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Database: UniProt
Entry: P46934
LinkDB: P46934
Original site: P46934 
ID   NEDD4_HUMAN             Reviewed;        1319 AA.
AC   P46934; A1KY35; A6ND72; A7MD29; B4E2R7; B7ZM59; B7ZM60; B9EGN5;
AC   D6RF89;
DT   01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT   30-NOV-2010, sequence version 4.
DT   16-APR-2014, entry version 146.
DE   RecName: Full=E3 ubiquitin-protein ligase NEDD4;
DE            EC=6.3.2.-;
DE   AltName: Full=Cell proliferation-inducing gene 53 protein;
DE   AltName: Full=Neural precursor cell expressed developmentally down-regulated protein 4;
DE            Short=NEDD-4;
GN   Name=NEDD4; Synonyms=KIAA0093, NEDD4-1; ORFNames=PIG53;
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 [GENOMIC DNA], IDENTIFICATION BY MASS
RP   SPECTROMETRY, FUNCTION, UBIQUITIN LIGASE ACTIVITY, AND INTERACTION
RP   WITH PTEN.
RX   PubMed=17218260; DOI=10.1016/j.cell.2006.11.039;
RA   Wang X., Trotman L.C., Koppie T., Alimonti A., Chen Z., Gao Z.,
RA   Wang J., Erdjument-Bromage H., Tempst P., Cordon-Cardo C.,
RA   Pandolfi P.P., Jiang X.;
RT   "NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN.";
RL   Cell 128:129-139(2007).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANTS
RP   GLN-679 AND SER-698.
RC   TISSUE=Bone marrow;
RX   PubMed=7788527; DOI=10.1093/dnares/2.1.37;
RA   Nagase T., Miyajima N., Tanaka A., Sazuka T., Seki N., Sato S.,
RA   Tabata S., Ishikawa K., Kawarabayasi Y., Kotani H., Nomura N.;
RT   "Prediction of the coding sequences of unidentified human genes. III.
RT   The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by
RT   analysis of cDNA clones from human cell line KG-1.";
RL   DNA Res. 2:37-43(1995).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANTS
RP   GLN-679 AND SER-698.
RC   TISSUE=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.,
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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANTS
RP   GLN-679 AND SER-698.
RA   Kim J.W.;
RT   "Identification of a human cell proliferation inducing gene.";
RL   Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC   TISSUE=Adipose tissue;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA   Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA   Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS GLN-679
RP   AND SER-698.
RX   PubMed=16572171; DOI=10.1038/nature04601;
RA   Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA   Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA   FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA   Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA   Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA   DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA   Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA   Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA   Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA   Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA   Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA   Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA   Nusbaum C.;
RT   "Analysis of the DNA sequence and duplication history of human
RT   chromosome 15.";
RL   Nature 440:671-675(2006).
RN   [7]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 4), AND
RP   VARIANTS GLN-679 AND SER-698.
RC   TISSUE=Brain, 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   [9]
RP   FUNCTION, AND INTERACTION WITH RAPGEF2.
RX   PubMed=11598133; DOI=10.1074/jbc.M108373200;
RA   Pham N., Rotin D.;
RT   "Nedd4 regulates ubiquitination and stability of the guanine-
RT   nucleotide exchange factor CNrasGEF.";
RL   J. Biol. Chem. 276:46995-47003(2001).
RN   [10]
RP   INTERACTION WITH HTLV-1 MATRIX PROTEIN P19.
RX   PubMed=14581525; DOI=10.1128/JVI.77.22.11882-11895.2003;
RA   Bouamr F., Melillo J.A., Wang M.Q., Nagashima K., de Los Santos M.,
RA   Rein A., Goff S.P.;
RT   "PPPYVEPTAP motif is the late domain of human T-cell leukemia virus
RT   type 1 Gag and mediates its functional interaction with cellular
RT   proteins Nedd4 and Tsg101.";
RL   J. Virol. 77:11882-11895(2003).
RN   [11]
RP   SUBCELLULAR LOCATION.
