000269|PubMed:7533181, ECO:0000269|PubMed:9184224}. CC -!- SUBUNIT: Component of the death-induced signaling complex (DISC) CC composed of cell surface receptor FAS/CD95, adapter protein FADD and CC the CASP8 protease; recruitment of CASP8 to the complex is required for CC processing of CASP8 into the p18 and p10 subunits (PubMed:9184224, CC PubMed:21109225, PubMed:9322534). Interacts directly (via DED domain) CC with NOL3 (via CARD domain); inhibits death-inducing signaling complex CC (DISC) assembly by inhibiting the increase in FAS-FADD binding induced CC by FAS activation (By similarity). Binds DAXX. Interacts with HIPK3 (By CC similarity). Part of a complex containing HIPK3 and FADD (By CC similarity). Binds RIPK1 and FAIM2 (PubMed:7538908, PubMed:10535980). CC Interacts with BABAM2 and FEM1B (PubMed:10542291, PubMed:15465831). CC Interacts with CALM (PubMed:24914971). In the absence of stimulation, CC interacts with BIRC2, DDX3X and GSK3B. The interaction with BIRC2 and CC DDX3X is further enhanced upon receptor stimulation and accompanied by CC DDX3X and BIRC2 cleavage (PubMed:18846110). CC {ECO:0000250|UniProtKB:P25446, ECO:0000250|UniProtKB:Q63199, CC ECO:0000269|PubMed:10535980, ECO:0000269|PubMed:10542291, CC ECO:0000269|PubMed:15465831, ECO:0000269|PubMed:18846110, CC ECO:0000269|PubMed:19118384, ECO:0000269|PubMed:21109225, CC ECO:0000269|PubMed:24914971, ECO:0000269|PubMed:7538908, CC ECO:0000269|PubMed:9184224, ECO:0000269|PubMed:9322534}. CC -!- INTERACTION: CC P25445; P62158: CALM3; NbExp=4; IntAct=EBI-494743, EBI-397435; CC P25445; Q14790: CASP8; NbExp=14; IntAct=EBI-494743, EBI-78060; CC P25445; Q03135: CAV1; NbExp=3; IntAct=EBI-494743, EBI-603614; CC P25445; Q9UER7: DAXX; NbExp=3; IntAct=EBI-494743, EBI-77321; CC P25445; Q13158: FADD; NbExp=21; IntAct=EBI-494743, EBI-494804; CC P25445; P25445: FAS; NbExp=3; IntAct=EBI-494743, EBI-494743; CC P25445; P48023: FASLG; NbExp=4; IntAct=EBI-494743, EBI-495538; CC P25445; P29590: PML; NbExp=4; IntAct=EBI-494743, EBI-295890; CC P25445; Q15156: PML-RAR; NbExp=6; IntAct=EBI-494743, EBI-867256; CC P25445; Q12923: PTPN13; NbExp=3; IntAct=EBI-494743, EBI-355227; CC P25445; P12931: SRC; NbExp=2; IntAct=EBI-494743, EBI-621482; CC P25445; P12815: Pdcd6; Xeno; NbExp=2; IntAct=EBI-494743, EBI-309164; CC P25445-1; Q14790: CASP8; NbExp=3; IntAct=EBI-15749113, EBI-78060; CC P25445-1; Q03135: CAV1; NbExp=3; IntAct=EBI-15749113, EBI-603614; CC P25445-1; Q13158: FADD; NbExp=17; IntAct=EBI-15749113, EBI-494804; CC P25445-1; P07947: YES1; NbExp=2; IntAct=EBI-15749113, EBI-515331; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane CC {ECO:0000269|PubMed:1713127, ECO:0000269|PubMed:25301068}; Single-pass CC type I membrane protein {ECO:0000305}. Membrane raft CC {ECO:0000269|PubMed:25301068}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Secreted. CC -!- SUBCELLULAR LOCATION: [Isoform 5]: Secreted. CC -!- SUBCELLULAR LOCATION: [Isoform 6]: Secreted. