ID   C8AP2_HUMAN             Reviewed;        1982 AA.
AC   Q9UKL3; A2RUB7; Q6PH76; Q7LCQ7; Q86YD9; Q9NUQ4; Q9NZV9; Q9P2N1;
AC   Q9Y563;
DT   20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   05-OCT-2010, entry version 63.
DE   RecName: Full=CASP8-associated protein 2;
DE   AltName: Full=FLICE-associated huge protein;
GN   Name=CASP8AP2; Synonyms=FLASH, KIAA1315, RIP25;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=T-cell;
RA   Kimura T., Imai Y., Yonehara S.;
RT   "Reply: searching for FLASH domains.";
RL   Nature 401:662-663(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Peripheral blood leukocyte;
RA   Yan M.D., Sun L.Y., Liu X.Y., Zheng Z.C.;
RT   "RIP25, a human homolog of Mus musculus FLASH, is involved in IL-2
RT   signaling.";
RL   Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   MEDLINE=20181126; PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA   Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. XVI.
RT   The complete sequences of 150 new cDNA clones from brain which code
RT   for large proteins in vitro.";
RL   DNA Res. 7:65-73(2000).
RN   [4]
RP   SEQUENCE REVISION.
RX   MEDLINE=22158633; PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA   Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT   "Construction of expression-ready cDNA clones for KIAA genes: manual
RT   curation of 330 KIAA cDNA clones.";
RL   DNA Res. 9:99-106(2002).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA   Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA   Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA   Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA   Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA   Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA   Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA   Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Skin, and Testis;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1478-1982.
RC   TISSUE=Placenta;
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.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   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.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., 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   [8]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 714-1982.
RX   MEDLINE=20005496; PubMed=10537104; DOI=10.1038/44317;
RA   Koonin E.V., Aravind L., Hofmann K., Tschopp J., Dixit V.M.;
RT   "Apoptosis. Searching for FLASH domains.";
RL   Nature 401:662-662(1999).
RN   [9]
RP   FUNCTION, INTERACTION WITH NCOA2, SUBCELLULAR LOCATION, AND INDUCTION.
RX   PubMed=12477726; DOI=10.1074/jbc.M209234200;
RA   Kino T., Chrousos G.P.;
RT   "Tumor necrosis factor alpha receptor- and Fas-associated FLASH
RT   inhibit transcriptional activity of the glucocorticoid receptor by
RT   binding to and interfering with its interaction with p160 type nuclear
RT   receptor coactivators.";
RL   J. Biol. Chem. 278:3023-3029(2003).
RN   [10]
RP   FUNCTION, AND INTERACTION WITH NCOA3.
RX   PubMed=15698540; DOI=10.1016/j.jsbmb.2004.09.003;
RA   Kino T., Ichijo T., Chrousos G.P.;
RT   "FLASH interacts with p160 coactivator subtypes and differentially
RT   suppresses transcriptional activity of steroid hormone receptors.";
RL   J. Steroid Biochem. Mol. Biol. 92:357-363(2004).
RN   [11]
RP   FUNCTION, INTERACTION WITH NPAT, AND SUBCELLULAR LOCATION.
RX   PubMed=17003125; DOI=10.1073/pnas.0604227103;
RA   Barcaroli D., Bongiorno-Borbone L., Terrinoni A., Hofmann T.G.,
RA   Rossi M., Knight R.A., Matera A.G., Melino G., De Laurenzi V.;
RT   "FLASH is required for histone transcription and S-phase
RT   progression.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:14808-14812(2006).
RN   [12]
RP   UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-92 AND LYS-93, AND MASS
RP   SPECTROMETRY.
RC   TISSUE=Mammary cancer;
RX   PubMed=17370265; DOI=10.1002/pmic.200600410;
RA   Denis N.J., Vasilescu J., Lambert J.-P., Smith J.C., Figeys D.;
RT   "Tryptic digestion of ubiquitin standards reveals an improved strategy
RT   for identifying ubiquitinated proteins by mass spectrometry.";
RL   Proteomics 7:868-874(2007).