RX   PubMed=18819914; DOI=10.1074/jbc.M804120200;
RA   Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J.,
RA   Tan S.S.;
RT   "Nedd4 family-interacting protein 1 (Ndfip1) is required for the
RT   exosomal secretion of Nedd4 family proteins.";
RL   J. Biol. Chem. 283:32621-32627(2008).
RN   [12]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-747, AND IDENTIFICATION
RP   BY 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   [13]
RP   FUNCTION, AND INTERACTION WITH ISG15.
RX   PubMed=18305167; DOI=10.1073/pnas.0710629105;
RA   Okumura A., Pitha P.M., Harty R.N.;
RT   "ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner
RT   by blocking Nedd4 ligase activity.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:3974-3979(2008).
RN   [14]
RP   FUNCTION, AND INTERACTION WITH PTEN.
RX   PubMed=18562292; DOI=10.1073/pnas.0803233105;
RA   Fouladkou F., Landry T., Kawabe H., Neeb A., Lu C., Brose N.,
RA   Stambolic V., Rotin D.;
RT   "The ubiquitin ligase Nedd4-1 is dispensable for the regulation of
RT   PTEN stability and localization.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:8585-8590(2008).
RN   [15]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-747, AND IDENTIFICATION
RP   BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [16]
RP   FUNCTION, AND INTERACTION WITH TNK2.
RX   PubMed=20086093; DOI=10.1128/MCB.00013-10;
RA   Lin Q., Wang J., Childress C., Sudol M., Carey D.J., Yang W.;
RT   "HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates
RT   epidermal growth factor (EGF)-induced degradation of EGF receptor and
RT   ACK.";
RL   Mol. Cell. Biol. 30:1541-1554(2010).
RN   [17]
RP   INTERACTION WITH RAP2A AND TNIK.
RX   PubMed=20159449; DOI=10.1016/j.neuron.2010.01.007;
RA   Kawabe H., Neeb A., Dimova K., Young S.M. Jr., Takeda M.,
RA   Katsurabayashi S., Mitkovski M., Malakhova O.A., Zhang D.E.,
RA   Umikawa M., Kariya K., Goebbels S., Nave K.A., Rosenmund C., Jahn O.,
RA   Rhee J., Brose N.;
RT   "Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite
RT   development.";
RL   Neuron 65:358-372(2010).
RN   [18]
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.,
RA   Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full
RT   phosphorylation site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [19]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA   Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [20]
RP   INTERACTION WITH FGFR1, AND FUNCTION IN UBIQUITINATION OF FGFR1.
RX   PubMed=21765395; DOI=10.1038/emboj.2011.234;
RA   Persaud A., Alberts P., Hayes M., Guettler S., Clarke I., Sicheri F.,
RA   Dirks P., Ciruna B., Rotin D.;
RT   "Nedd4-1 binds and ubiquitylates activated FGFR1 to control its
RT   endocytosis and function.";
RL   EMBO J. 30:3259-3273(2011).
RN   [21]
RP   INTERACTION WITH OTUD7B.
RX   PubMed=22179831; DOI=10.1038/onc.2011.587;
RA   Pareja F., Ferraro D.A., Rubin C., Cohen-Dvashi H., Zhang F.,
RA   Aulmann S., Ben-Chetrit N., Pines G., Navon R., Crosetto N.,
RA   Kostler W., Carvalho S., Lavi S., Schmitt F., Dikic I., Yakhini Z.,
RA   Sinn P., Mills G.B., Yarden Y.;
RT   "Deubiquitination of EGFR by Cezanne-1 contributes to cancer
RT   progression.";
RL   Oncogene 31:4599-4608(2012).
RN   [22]
RP   X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1-152 (ISOFORM 4).
RG   Structural genomics consortium (SGC);
RT   "Crystal structure of the C2 domain of the E3 ubiquitin-protein ligase
RT   Nedd4.";
RL   Submitted (OCT-2007) to the PDB data bank.
RN   [23]
RP   STRUCTURE BY NMR OF 834-878.
RA   Iglesias-Bexiga M.;
RT   "Human NEDD4 3rd WW domain complex with ebola Zaire virus matrix
RT   protein VP40 derived peptide.";
RL   Submitted (OCT-2009) to the PDB data bank.