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; CC IsoId=P25445-1; Sequence=Displayed; CC Name=2; Synonyms=del2, D; CC IsoId=P25445-2; Sequence=VSP_006481, VSP_006482; CC Name=3; Synonyms=del3, E; CC IsoId=P25445-3; Sequence=VSP_006483, VSP_006484; CC Name=4; Synonyms=B; CC IsoId=P25445-4; Sequence=VSP_006485, VSP_006486; CC Name=5; Synonyms=C; CC IsoId=P25445-5; Sequence=VSP_006487, VSP_006488; CC Name=6; Synonyms=TMdel, A; CC IsoId=P25445-6; Sequence=VSP_006489; CC Name=7; Synonyms=FasExo8Del; CC IsoId=P25445-7; Sequence=VSP_045235, VSP_045236; CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 6 are expressed at equal CC levels in resting peripheral blood mononuclear cells. After activation CC there is an increase in isoform 1 and decrease in the levels of isoform CC 6. {ECO:0000269|PubMed:7575433}. CC -!- DOMAIN: Contains a death domain involved in the binding of FADD, and CC maybe to other cytosolic adapter proteins. CC -!- PTM: (Microbial infection) Glycosylated at Arg-250 by enteropathogenic CC E.coli protein NleB1: arginine GlcNAcylation prevents CC homotypic/heterotypic death domain interactions. CC {ECO:0000305|PubMed:23955153}. CC -!- PTM: Palmitoylated (PubMed:25301068). Palmitoylation by ZDHHC7 prevents CC the lysosomal degradation of FAS regulating its expression at the CC plasma membrane (PubMed:25301068). {ECO:0000269|PubMed:25301068}. CC -!- PTM: N- and O-glycosylated. O-glycosylated with core 1 or possibly core CC 8 glycans. {ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:22171320}. CC -!- DISEASE: Autoimmune lymphoproliferative syndrome 1A (ALPS1A) CC [MIM:601859]: A disorder of apoptosis that manifests in early childhood CC and results in the accumulation of autoreactive lymphocytes. It is CC characterized by non-malignant lymphadenopathy with hepatosplenomegaly, CC and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. CC {ECO:0000269|PubMed:10090885, ECO:0000269|PubMed:10340403, CC ECO:0000269|PubMed:10515860, ECO:0000269|PubMed:11418480, CC ECO:0000269|PubMed:17336828, ECO:0000269|PubMed:20935634, CC ECO:0000269|PubMed:7540117, ECO:0000269|PubMed:8929361, CC ECO:0000269|PubMed:9028321, ECO:0000269|PubMed:9028957, CC ECO:0000269|PubMed:9322534, ECO:0000269|PubMed:9821419, CC ECO:0000269|PubMed:9927496}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: 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 -!- MISCELLANEOUS: [Isoform 3]: 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 -!- MISCELLANEOUS: [Isoform 4]: 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 -!- MISCELLANEOUS: [Isoform 5]: 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 -!- MISCELLANEOUS: [Isoform 7]: Dominant negative isoform, resistant to CC Fas-mediated apoptosis. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Autoimmune Lymphoproliferative Syndrome Database CC (ALPSbase); Note=Mutations in TNFRSF6 causing ALPS type Ia; CC URL="https://www.niaid.nih.gov/diseases-conditions/autoimmune-lymphoproliferative-syndrome-alps"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/tnfrsf6/"; 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; M67454; AAA63174.1; -; mRNA. DR EMBL; X63717; CAA45250.1; -; mRNA. DR EMBL; X83490; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; X83491; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; X83492; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; X83493; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; Z47993; CAA88031.1; -; mRNA. DR