ID WWP2_HUMAN Reviewed; 870 AA. AC O00308; A6NEP1; B2R706; B4DTL5; F5H213; H3BRF3; I3RSG8; Q6ZTQ5; Q96CZ2; AC Q9BWN6; DT 20-JUN-2003, integrated into UniProtKB/Swiss-Prot. DT 20-JUN-2003, sequence version 2. DT 02-DEC-2020, entry version 199. DE RecName: Full=NEDD4-like E3 ubiquitin-protein ligase WWP2; DE EC=2.3.2.26 {ECO:0000269|PubMed:19274063, ECO:0000269|PubMed:19651900}; DE AltName: Full=Atrophin-1-interacting protein 2; DE Short=AIP2; DE AltName: Full=HECT-type E3 ubiquitin transferase WWP2; DE AltName: Full=WW domain-containing protein 2; GN Name=WWP2; 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 INTERACTION WITH WBP1; WBP2; RP SCNN1A; SCNN1B AND SCNN1G. RC TISSUE=Bone marrow, and Brain; RX PubMed=9169421; DOI=10.1074/jbc.272.23.14611; RA Pirozzi G., McConnell S.J., Uveges A.J., Carter J.M., Sparks A.B., RA Kay B.K., Fowlkes D.M.; RT "Identification of novel human WW domain-containing proteins by cloning of RT ligand targets."; RL J. Biol. Chem. 272:14611-14616(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Jiang G.Y., Yang J.H., Liu S.F.; RT "Bioinformatic analysis of E3 ligase WWP2 in 14 different vertebrates."; RL Submitted (SEP-2011) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3). RC TISSUE=Placenta, Testis, and Trachea; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [5] 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4). RC TISSUE=Brain, Ovary, and Placenta; 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 [7] RP INTERACTION WITH ATN1, AND TISSUE SPECIFICITY. RX PubMed=9647693; DOI=10.1006/mcne.1998.0677; RA Wood J.D., Yuan J., Margolis R.L., Colomer V., Duan K., Kushi J., RA Kaminsky Z., Kleiderlein J.J. Jr., Sharp A.H., Ross C.A.; RT "Atrophin-1, the DRPLA gene product, interacts with two families of WW RT domain-containing proteins."; RL Mol. Cell. Neurosci. 11:149-160(1998). RN [8] RP INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G. RX PubMed=12167593; DOI=10.1152/ajprenal.00080.2002; RA McDonald F.J., Western A.H., McNeil J.D., Thomas B.C., Olson D.R., RA Snyder P.M.; RT "Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial RT Na(+) channel."; RL Am. J. Physiol. 283:F431-F436(2002). RN [9] RP INTERACTION WITH ADENOVIRUS TYPE 2 PIII (MICROBIAL INFECTION). RX PubMed=12450395; DOI=10.1021/bi020125b; RA Galinier R., Gout E., Lortat-Jacob H., Wood J., Chroboczek J.; RT "Adenovirus protein involved in virus internalization recruits ubiquitin- RT protein ligases."; RL Biochemistry 41:14299-14305(2002). RN [10] RP INTERACTION WITH NDFIP1. RX PubMed=11748237; DOI=10.1074/jbc.m110443200; RA Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S.; RT "N4WBP5, a potential target for ubiquitination by the Nedd4 family of RT proteins, is a novel Golgi-associated protein."; RL J. Biol. Chem. 277:9307-9317(2002). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [12] RP AUTOINHIBITION BY C2 DOMAIN. RX PubMed=17719543; DOI=10.1016/j.cell.2007.06.050; RA Wiesner S., Ogunjimi A.A., Wang H.R., Rotin D., Sicheri F., Wrana J.L., RA Forman-Kay J.D.; RT "Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 RT domain."; RL Cell 130:651-662(2007). RN [13] RP FUNCTION IN UBIQUITINATION OF POU5F1, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, DEVELOPMENTAL STAGE, INTERACTION WITH POU5F1, AND MUTAGENESIS RP OF CYS-838. RX PubMed=19274063; DOI=10.1038/cr.2009.31; RA Xu H., Wang W., Li C., Yu H., Yang A., Wang B., Jin