RN   [24]
RP   STRUCTURE BY NMR OF 834-878.
RA   Iglesias-Bexiga M., Luque I., Macias M.;
RT   "Human NEDD4 3rd WW domain complex with human T-cell leukemia virus
RT   GAP-Pro polyprotein derived peptide.";
RL   Submitted (OCT-2009) to the PDB data bank.
RN   [25]
RP   X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 938-1319 IN COMPLEX WITH
RP   UBIQUITIN, AND FUNCTION.
RX   PubMed=21399620; DOI=10.1038/embor.2011.21;
RA   Maspero E., Mari S., Valentini E., Musacchio A., Fish A.,
RA   Pasqualato S., Polo S.;
RT   "Structure of the HECT:ubiquitin complex and its role in ubiquitin
RT   chain elongation.";
RL   EMBO Rep. 12:342-349(2011).
RN   [26]
RP   VARIANT [LARGE SCALE ANALYSIS] HIS-627.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA   Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA   Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA   Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA   Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal
RT   cancers.";
RL   Science 314:268-274(2006).
CC   -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from
CC       an E2 ubiquitin-conjugating enzyme in the form of a thioester and
CC       then directly transfers the ubiquitin to targeted substrates.
CC       Involved in the pathway leading to the degradation of VEGFR-
CC       2/KDFR, independently of its ubiquitin-ligase activity.
CC       Monoubiquitinates IGF1R at multiple sites, thus leading to
CC       receptor internalization and degradation in lysosomes.
CC       Ubiquitinates FGFR1, leading to receptor internalization and
CC       degradation in lysosomes. Promotes ubiquitination of RAPGEF2.
CC       According to PubMed:18562292 the direct link between NEDD4 and
CC       PTEN regulation through polyubiquitination described in
CC       PubMed:17218260 is questionable. Involved in ubiquitination of
CC       ERBB4 intracellular domain E4ICD. Involved in the budding of many
CC       viruses. Part of a signaling complex composed of NEDD4, RAP2A and
CC       TNIK which regulates neuronal dendrite extension and arborization
CC       during development. Ubiquitinates TNK2 and regulates EGF-induced
CC       degradation of EGFR and TNF2. Involved in the ubiquitination of
CC       ebola virus VP40 protein and this ubiquitination plays a role in
CC       facilitating viral budding.
CC   -!- ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding (By
CC       similarity).
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC   -!- SUBUNIT: Interacts with UBE2D2. Binds SCNN1A, SCNN1B and SCNN1G.
CC       Binds, in vitro, through the WW2 and WW3 domains, to neural
CC       isoforms of ENAH that contain the PPSY motif. Interacts with
CC       BEAN1, LITAF, RNF11, WBP1, WBP2, TMEPAI and PRRG2 (By similarity).
CC       Interacts with NDFIP1 and NDFIP2; this interaction activates the
CC       E3 ubiquitin-protein ligase and may induce its recruitment to
CC       exosomes (By similarity). Interaction with PTEN is questionable
CC       according to PubMed:18562292. Interacts with viral proteins that
CC       contain a late- budding motif P-P-P-Y. This interaction is
CC       essential for viral particle budding of a lot of retroviruses,
CC       like HTLV-1 Gag and MLV Gag. Interacts (via C2 domain) with GRB10
CC       (via SH2 domain). Interacts with ERBB4 (By similarity). Interacts
CC       with TNIK; the interaction is direct, allows the TNIK-dependent
CC       recruitment of RAP2A and its ubiquitination by NEDD4. Interacts
CC       (via WW3 domain) with TNK2; EGF promotes this interaction.
CC       Interacts (via WW3 domain) with FGFR1 (via C-terminus). Interacts
CC       with OTUD7B. Interacts with ISG15. Interacts (via WW domain) with
CC       RAPGEF2; this interaction leads to ubiquitination and degradation
CC       via the proteasome pathway.