EMBL; Z47994; CAA88032.1; -; mRNA. DR EMBL; Z47995; CAA88033.1; -; mRNA. DR EMBL; Z66556; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; Z70519; CAA94430.1; -; mRNA. DR EMBL; Z70520; CAA94431.1; -; mRNA. DR EMBL; AY495076; AAS76663.1; -; mRNA. DR EMBL; X89101; CAA61473.1; -; mRNA. DR EMBL; FM246458; CAR92543.1; -; mRNA. DR EMBL; AK290978; BAF83667.1; -; mRNA. DR EMBL; AY450925; AAR08906.1; -; Genomic_DNA. DR EMBL; AL157394; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471066; EAW50151.1; -; Genomic_DNA. DR EMBL; BC012479; AAH12479.1; -; mRNA. DR CCDS; CCDS7393.1; -. [P25445-1] DR CCDS; CCDS7394.1; -. [P25445-6] DR CCDS; CCDS7395.1; -. [P25445-7] DR PIR; A40036; A40036. DR PIR; I37383; I37383. DR PIR; I37384; I37384. DR PIR; S58662; S58662. DR RefSeq; NP_000034.1; NM_000043.5. [P25445-1] DR RefSeq; NP_001307548.1; NM_001320619.1. DR RefSeq; NP_690610.1; NM_152871.3. [P25445-6] DR RefSeq; NP_690611.1; NM_152872.3. [P25445-7] DR PDB; 1DDF; NMR; -; A=218-335. DR PDB; 2NA7; NMR; -; A/B/C=171-198. DR PDB; 3EWT; X-ray; 2.40 A; E=230-254. DR PDB; 3EZQ; X-ray; 2.73 A; A/C/E/G/I/K/M/O=223-335. DR PDB; 3THM; X-ray; 2.10 A; F=17-172. DR PDB; 3TJE; X-ray; 1.93 A; F=17-172. DR PDBsum; 1DDF; -. DR PDBsum; 2NA7; -. DR PDBsum; 3EWT; -. DR PDBsum; 3EZQ; -. DR PDBsum; 3THM; -. DR PDBsum; 3TJE; -. DR AlphaFoldDB; P25445; -. DR SMR; P25445; -. DR BioGRID; 106851; 354. DR CORUM; P25445; -. DR DIP; DIP-924N; -. DR IntAct; P25445; 86. DR MINT; P25445; -. DR STRING; 9606.ENSP00000498466; -. DR ChEMBL; CHEMBL4523207; -. DR GlyConnect; 773; 1 O-Linked glycan (1 site). DR GlyCosmos; P25445; 7 sites, 4 glycans. DR GlyGen; P25445; 10 sites, 5 O-linked glycans (7 sites). DR iPTMnet; P25445; -. DR PhosphoSitePlus; P25445; -. DR SwissPalm; P25445; -. DR BioMuta; FAS; -. DR DMDM; 119833; -. DR CPTAC; CPTAC-5953; -. DR CPTAC; CPTAC-5954; -. DR EPD; P25445; -. DR jPOST; P25445; -. DR MassIVE; P25445; -. DR MaxQB; P25445; -. DR PaxDb; 9606-ENSP00000347979; -. DR PeptideAtlas; P25445; -. DR ProteomicsDB; 54273; -. [P25445-1] DR ProteomicsDB; 54276; -. [P25445-4] DR ProteomicsDB; 54277; -. [P25445-5] DR ProteomicsDB; 54278; -. [P25445-6] DR ProteomicsDB; 64806; -. DR Pumba; P25445; -. DR TopDownProteomics; P25445-7; -. [P25445-7] DR ABCD; P25445; 12 sequenced antibodies. DR Antibodypedia; 4525; 3239 antibodies from 54 providers. DR CPTC; P25445; 2 antibodies. DR DNASU; 355; -. DR Ensembl; ENST00000355279.2; ENSP00000347426.2; ENSG00000026103.25. [P25445-7] DR Ensembl; ENST00000357339.7; ENSP00000349896.2; ENSG00000026103.25. [P25445-6] DR Ensembl; ENST00000479522.6; ENSP00000424113.1; ENSG00000026103.25. [P25445-3] DR Ensembl; ENST00000484444.6; ENSP00000420975.1; ENSG00000026103.25. [P25445-2] DR Ensembl; ENST00000488877.6; ENSP00000425159.1; ENSG00000026103.25. [P25445-4] DR Ensembl; ENST00000492756.7; ENSP00000422453.1; ENSG00000026103.25. [P25445-5] DR Ensembl; ENST00000494410.5; ENSP00000423755.1; ENSG00000026103.25. [P25445-4] DR Ensembl; ENST00000652046.1; ENSP00000498466.1; ENSG00000026103.25. [P25445-1] DR Ensembl; ENST00000697036.1; ENSP00000513060.1; ENSG00000026103.25. [P25445-4] DR GeneID; 355; -. DR KEGG; hsa:355; -. DR MANE-Select; ENST00000652046.1; ENSP00000498466.1; NM_000043.6; NP_000034.1. DR