RN   [13]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1278, AND MASS
RP   SPECTROMETRY.
RC   TISSUE=Embryonic kidney;
RX   PubMed=17525332; DOI=10.1126/science.1140321;
RA   Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA   Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA   Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT   "ATM and ATR substrate analysis reveals extensive protein networks
RT   responsive to DNA damage.";
RL   Science 316:1160-1166(2007).
RN   [14]
RP   INTERACTION WITH CASP8AP2.
RX   PubMed=19546234; DOI=10.1128/MCB.00289-09;
RA   Kiriyama M., Kobayashi Y., Saito M., Ishikawa F., Yonehara S.;
RT   "Interaction of FLASH with arsenite resistance protein 2 is involved
RT   in cell cycle progression at S phase.";
RL   Mol. Cell. Biol. 29:4729-4741(2009).
CC   -!- FUNCTION: Participates in TNF-alpha-induced blockade of
CC       glucocorticoid receptor (GR) transactivation at the nuclear
CC       receptor coactivator level, upstream and independently of NF-
CC       kappa-B. Suppresses both NCOA2- and NCOA3-induced enhancement of
CC       GR transactivation. Involved in TNF-alpha-induced activation of
CC       NF-kappa-B via a TRAF2-dependent pathway. Acts as a downstream
CC       mediator for CASP8-induced activation of NF-kappa-B. Required for
CC       the activation of CASP8 in FAS-mediated apoptosis. Required for
CC       histone gene transcription and progression through S phase.
CC   -!- SUBUNIT: Self-associates. Component of the death-inducing
CC       signaling complex (DISC) with CASP8, FADD and FAS. Interacts with
CC       NCOA2, NCOA3, SRRT/ARS2 and TRAF2. Interacts with NPAT.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Localizes to
CC       discrete nuclear foci.
CC   -!- INDUCTION: By TNF which induces strong nuclear localization.
CC   -!- PTM: Phosphorylated upon DNA damage, probably by ATM or ATR.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH56685.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 364;
CC       Sequence=BAA92067.1; Type=Erroneous initiation;
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DR   EMBL; AF154415; AAF03367.1; -; mRNA.
DR   EMBL; AF164678; AAD45537.2; -; mRNA.
DR   EMBL; AB037736; BAA92553.2; -; mRNA.
DR   EMBL; CH471051; EAW48540.1; -; Genomic_DNA.
DR   EMBL; CH471051; EAW48542.1; -; Genomic_DNA.
DR   EMBL; BC042577; AAH42577.1; -; mRNA.
DR   EMBL; BC056685; AAH56685.1; ALT_SEQ; mRNA.
DR   EMBL; BC132828; AAI32829.1; -; mRNA.
DR   EMBL; BC132830; AAI32831.1; -; mRNA.
DR   EMBL; AK002070; BAA92067.1; ALT_INIT; mRNA.
DR   EMBL; AF165161; AAD45157.1; -; mRNA.
DR   IPI; IPI00100798; -.
DR   RefSeq; NP_001131139.1; -.
DR   RefSeq; NP_001131140.1; -.
DR   RefSeq; NP_036247.1; -.
DR   UniGene; Hs.558218; -.
DR   ProteinModelPortal; Q9UKL3; -.
DR   SMR; Q9UKL3; 1914-1979.
DR   IntAct; Q9UKL3; 2.
DR   MINT; MINT-91616; -.
DR   STRING; Q9UKL3; -.
DR   PhosphoSite; Q9UKL3; -.
DR   PRIDE; Q9UKL3; -.
DR   Ensembl; ENST00000455594; ENSP00000391210; ENSG00000118412.
DR   GeneID; 9994; -.
DR   KEGG; hsa:9994; -.
DR   UCSC; uc003pnt.1; human.
DR   CTD; 9994; -.
DR   GeneCards; GC06P090539; -.