Y.; RT "WWP2 promotes degradation of transcription factor OCT4 in human embryonic RT stem cells."; RL Cell Res. 19:561-573(2009). RN [14] RP ACTIVATION BY NDFIP1 AND NDFIP2, AND AUTOUBIQUITINATION. RX PubMed=19343052; DOI=10.1038/embor.2009.30; RA Mund T., Pelham H.R.; RT "Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP RT proteins."; RL EMBO Rep. 10:501-507(2009). RN [15] RP FUNCTION IN UBIQUITINATION OF EGR2, AND INTERACTION WITH EGR2. RX PubMed=19651900; DOI=10.1128/mcb.00407-09; RA Chen A., Gao B., Zhang J., McEwen T., Ye S.Q., Zhang D., Fang D.; RT "The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell RT death by catalyzing EGR2 ubiquitination."; RL Mol. Cell. Biol. 29:5348-5356(2009). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH ERBB4, AND RP SUBCELLULAR LOCATION. RX PubMed=20858735; DOI=10.1158/1541-7786.mcr-10-0042; RA Gilmore-Hebert M., Ramabhadran R., Stern D.F.; RT "Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage RT response pathways."; RL Mol. Cancer Res. 8:1388-1398(2010). RN [17] 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 [18] RP UBIQUITINATION, AND MUTAGENESIS OF LYS-498 AND HIS-500. RX PubMed=21572392; DOI=10.1038/emboj.2011.155; RA Cui Y., He S., Xing C., Lu K., Wang J., Xing G., Meng A., Jia S., He F., RA Zhang L.; RT "SCF(FBXL15) regulates BMP signalling by directing the degradation of HECT- RT type ubiquitin ligase Smurf1."; RL EMBO J. 30:2675-2689(2011). RN [19] RP INTERACTION WITH ARRDC1; ARRDC2 AND ARRDC3, AND DOMAIN. RX PubMed=21191027; DOI=10.1128/jvi.02045-10; RA Rauch S., Martin-Serrano J.; RT "Multiple interactions between the ESCRT machinery and arrestin-related RT proteins: implications for PPXY-dependent budding."; RL J. Virol. 85:3546-3556(2011). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [21] RP INTERACTION WITH ARRDC4. RX PubMed=23236378; DOI=10.1371/journal.pone.0050557; RA Shea F.F., Rowell J.L., Li Y., Chang T.H., Alvarez C.E.; RT "Mammalian alpha arrestins link activated seven transmembrane receptors to RT Nedd4 family e3 ubiquitin ligases and interact with beta arrestins."; RL PLoS ONE 7:E50557-E50557(2012). RN [22] RP INTERACTION WITH ARRDC1, AND DOMAIN. RX PubMed=22315426; DOI=10.1073/pnas.1200448109; RA Nabhan J.F., Hu R., Oh R.S., Cohen S.N., Lu Q.; RT "Formation and release of arrestin domain-containing protein 1-mediated RT microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 RT protein."; RL Proc. Natl. Acad. Sci. U.S.A. 109:4146-4151(2012). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.51 ANGSTROMS) OF 492-865. RX PubMed=26457515; DOI=10.1107/s2053230x1501554x; RA Gong W., Zhang X., Zhang W., Li J., Li Z.; RT "Structure of the HECT domain of human WWP2."; RL Acta Crystallogr. F 71:1251-1257(2015). CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an CC E2 ubiquitin-conjugating enzyme in the form of a thioester and then CC directly transfers the ubiquitin to targeted substrates. CC Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it CC to proteasomal degradation; in embryonic stem cells (ESCs) the CC ubiquitination is proposed to regulate POU5F1 protein level. CC Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T- CC cells the ubiquitination inhibits activation-induced cell death. CC Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of CC NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal CC degradation. {ECO:0000269|PubMed:19274063, CC ECO:0000269|PubMed:19651900}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.26; Evidence={ECO:0000269|PubMed:19274063, CC ECO:0000269|PubMed:19651900}; CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding. CC {ECO:0000269|PubMed:19343052}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:19274063, ECO:0000269|PubMed:19651900}. CC -!