UCSC; uc001kfr.4; human. [P25445-1] DR AGR; HGNC:11920; -. DR CTD; 355; -. DR DisGeNET; 355; -. DR GeneCards; FAS; -. DR GeneReviews; FAS; -. DR HGNC; HGNC:11920; FAS. DR HPA; ENSG00000026103; Low tissue specificity. DR MalaCards; FAS; -. DR MIM; 134637; gene. DR MIM; 601859; phenotype. DR neXtProt; NX_P25445; -. DR OpenTargets; ENSG00000026103; -. DR Orphanet; 3261; Autoimmune lymphoproliferative syndrome. DR Orphanet; 117; Behcet disease. DR Orphanet; 3437; Vogt-Koyanagi-Harada disease. DR PharmGKB; PA36613; -. DR VEuPathDB; HostDB:ENSG00000026103; -. DR eggNOG; ENOG502S0SV; Eukaryota. DR GeneTree; ENSGT00950000183126; -. DR HOGENOM; CLU_067123_1_0_1; -. DR InParanoid; P25445; -. DR OMA; RDTKCRC; -. DR OrthoDB; 24515at2759; -. DR PhylomeDB; P25445; -. DR TreeFam; TF333916; -. DR PathwayCommons; P25445; -. DR Reactome; R-HSA-140534; Caspase activation via Death Receptors in the presence of ligand. 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-6803211; TP53 Regulates Transcription of Death Receptors and Ligands. DR Reactome; R-HSA-69416; Dimerization of procaspase-8. DR Reactome; R-HSA-75157; FasL/ CD95L signaling. DR SignaLink; P25445; -. DR SIGNOR; P25445; -. DR BioGRID-ORCS; 355; 9 hits in 1151 CRISPR screens. DR ChiTaRS; FAS; human. DR EvolutionaryTrace; P25445; -. DR GeneWiki; Fas_receptor; -. DR GenomeRNAi; 355; -. DR Pharos; P25445; Tbio. DR PRO; PR:P25445; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; P25445; Protein. DR Bgee; ENSG00000026103; Expressed in rectum and 191 other cell types or tissues. DR ExpressionAtlas; P25445; baseline and differential. DR GO; GO:0031265; C:CD95 death-inducing signaling complex; IDA:UniProtKB. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0031264; C:death-inducing signaling complex; IDA:UniProtKB. DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0005516; F:calmodulin binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019900; F:kinase binding; IPI:BHF-UCL. DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc. DR GO; GO:0005031; F:tumor necrosis factor receptor activity; IBA:GO_Central. DR GO; GO:0006924; P:activation-induced cell death of T cells; IBA:GO_Central. DR GO; GO:0006915; P:apoptotic process; IDA:MGI. DR GO; GO:0034198; P:cellular response to amino acid starvation; IMP:CAFA. DR GO; GO:0071455; P:cellular response to hyperoxia; IMP:UniProtKB. DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IMP:UniProtKB. DR GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; IBA:GO_Central. DR GO; GO:0036337; P:Fas signaling pathway; IMP:CAFA. DR GO; GO:0006955; P:immune response; IEA:InterPro. DR GO; GO:0097049; P:motor neuron apoptotic process; IBA:GO_Central. DR GO; GO:0097527; P:necroptotic signaling pathway; IMP:BHF-UCL. DR GO; GO:0043066; P:negative regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001235; P:positive regulation of apoptotic signaling pathway; IMP:CAFA. DR GO; GO:2001269; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IMP:CAFA. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:CAFA. DR GO; GO:0065003; P:protein-containing complex assembly; TAS:ProtInc. DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB. DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; IMP:CAFA. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR CDD; cd08316; Death_FAS_TNFRSF6; 1. DR CDD; cd10579; TNFRSF6; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR Gene3D; 2.10.50.10; Tumor Necrosis Factor Receptor, subunit A, domain 2; 2. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR000488; Death_domain. DR InterPro; IPR008063; Fas_rcpt. DR InterPro; IPR001368; TNFR/NGFR_Cys_rich_reg. DR InterPro; IPR033998; TNFRSF6_death. DR InterPro; IPR033999; TNFRSF6_N. DR PANTHER; PTHR46874; TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY MEMBER 6; 1. DR PANTHER; PTHR46874:SF1; TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY MEMBER 6; 1. DR Pfam; PF00531; Death; 1. DR Pfam; PF00020; TNFR_c6; 1. DR PRINTS; PR01680; TNFACTORR6. DR SMART; SM00005; DEATH; 1. DR SMART; SM00208; TNFR; 3. DR SUPFAM; SSF47986; DEATH domain; 1. DR SUPFAM; SSF57586; TNF receptor-like; 2. DR PROSITE; PS50017; DEATH_DOMAIN; 1. DR PROSITE; PS00652; TNFR_NGFR_1; 2. DR PROSITE; PS50050; TNFR_NGFR_2; 2. DR Genevisible; P25445; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Calmodulin-binding; KW Cell membrane; Direct protein sequencing; Disease variant; Disulfide bond; KW Glycoprotein; Lipoprotein; Membrane; Palmitate; Phosphoprotein; Receptor; KW Reference proteome; Repeat; Secreted; Signal; Transmembrane; KW Transmembrane helix. FT SIGNAL 1..25 FT /evidence="ECO:0000255" FT CHAIN 26..335 FT /note="Tumor necrosis factor receptor superfamily member 6" FT /id="PRO_0000034563" FT TOPO_DOM 26..173 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 174..190 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 191..335 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REPEAT 47..83 FT /note="TNFR-Cys 1" FT REPEAT 84..127 FT /note="TNFR-Cys 2" FT REPEAT 128..166 FT /note="TNFR-Cys 3" FT DOMAIN 230..314 FT /note="Death" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064" FT REGION 212..317 FT /note="Interaction with HIPK3" FT /evidence="ECO:0000250" FT REGION 230..254 FT /note="Interaction with CALM" FT /evidence="ECO:0000269|PubMed:24914971" FT MOD_RES 209 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 214 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P25446" FT MOD_RES 225 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT LIPID 199 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:25301068" FT CARBOHYD 28 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:22171320" FT CARBOHYD 118 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 136 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 250 FT /note="(Microbial infection) N-beta-linked (GlcNAc) FT arginine" FT /evidence="ECO:0000269|PubMed:30979585, FT ECO:0000305|PubMed:23955153" FT DISULFID 59..73 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT DISULFID 63..82 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT DISULFID 85..101 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT DISULFID 104..119 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT DISULFID 107..127 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT DISULFID 129..143 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT DISULFID 146..157 