DR   H-InvDB; HIX0006071; -.
DR   HGNC; HGNC:1510; CASP8AP2.
DR   HPA; CAB010396; -.
DR   MIM; 606880; gene.
DR   PharmGKB; PA26093; -.
DR   HOVERGEN; HBG080371; -.
DR   InParanoid; Q9UKL3; -.
DR   NextBio; 37755; -.
DR   ArrayExpress; Q9UKL3; -.
DR   Bgee; Q9UKL3; -.
DR   CleanEx; HS_CASP8AP2; -.
DR   Genevestigator; Q9UKL3; -.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0008656; F:caspase activator activity; ISS:UniProtKB.
DR   GO; GO:0005123; F:death receptor binding; TAS:ProtInc.
DR   GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB.
DR   GO; GO:0006919; P:activation of caspase activity; ISS:UniProtKB.
DR   GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR   GO; GO:0008625; P:induction of apoptosis via death domain rec...; ISS:UniProtKB.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   GO; GO:0006350; P:transcription; IEA:UniProtKB-KW.
DR   InterPro; IPR009057; Homeodomain-like.
DR   SUPFAM; SSF46689; Homeodomain_like; 1.
PE   1: Evidence at protein level;
KW   Activator; Apoptosis; Cell cycle; Complete proteome; Cytoplasm;
KW   Isopeptide bond; Nucleus; Phosphoprotein; Polymorphism; Repressor;
KW   Transcription; Transcription regulation; Ubl conjugation.
FT   CHAIN         1   1982       CASP8-associated protein 2.
FT                                /FTId=PRO_0000076188.
FT   REGION     1709   1982       NCOA2-binding.
FT   MOD_RES    1278   1278       Phosphoserine.
FT   CROSSLNK     92     92       Glycyl lysine isopeptide (Lys-Gly)
FT                                (interchain with G-Cter in ubiquitin).
FT   CROSSLNK     93     93       Glycyl lysine isopeptide (Lys-Gly)
FT                                (interchain with G-Cter in ubiquitin).
FT   VARIANT    1659   1659       P -> S (in dbSNP:rs3799896).
FT                                /FTId=VAR_050700.
FT   CONFLICT    278    278       L -> S (in Ref. 2; AAD45537).
FT   CONFLICT    362    362       D -> E (in Ref. 6; AAH56685).
FT   CONFLICT    638    638       L -> P (in Ref. 2; AAD45537).
FT   CONFLICT    668    668       M -> T (in Ref. 2; AAD45537).
FT   CONFLICT    861    861       N -> S (in Ref. 2; AAD45537).
FT   CONFLICT   1713   1713       C -> Y (in Ref. 2; AAD45537).
FT   CONFLICT   1754   1754       Missing (in Ref. 3; BAA92553).
FT   CONFLICT   1832   1832       S -> P (in Ref. 7; BAA92067).