- SUBUNIT: Interacts with POU5F1, RBP1, EGR2 and SLC11A2 (By similarity). CC Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts CC with ERBB4, NDFIP1 AND NDFIP2. Interacts with ARRDC4 (PubMed:23236378). CC Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates CC ARRDC1 (PubMed:22315426, PubMed:21191027). Interacts (via WW domains) CC with ARRDC2 and ARRDC3 (PubMed:21191027). CC {ECO:0000250|UniProtKB:Q9DBH0, ECO:0000269|PubMed:11748237, CC ECO:0000269|PubMed:12167593, ECO:0000269|PubMed:19274063, CC ECO:0000269|PubMed:19651900, ECO:0000269|PubMed:20858735, CC ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:22315426, CC ECO:0000269|PubMed:23236378, ECO:0000269|PubMed:9169421, CC ECO:0000269|PubMed:9647693}. CC -!- SUBUNIT: (Microbial infection) Interacts with adenovirus type 2 PIII. CC {ECO:0000269|PubMed:12450395}. CC -!- INTERACTION: CC O00308; P78563: ADARB1; NbExp=5; IntAct=EBI-743923, EBI-2967304; CC O00308; Q8N8A2: ANKRD44; NbExp=5; IntAct=EBI-743923, EBI-1245329; CC O00308; Q8N5I2: ARRDC1; NbExp=5; IntAct=EBI-743923, EBI-2339564; CC O00308; Q96B67: ARRDC3; NbExp=5; IntAct=EBI-743923, EBI-2875665; CC O00308; Q8N7B9-2: EFCAB3; NbExp=3; IntAct=EBI-743923, EBI-11958551; CC O00308; Q15884: FAM189A2; NbExp=3; IntAct=EBI-743923, EBI-8636612; CC O00308; Q7L5A3: FAM214B; NbExp=3; IntAct=EBI-743923, EBI-745689; CC O00308; Q96D16: FBXL18; NbExp=3; IntAct=EBI-743923, EBI-744419; CC O00308; Q8TAE8: GADD45GIP1; NbExp=3; IntAct=EBI-743923, EBI-372506; CC O00308; Q8NHY3: GAS2L2; NbExp=3; IntAct=EBI-743923, EBI-7960826; CC O00308; Q86UU5: GGN; NbExp=3; IntAct=EBI-743923, EBI-10259069; CC O00308; Q9BUJ2: HNRNPUL1; NbExp=9; IntAct=EBI-743923, EBI-1018153; CC O00308; Q8IZ03: IFIT2; NbExp=3; IntAct=EBI-743923, EBI-746217; CC O00308; Q3B8N2: LGALS9B; NbExp=5; IntAct=EBI-743923, EBI-10240775; CC O00308; Q71SY5: MED25; NbExp=3; IntAct=EBI-743923, EBI-394558; CC O00308; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-743923, EBI-11022007; CC O00308; Q9NR12: PDLIM7; NbExp=6; IntAct=EBI-743923, EBI-350517; CC O00308; Q01860: POU5F1; NbExp=4; IntAct=EBI-743923, EBI-475687; CC O00308; P54646: PRKAA2; NbExp=3; IntAct=EBI-743923, EBI-1383852; CC O00308; Q9Y272: RASD1; NbExp=3; IntAct=EBI-743923, EBI-740818; CC O00308; Q9BVN2: RUSC1; NbExp=3; IntAct=EBI-743923, EBI-6257312; CC O00308; Q15599: SLC9A3R2; NbExp=3; IntAct=EBI-743923, EBI-1149760; CC O00308; Q15796: SMAD2; NbExp=4; IntAct=EBI-743923, EBI-1040141; CC O00308; P84022: SMAD3; NbExp=7; IntAct=EBI-743923, EBI-347161; CC O00308; O15105: SMAD7; NbExp=5; IntAct=EBI-743923, EBI-3861591; CC O00308; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-743923, EBI-358489; CC O00308; Q99954: SMR3A; NbExp=3; IntAct=EBI-743923, EBI-12067698; CC O00308; P14678-2: SNRPB; NbExp=3; IntAct=EBI-743923, EBI-372475; CC O00308; P09234: SNRPC; NbExp=3; IntAct=EBI-743923, EBI-766589; CC O00308; Q5TAL4: SNRPC; NbExp=3; IntAct=EBI-743923, EBI-10246938; CC O00308; Q9BUZ4: TRAF4; NbExp=7; IntAct=EBI-743923, EBI-3650647; CC O00308; Q96LR5: UBE2E2; NbExp=3; IntAct=EBI-743923, EBI-2129763; CC