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT DISULFID 149..165 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00206" FT VAR_SEQ 66..103 FT /note="GERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRR -> DVNMESSRNA FT HSPATPSAKRKDPDLTWGGFVFFFCQFH (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7533181, FT ECO:0000303|PubMed:7575433" FT /id="VSP_006481" FT VAR_SEQ 66..86 FT /note="GERKARDCTVNGDEPDCVPCQ -> DVNMESSRNAHSPATPSAKRK (in FT isoform 3)" FT /evidence="ECO:0000303|PubMed:7533181, FT ECO:0000303|PubMed:7575433" FT /id="VSP_006483" FT VAR_SEQ 87..335 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:7533181, FT ECO:0000303|PubMed:7575433" FT /id="VSP_006484" FT VAR_SEQ 104..335 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7533181, FT ECO:0000303|PubMed:7575433" FT /id="VSP_006482" FT VAR_SEQ 112..149 FT /note="GLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKC -> DVNMESSRNA FT HSPATPSAKRKDPDLTWGGFVFFFCQFH (in isoform 4)" FT /evidence="ECO:0000303|PubMed:7575433, FT ECO:0000303|PubMed:8648105" FT /id="VSP_006485" FT VAR_SEQ 112..132 FT /note="GLEVEINCTRTQNTKCRCKPN -> DVNMESSRNAHSPATPSAKRK (in FT isoform 5)" FT /evidence="ECO:0000303|PubMed:8648105, ECO:0000303|Ref.8" FT /id="VSP_006487" FT VAR_SEQ 133..335 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:8648105, ECO:0000303|Ref.8" FT /id="VSP_006488" FT VAR_SEQ 150..335 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:7575433, FT ECO:0000303|PubMed:8648105" FT /id="VSP_006486" FT VAR_SEQ 169..189 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:7533181, FT ECO:0000303|PubMed:7575433" FT /id="VSP_006489" FT VAR_SEQ 218..220 FT /note="ETV -> MLT (in isoform 7)" FT /evidence="ECO:0000303|PubMed:8598453" FT /id="VSP_045235" FT VAR_SEQ 221..335 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000303|PubMed:8598453" FT /id="VSP_045236" FT VARIANT 16 FT /note="A -> T (in dbSNP:rs3218619)" FT /evidence="ECO:0000269|Ref.11" FT /id="VAR_020008" FT VARIANT 25 FT /note="A -> T (in non-Hodgkin lymphoma; somatic mutation; FT dbSNP:rs606231364)" FT /evidence="ECO:0000269|PubMed:9787134" FT /id="VAR_013416" FT VARIANT 28 FT /note="T -> A (in ALPS1A; associated with autoimmune FT hepatitis type 2)" FT /evidence="ECO:0000269|PubMed:9322534" FT /id="VAR_013417" FT VARIANT 82 FT /note="C -> R (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:9927496" FT /id="VAR_013418" FT VARIANT 118 FT /note="N -> S (in squamous cell carcinoma; burn-scar FT related; somatic mutation; dbSNP:rs121913083)" FT /evidence="ECO:0000269|PubMed:10620127" FT /id="VAR_018321" FT VARIANT 121 FT /note="R -> W (in ALPS1A; dbSNP:rs121913078)" FT /evidence="ECO:0000269|PubMed:9028321" FT /id="VAR_013419" FT VARIANT 122 FT /note="T -> I (in dbSNP:rs3218614)" FT /evidence="ECO:0000269|Ref.11" FT /id="VAR_020009" FT VARIANT 178 FT /note="C -> R (in squamous cell carcinoma; burn-scar FT related; somatic mutation; dbSNP:rs121913084)" FT /evidence="ECO:0000269|PubMed:10620127" FT /id="VAR_018322" FT VARIANT 180 FT /note="L -> F (in non-Hodgkin lymphoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:9787134" FT /id="VAR_013420" FT VARIANT 183 FT /note="P -> L (in non-Hodgkin lymphoma; somatic mutation; FT dbSNP:rs758835365)" FT /evidence="ECO:0000269|PubMed:9787134" FT /id="VAR_013421" FT VARIANT 184 FT /note="I -> V (in dbSNP:rs28362322)" FT /id="VAR_052347" FT VARIANT 198 FT /note="T -> I (in non-Hodgkin lymphoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:9787134" FT /id="VAR_013422" FT VARIANT 232 FT /note="Y -> C (in ALPS1A; no effect on interaction with FT FADD; dbSNP:rs121913079)" FT /evidence="ECO:0000269|PubMed:20935634, FT ECO:0000269|PubMed:9028321" FT /id="VAR_013423" FT VARIANT 241 FT /note="T -> K (in ALPS1A; dbSNP:rs201072885)" FT /evidence="ECO:0000269|PubMed:10090885" FT /id="VAR_013424" FT VARIANT 241 FT /note="T -> P (in ALPS1A; dbSNP:rs121913076)" FT /evidence="ECO:0000269|PubMed:11418480, FT ECO:0000269|PubMed:7540117" FT /id="VAR_013425" FT VARIANT 249 FT /note="V -> L (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:10515860" FT /id="VAR_065128" FT VARIANT 250 FT /note="R -> P (in ALPS1A; dbSNP:rs121913080)" FT /evidence="ECO:0000269|PubMed:10515860, FT ECO:0000269|PubMed:9927496" FT /id="VAR_013426" FT VARIANT 250 FT /note="R -> Q (in ALPS1A; no effect on interaction with FT FADD)" FT /evidence="ECO:0000269|PubMed:10090885, FT ECO:0000269|PubMed:20935634" FT /id="VAR_013427" FT VARIANT 253 FT /note="G -> D (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:10515860" FT /id="VAR_065129" FT VARIANT 253 FT /note="G -> S (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:10515860" FT /id="VAR_065130" FT VARIANT 255 FT /note="N -> D (in squamous cell carcinoma; burn-scar FT related; somatic mutation; dbSNP:rs121913082)" FT /evidence="ECO:0000269|PubMed:10620127" FT /id="VAR_018323" FT VARIANT 257 FT /note="A -> D (in ALPS1A; loss of interaction with FADD; FT dbSNP:rs1848674892)" FT /evidence="ECO:0000269|PubMed:20935634, FT ECO:0000269|PubMed:9028957" FT /id="VAR_013428" FT VARIANT 259 FT /note="I -> R (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:10515860" FT /id="VAR_065131" FT VARIANT 260 FT /note="D -> G (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:9927496" FT /id="VAR_013429" FT VARIANT 260 FT /note="D -> V (in ALPS1A; also found in non-Hodgkin FT lymphoma; somatic mutation; loss of interaction with FADD; FT dbSNP:rs28929498)" FT /evidence="ECO:0000269|PubMed:11418480, FT ECO:0000269|PubMed:20935634, ECO:0000269|PubMed:9787134, FT ECO:0000269|PubMed:9821419" FT /id="VAR_013431" FT VARIANT 260 FT /note="D -> Y (in ALPS1A; loss of interaction with FADD; FT dbSNP:rs121913086)" FT /evidence="ECO:0000269|PubMed:20935634, FT ECO:0000269|PubMed:8929361" FT /id="VAR_013430" FT VARIANT 262 FT /note="I -> S (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:17336828" FT /id="VAR_058910" FT VARIANT 264 FT /note="N -> K (in non-Hodgkin lymphoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:9787134" FT /id="VAR_013432" FT VARIANT 270 FT /note="T -> I (in ALPS1A; dbSNP:rs121913081)" FT /evidence="ECO:0000269|PubMed:11418480, FT ECO:0000269|PubMed:9927496" FT /id="VAR_013433" FT VARIANT 270 FT /note="T -> K (in ALPS1A; loss of interaction with FADD)" FT /evidence="ECO:0000269|PubMed:10515860, FT ECO:0000269|PubMed:20935634" FT /id="VAR_065132" FT VARIANT 272 FT /note="E -> G (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:10340403, FT