SQ   SEQUENCE   1982 AA;  222658 MW;  AF2B1A7798C19E39 CRC64;
     MAADDDNGDG TSLFDVFSAS PLKNNDEGSL DIYAGLDSAV SDSASKSCVP SRNCLDLYEE
     ILTEEGTAKE ATYNDLQVEY GKCQLQMKEL MKKFKEIQTQ NFSLINENQS LKKNISALIK
     TARVEINRKD EEISNLHQRL SEFPHFRNNH KTARTFDTVK TKDLKSRSPH LDDCSKTDHR
     AKSDVSKDVH HSTSLPNLEK EGKPHSDKRS TSHLPTSVEK HCTNGVWSRS HYQVGEGSSN
     EDSRRGRKDI RHSQFNRGTE RVRKDLSTGC GDGEPRILEA SQRLQGHPEK YGKGEPKTES
     KSSKFKSNSD SDYKGERINS SWEKETPGER SHSRVDSQSD KKLERQSERS QNINRKEVKS
     QDKEERKVDQ KPKSVVKDQD HWRRSERASL PHSKNEITFS HNSSKYHLEE RRGWEDCKRD
     KSVNSHSFQD GRCPSSLSNS RTHKNIDSKE VDAMHQWENT PLKAERHRTE DKRKREQESK
     EENRHIRNEK RVPTEHLQKT NKETKKTTTD LKKQNEPKTD KGEVLDNGVS EGADNKELAM
     KAESGPNETK NKDLKLSFMK KLNLTLSPAK KQPVSQDNQH KITDIPKSSG VCDSESSMQV
     KTVAYVPSIS EHILGEAAVS EHTMGETKST LLEPKVALLA VTEPRIGISE TNKEDENSLL
     VRSVDNTMHC EEPICGTETS FPSPMEIQQT ESLFPSTGMK QTINNGRAAA PVVMDVLQTD
     VSQNFGLELD TKRNDNSDYC GISEGMEMKV ALSTTVSETT ESILQPSIEE ADILPIMLSE
     DNNPKFEPSV IVTPLVESKS CHLEPCLPKE TLDSSLQQTE LMDHRMATGE TNSVYHDDDN
     SVLSIDLNHL RPIPEAISPL NSPVRPVAKV LRNESPPQVP VYNNSHKDVF LPNSAHSTSK
     SQSDLNKENQ KPIYKSDKCT EADTCKNSPL DELEEGEIRS DSETSKPQES FEKNSKRRVS
     ADVRKSKTIP RRGKSTVCLD KDSRKTHVRI HQTNNKWNKR PDKSSRSSKT EKKDKVMSTS
     SLEKIVPIIA VPSSEQEIMH MLRMIRKHVR KNYMKFKAKF SLIQFHRIIE SAILSFTSLI
     KHLNLHKISK SVTTLQKNLC DIIESKLKQV KKNGIVDRLF EQQLPDMKKK LWKFVDDQLD
     YLFAKLKKIL VCDSKSFGRD SDEGKLEKTS KQNAQYSNSQ KRSVDNSNRE LLKEKLSKSE
     DPVHYKSLVG CKKSEENYQD QNNSSINTVK HDIKKNFNIC FDNIKNSQSE ERSLEVHCPS
     TPKSEKNEGS SIEDAQTSQH ATLKPERSFE ILTEQQASSL TFNLVSDAQM GEIFKSLLQG
     SDLLDSSVNC TEKSEWELKT PEKQLLETLK CESIPACTTE ELVSGVASPC PKMISDDNWS
     LLSSEKGPSL SSGLSLPVHP DVLDESCMFE VSTNLPLSKD NVCSVEKSKP CVSSILLEDL
     AVSLTVPSPL KSDGHLSFLK PDMSSSSTPE EVISAHFSED ALLEEEDASE QDIHLALESD
     NSSSKSSCSS SWTSRSVAPG FQYHPNLPMH AVIMEKSNDH FIVKIRRATP STSSGLKQSM
     MPDELLTSLP RHGKEADEGP EKEYISCQNT VFKSVEELEN SNKNVDGSKS THEEQSSMIQ
     TQVPDIYEFL KDASDKMGHS DEVADECFKL HQVWETKVPE SIEELPSMEE ISHSVGEHLP
     NTYVDLTKDP VTETKNLGEF IEVTVLHIDQ LGCSGGNLNQ SAQILDNSLQ ADTVGAFIDL
     TQDASSEAKS EGNHPALAVE DLGCGVIQVD EDNCKEEKAQ VANRPLKCIV EETYIDLTTE
     SPSSCEVKKD ELKSEPGSNC DNSELPGTLH NSHKKRRNIS DLNHPHKKQR KETDLTNKEK
     TKKPTQDSCE NTEAHQKKAS KKKAPPVTKD PSSLKATPGI KDSSAALATS TSLSAKNVIK
     KKGEIIILWT RNDDREILLE CQKRGPSFKT FAYLAAKLDK NPNQVSERFQ QLMKLFEKSK
     CR
//