O00308; Q969T4: UBE2E3; NbExp=3; IntAct=EBI-743923, EBI-348496; CC O00308; Q9HAC8: UBTD1; NbExp=3; IntAct=EBI-743923, EBI-745871; CC O00308; A5D8V6: VPS37C; NbExp=6; IntAct=EBI-743923, EBI-2559305; CC O00308; P61964: WDR5; NbExp=3; IntAct=EBI-743923, EBI-540834; CC O00308; O43516: WIPF1; NbExp=4; IntAct=EBI-743923, EBI-346356; CC O00308; A0A0S2Z5X4: ZNF688; NbExp=3; IntAct=EBI-743923, EBI-16429014; CC O00308; Q8WU02; NbExp=3; IntAct=EBI-743923, EBI-747182; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19274063, CC ECO:0000269|PubMed:20858735}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=O00308-1; Sequence=Displayed; CC Name=2; CC IsoId=O00308-2; Sequence=VSP_044706; CC Name=3; CC IsoId=O00308-3; Sequence=VSP_046461; CC Name=4; CC IsoId=O00308-4; Sequence=VSP_054711; CC -!- TISSUE SPECIFICITY: Detected in heart, throughout the brain, placenta, CC lung, liver, muscle, kidney and pancreas. Also detected in spleen and CC peripheral blood leukocytes. {ECO:0000269|PubMed:19274063, CC ECO:0000269|PubMed:9647693}. CC -!- DEVELOPMENTAL STAGE: Highly expressed in undifferentiated embryonic CC stem cells and expression is reduced after embryoid body (EB) CC formation. Not detectable at day 13 of EB formation; low levels are CC again detected at day 18 of EB formation. CC {ECO:0000269|PubMed:19274063}. CC -!- DOMAIN: The C2 domain is involved in autoinhibition of the catalytic CC activity by interacting with the HECT domain. {ECO:0000250}. CC -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing CC proteins. {ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:22315426}. CC -!- PTM: Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex, CC leading to its degradation by the proteasome. CC {ECO:0000269|PubMed:19343052, ECO:0000269|PubMed:21572392}. CC -!- MISCELLANEOUS: A cysteine residue is required for ubiquitin-thioester CC formation. CC -!- SEQUENCE CAUTION: CC Sequence=BAC86528.1; Type=Frameshift; Evidence={ECO:0000305}; 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; U96114; AAC51325.1; -; mRNA. DR EMBL; JN712744; AFK29253.1; -; mRNA. DR EMBL; AK126332; BAC86528.1; ALT_FRAME; mRNA. DR EMBL; AK300266; BAG62027.1; -; mRNA. DR EMBL; AK312792; BAG35653.1; -; mRNA. DR EMBL; AC026468; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC092115; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471092; EAW83287.1; -; Genomic_DNA. DR EMBL; BC000108; AAH00108.1; -; mRNA. DR EMBL; BC013645; AAH13645.1; -; mRNA. DR EMBL; BC064531; AAH64531.1; -; mRNA. DR CCDS; CCDS10885.1; -. [O00308-1] DR CCDS; CCDS58475.1; -. [O00308-4] DR CCDS; CCDS58476.1; -. [O00308-2] DR CCDS; CCDS58477.1; -. [O00308-3] DR RefSeq; NP_001257382.1; NM_001270453.1. [O00308-2] DR RefSeq; NP_001257383.1; NM_001270454.1. [O00308-1] DR RefSeq; NP_001257384.1; NM_001270455.1. [O00308-4] DR RefSeq; NP_008945.2; NM_007014.4. [O00308-1] DR RefSeq; NP_955456.1; NM_199424.2. [O00308-3] DR RefSeq; XP_011521125.1; XM_011522823.2. [O00308-1] DR RefSeq; XP_011521127.1; XM_011522825.1. [O00308-1] DR RefSeq; XP_011521128.1; XM_011522826.2. [O00308-2] DR RefSeq; XP_016878368.1; XM_017022879.1. [O00308-1] DR RefSeq; XP_016878369.1; XM_017022880.1. [O00308-1] DR RefSeq; XP_016878370.1; XM_017022881.1. [O00308-1] DR PDB; 4Y07; X-ray; 2.51 A; A=492-865. DR PDB; 5TJ7; X-ray; 2.60 A; A/B/C/D=334-865. DR PDB; 5TJ8; X-ray; 2.30 A; A=334-865. DR PDB; 5TJQ; X-ray; 2.75 A; A=334-865. DR PDB; 6J1Z; X-ray; 2.70 