ECO:0000269|PubMed:11418480" FT /id="VAR_013434" FT VARIANT 272 FT /note="E -> K (in ALPS1A; also found in non-Hodgkin FT lymphoma; somatic mutation; loss of interaction with FADD)" FT /evidence="ECO:0000269|PubMed:10515860, FT ECO:0000269|PubMed:20935634, ECO:0000269|PubMed:9787134" FT /id="VAR_013435" FT VARIANT 278 FT /note="L -> F (in non-Hodgkin lymphoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:9787134" FT /id="VAR_013436" FT VARIANT 299 FT /note="K -> N (in non-Hodgkin lymphoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:9787134" FT /id="VAR_013437" FT VARIANT 305 FT /note="T -> I (in dbSNP:rs3218611)" FT /evidence="ECO:0000269|Ref.11" FT /id="VAR_020942" FT VARIANT 310 FT /note="I -> S (in ALPS1A)" FT /evidence="ECO:0000269|PubMed:9028957" FT /id="VAR_013438" FT MUTAGEN 199 FT /note="C->V: Loss of palmitoylation." FT /evidence="ECO:0000269|PubMed:25301068" FT MUTAGEN 250 FT /note="R->A: Abolished GlcNAcylation by E.coli NleB1." FT /evidence="ECO:0000269|PubMed:30979585" FT MUTAGEN 250 FT /note="R->E: Strongly decreased interaction with FADD." FT /evidence="ECO:0000269|PubMed:20935634" FT MUTAGEN 261 FT /note="E->K: Loss of interaction with FADD." FT /evidence="ECO:0000269|PubMed:20935634" FT MUTAGEN 283 FT /note="Q->K: Loss of interaction with FADD." FT /evidence="ECO:0000269|PubMed:20935634" FT MUTAGEN 287 FT /note="K->D: Strongly decreased interaction with FADD." FT /evidence="ECO:0000269|PubMed:20935634" FT MUTAGEN 291 FT /note="Y->D: Decreased interaction with FADD." FT /evidence="ECO:0000269|PubMed:19118384" FT MUTAGEN 313 FT /note="I->D: Constitutive activation. Promotes apoptosis, FT both in the presence and in the absence of stimulation by a FT ligand." FT /evidence="ECO:0000269|PubMed:19118384" FT CONFLICT 224 FT /note="L -> F (in Ref. 11; AAR08906)" FT /evidence="ECO:0000305" FT CONFLICT 242 FT /note="L -> P (in Ref. 9; CAR92543)" FT /evidence="ECO:0000305" FT STRAND 67..71 FT /evidence="ECO:0007829|PDB:3TJE" FT STRAND 75..77 FT /evidence="ECO:0007829|PDB:3TJE" FT STRAND 82..84 FT /evidence="ECO:0007829|PDB:3TJE" FT TURN 87..89 FT /evidence="ECO:0007829|PDB:3TJE" FT HELIX 109..111 FT /evidence="ECO:0007829|PDB:3TJE" FT STRAND 113..117 FT /evidence="ECO:0007829|PDB:3TJE" FT STRAND 126..129 FT /evidence="ECO:0007829|PDB:3TJE" FT STRAND 137..139 FT /evidence="ECO:0007829|PDB:3TJE" FT HELIX 174..181 FT /evidence="ECO:0007829|PDB:2NA7" FT HELIX 184..193 FT /evidence="ECO:0007829|PDB:2NA7" FT HELIX 232..242 FT /evidence="ECO:0007829|PDB:3EWT" FT TURN 251..253 FT /evidence="ECO:0007829|PDB:1DDF" FT HELIX 256..265 FT /evidence="ECO:0007829|PDB:3EZQ" FT HELIX 270..282 FT /evidence="ECO:0007829|PDB:3EZQ" FT HELIX 287..319 FT /evidence="ECO:0007829|PDB:3EZQ" FT HELIX 327..334 FT /evidence="ECO:0007829|PDB:3EZQ" SQ SEQUENCE 335 AA; 37732 MW; 0139942535111410 CRC64; MLGIWTLLPL VLTSVARLSS KSVNAQVTDI NSKGLELRKT VTTVETQNLE GLHHDGQFCH KPCPPGERKA RDCTVNGDEP DCVPCQEGKE YTDKAHFSSK CRRCRLCDEG HGLEVEINCT RTQNTKCRCK PNFFCNSTVC EHCDPCTKCE HGIIKECTLT SNTKCKEEGS RSNLGWLCLL LLPIPLIVWV KRKEVQKTCR KHRKENQGSH ESPTLNPETV AINLSDVDLS KYITTIAGVM TLSQVKGFVR KNGVNEAKID EIKNDNVQDT AEQKVQLLRN WHQLHGKKEA YDTLIKDLKK ANLCTLAEKI QTIILKDITS DSENSNFRNE IQSLV //