A; A=330-406, A=480-870. DR PDB; 6RSS; NMR; -; A=438-480. DR PDBsum; 4Y07; -. DR PDBsum; 5TJ7; -. DR PDBsum; 5TJ8; -. DR PDBsum; 5TJQ; -. DR PDBsum; 6J1Z; -. DR PDBsum; 6RSS; -. DR SMR; O00308; -. DR BioGRID; 116244; 770. DR IntAct; O00308; 92. DR MINT; O00308; -. DR STRING; 9606.ENSP00000352069; -. DR MoonDB; O00308; Predicted. DR iPTMnet; O00308; -. DR PhosphoSitePlus; O00308; -. DR BioMuta; WWP2; -. DR EPD; O00308; -. DR jPOST; O00308; -. DR MassIVE; O00308; -. DR MaxQB; O00308; -. DR PaxDb; O00308; -. DR PeptideAtlas; O00308; -. DR PRIDE; O00308; -. DR ProteomicsDB; 25823; -. DR ProteomicsDB; 42051; -. DR ProteomicsDB; 47835; -. [O00308-1] DR Antibodypedia; 29892; 190 antibodies. DR DNASU; 11060; -. DR Ensembl; ENST00000356003; ENSP00000348283; ENSG00000198373. [O00308-2] DR Ensembl; ENST00000359154; ENSP00000352069; ENSG00000198373. [O00308-1] DR Ensembl; ENST00000568684; ENSP00000456216; ENSG00000198373. [O00308-3] DR Ensembl; ENST00000569174; ENSP00000455311; ENSG00000198373. [O00308-4] DR GeneID; 11060; -. DR KEGG; hsa:11060; -. DR UCSC; uc002exv.3; human. [O00308-1] DR CTD; 11060; -. DR DisGeNET; 11060; -. DR EuPathDB; HostDB:ENSG00000198373.12; -. DR GeneCards; WWP2; -. DR HGNC; HGNC:16804; WWP2. DR HPA; ENSG00000198373; Low tissue specificity. DR MIM; 602308; gene. DR neXtProt; NX_O00308; -. DR OpenTargets; ENSG00000198373; -. DR PharmGKB; PA134946925; -. DR eggNOG; KOG0940; Eukaryota. DR GeneTree; ENSGT00940000160726; -. DR HOGENOM; CLU_828900_0_0_1; -. DR InParanoid; O00308; -. DR OMA; TYWEKPT; -. DR PhylomeDB; O00308; -. DR TreeFam; TF323658; -. DR BRENDA; 2.3.2.B9; 2681. DR PathwayCommons; O00308; -. DR Reactome; R-HSA-8948751; Regulation of PTEN stability and activity. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR SignaLink; O00308; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 11060; 3 hits in 848 CRISPR screens. DR ChiTaRS; WWP2; human. DR GeneWiki; WWP2; -. DR GenomeRNAi; 11060; -. DR Pharos; O00308; Tbio. DR PRO; PR:O00308; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; O00308; protein. DR Bgee; ENSG00000198373; Expressed in tibia and 232 other tissues. DR ExpressionAtlas; O00308; baseline and differential. DR Genevisible; O00308; HS. DR GO; GO:0005737; C:cytoplasm; ISS:BHF-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0000151; C:ubiquitin ligase complex; TAS:ProtInc. DR GO; GO:0001085; F:RNA polymerase II transcription factor binding; IPI:BHF-UCL. DR GO; GO:0008134; F:transcription factor binding; IPI:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:0006464; P:cellular protein modification process; TAS:ProtInc. DR GO; GO:0006858; P:extracellular transport; IMP:UniProtKB. DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISS:BHF-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:UniProtKB. DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; TAS:Reactome. DR GO; GO:0051224; P:negative regulation of protein transport; IMP:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:BHF-UCL. DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:BHF-UCL. DR GO; GO:0032410; P:negative regulation of transporter activity; IDA:UniProtKB. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IBA:GO_Central. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB. DR GO; GO:0051865; P:protein autoubiquitination; IDA:FlyBase. DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB. DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0034765; P:regulation of ion transmembrane transport; IDA:BHF-UCL. DR GO; GO:0042391; P:regulation of membrane potential; IDA:BHF-UCL. DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; IDA:BHF-UCL. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central. DR GO; GO:0046718; P:viral entry into host cell; TAS:UniProtKB. DR CDD; cd00078; HECTc; 1. DR CDD; cd00201; WW; 4. DR Gene3D; 2.60.40.150; -; 1. DR InterPro; IPR000008; C2_dom. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR024928; E3_ub_ligase_SMURF1. DR InterPro; IPR000569; HECT_dom. DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase. DR InterPro; IPR001202; WW_dom. DR InterPro; IPR036020; WW_dom_sf. DR Pfam; PF00632; HECT; 1. DR Pfam; PF00397; WW; 4. DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1. DR SMART; SM00239; C2; 1. DR SMART; SM00119; HECTc; 1. DR SMART; SM00456; WW; 4. DR SUPFAM; SSF51045; SSF51045; 4. DR SUPFAM; SSF56204; SSF56204; 1. DR PROSITE; PS50004; C2; 1. DR PROSITE; PS50237; HECT; 1. DR PROSITE; PS01159; WW_DOMAIN_1; 4. DR PROSITE; PS50020; WW_DOMAIN_2; 4. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Host-virus interaction; Nucleus; KW Phosphoprotein; Reference proteome; Repeat; Transferase; Ubl conjugation; KW Ubl conjugation pathway. FT CHAIN 1..870 FT /note="NEDD4-like E3 ubiquitin-protein ligase WWP2" FT /id="PRO_0000120338" FT DOMAIN 1..117 FT /note="C2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT DOMAIN 300..333 FT /note="WW 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 330..363 FT /note="WW 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 405..437 FT /note="WW 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 444..477 FT /note="WW 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 536..870 FT /note="HECT" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104" FT ACT_SITE 838 FT /note="Glycyl thioester intermediate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104" FT MOD_RES 211 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:16964243, FT ECO:0000244|PubMed:21406692, ECO:0000244|PubMed:23186163" FT VAR_SEQ 1..439 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_046461" FT VAR_SEQ 1..116 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044706" FT VAR_SEQ 336..870 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_054711" FT MUTAGEN 498 FT /note="K->R: Does not affect FBXL15-mediated FT ubiquitination." FT /evidence="ECO:0000269|PubMed:21572392" FT MUTAGEN 500 FT /note="H->K: Does not affect FBXL15-mediated FT ubiquitination." FT /evidence="ECO:0000269|PubMed:21572392" FT MUTAGEN 838 FT /note="C->A: Abolishes ubiquitination of POU5F1." FT /evidence="ECO:0000269|PubMed:19274063" FT CONFLICT 136 FT /note="E -> K (in Ref. 1; AAC51325)" FT /evidence="ECO:0000305" FT CONFLICT 390 FT /note="F -> L (in Ref. 3; BAG62027)" FT /evidence="ECO:0000305" FT CONFLICT 394..395 FT /note="SS -> FW (in Ref. 1; AAC51325)" FT /evidence="ECO:0000305" FT CONFLICT 545 FT /note="Y -> F (in Ref. 3; BAC86528)" FT /evidence="ECO:0000305" FT STRAND 336..340 FT /evidence="ECO:0000244|PDB:6J1Z" FT STRAND 348..350 FT /evidence="ECO:0000244|PDB:5TJ7" FT TURN 351..354 FT /evidence="ECO:0000244|PDB:5TJ7" FT STRAND 355..359 FT /evidence="ECO:0000244|PDB:5TJ7" FT HELIX 363..386 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 443..445 FT /evidence="ECO:0000244|PDB:6RSS" FT STRAND 450..454 FT /evidence="ECO:0000244|PDB:6RSS" FT STRAND 460..464 FT /evidence="ECO:0000244|PDB:6RSS" FT TURN 465..468 FT /evidence="ECO:0000244|PDB:6RSS" FT STRAND 469..471 FT /evidence="ECO:0000244|PDB:6RSS" FT HELIX 477..479 FT /evidence="ECO:0000244|PDB:6RSS" FT HELIX 495..509 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 512..519 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 521..523 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 524..533 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 537..541 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 542..548 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 556..570 FT /evidence="ECO:0000244|PDB:5TJ8" FT TURN 574..577 FT /evidence="ECO:0000244|PDB:4Y07" FT STRAND 579..586 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 588..591 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 595..597 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 601..617 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 628..634 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 641..647 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 649..657 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 674..676 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 683..685 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 691..693 FT /evidence="ECO:0000244|PDB:5TJ8" FT TURN 698..700 FT /evidence="ECO:0000244|PDB:5TJQ" FT HELIX 702..712 FT /evidence="ECO:0000244|PDB:5TJ8" FT TURN 713..716 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 718..731 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 734..737 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 742..750 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 757..762 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 765..768 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 774..785 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 788..799 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 809..811 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 817..819 FT /evidence="ECO:0000244|PDB:5TJ7" FT STRAND 822..824 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 829..831 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 834..836 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 837..839 FT /evidence="ECO:0000244|PDB:5TJ8" FT STRAND 841..843 FT /evidence="ECO:0000244|PDB:5TJ8" FT HELIX 850..862 FT /evidence="ECO:0000244|PDB:5TJ8" SQ SEQUENCE 870 AA; 98912 MW; FCCD75CBA61F2204 CRC64; MASASSSRAG VALPFEKSQL TLKVVSAKPK VHNRQPRINS YVEVAVDGLP SETKKTGKRI GSSELLWNEI IILNVTAQSH LDLKVWSCHT LRNELLGTAS VNLSNVLKNN GGKMENMQLT LNLQTENKGS VVSGGELTIF LDGPTVDLGN VPNGSALTDG SQLPSRDSSG TAVAPENRHQ PPSTNCFGGR SRTHRHSGAS ARTTPATGEQ SPGARSRHRQ PVKNSGHSGL ANGTVNDEPT TATDPEEPSV VGVTSPPAAP LSVTPNPNTT SLPAPATPAE GEEPSTSGTQ QLPAAAQAPD ALPAGWEQRE LPNGRVYYVD HNTKTTTWER PLPPGWEKRT DPRGRFYYVD HNTRTTTWQR PTAEYVRNYE QWQSQRNQLQ GAMQHFSQRF LYQSSSASTD HDPLGPLPPG WEKRQDNGRV YYVNHNTRTT QWEDPRTQGM IQEPALPPGW EMKYTSEGVR YFVDHNTRTT TFKDPRPGFE SGTKQGSPGA YDRSFRWKYH QFRFLCHSNA LPSHVKISVS RQTLFEDSFQ QIMNMKPYDL RRRLYIIMRG EEGLDYGGIA REWFFLLSHE VLNPMYCLFE YAGKNNYCLQ INPASSINPD HLTYFRFIGR FIAMALYHGK FIDTGFTLPF YKRMLNKRPT LKDLESIDPE FYNSIVWIKE NNLEECGLEL YFIQDMEILG KVTTHELKEG GESIRVTEEN KEEYIMLLTD WRFTRGVEEQ TKAFLDGFNE VAPLEWLRYF DEKELELMLC GMQEIDMSDW QKSTIYRHYT KNSKQIQWFW QVVKEMDNEK RIRLLQFVTG TCRLPVGGFA ELIGSNGPQK FCIDKVGKET WLPRSHTCFN RLDLPPYKSY EQLREKLLYA IEETEGFGQE //