CC   -!- INTERACTION:
CC       P11362:FGFR1; NbExp=26; IntAct=EBI-726944, EBI-1028277;
CC       O95166:GABARAP; NbExp=6; IntAct=EBI-726944, EBI-712001;
CC       Q9H0R8:GABARAPL1; NbExp=6; IntAct=EBI-726944, EBI-746969;
CC       P60520:GABARAPL2; NbExp=6; IntAct=EBI-726944, EBI-720116;
CC       Q99732:LITAF; NbExp=4; IntAct=EBI-726944, EBI-725647;
CC       P60484:PTEN; NbExp=4; IntAct=EBI-726944, EBI-696162;
CC       Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-726944, EBI-396669;
CC       P51168:SCNN1B; NbExp=4; IntAct=EBI-726944, EBI-2547187;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Cell membrane;
CC       Peripheral membrane protein (By similarity). Note=Recruited to the
CC       plasma membrane by GRB10. Once complexed with GRB10 and IGF1R,
CC       follows IGF1R internalization, remaining associated with early
CC       endosomes. Uncouples from IGF1R-containing endosomes before the
CC       sorting of the receptor to the lysosomal compartment (By
CC       similarity). May be recruited to exosomes by NDFIP1.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=4;
CC       Name=1;
CC         IsoId=P46934-1; Sequence=Displayed;
CC         Note=No experimental confirmation available;
CC       Name=2;
CC         IsoId=P46934-2; Sequence=VSP_038259;
CC         Note=No experimental confirmation available;
CC       Name=3;
CC         IsoId=P46934-3; Sequence=VSP_038258;
CC         Note=No experimental confirmation available;
CC       Name=4;
CC         IsoId=P46934-4; Sequence=VSP_038256, VSP_038257;
CC   -!- DOMAIN: The WW domains mediate interaction with LITAF, RNF11,
CC       WBP1, WBP2, TMEPAI, NDFIP1 and PRRG2 (By similarity).
CC   -!- PTM: Auto-ubiquitinated (By similarity).
CC   -!- MISCELLANEOUS: A cysteine residue is required for ubiquitin-
CC       thioester formation.
CC   -!- SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein
CC       ligase) domain.
CC   -!- SIMILARITY: Contains 4 WW domains.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA07655.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR   EMBL; D42055; BAA07655.1; ALT_INIT; mRNA.
DR   EMBL; AK304394; BAG65229.1; -; mRNA.
DR   EMBL; AY550969; AAT52215.1; -; mRNA.
DR   EMBL; AL832063; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC009997; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC039057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471082; EAW77495.1; -; Genomic_DNA.
DR   EMBL; BC136605; AAI36606.1; -; mRNA.
DR   EMBL; BC144284; AAI44285.1; -; mRNA.
DR   EMBL; BC144285; AAI44286.1; -; mRNA.
DR   EMBL; BC152452; AAI52453.1; -; mRNA.
DR   EMBL; BC152562; AAI52563.1; -; mRNA.
DR   RefSeq; NP_001271267.1; NM_001284338.1.
DR   RefSeq; NP_001271268.1; NM_001284339.1.
DR   RefSeq; NP_001271269.1; NM_001284340.1.
DR   RefSeq; NP_006145.2; NM_006154.3.
DR   RefSeq; NP_940682.2; NM_198400.3.
DR   UniGene; Hs.1565; -.
DR   PDB; 2KPZ; NMR; -; A=834-878.
DR   PDB; 2KQ0; NMR; -; A=834-878.
DR   PDB; 2M3O; NMR; -; W=838-877.
DR   PDB; 2XBB; X-ray; 2.68 A; A/B=938-1319.
DR   PDB; 2XBF; X-ray; 2.50 A; A=938-1319.
DR   PDB; 3B7Y; X-ray; 1.80 A; A/B=517-571.
DR   PDB; 4BBN; X-ray; 2.51 A; A=938-1319.
DR   PDB; 4BE8; X-ray; 3.00 A; A=938-1319.
DR   PDB; 4N7F; X-ray; 1.10 A; A/B=841-874.
DR   PDB; 4N7H; X-ray; 1.70 A; A=840-872.
DR   PDBsum; 2KPZ; -.
DR   PDBsum; 2KQ0; -.
DR   PDBsum; 2M3O; -.
DR   PDBsum; 2XBB; -.
DR   PDBsum; 2XBF; -.
DR   PDBsum; 3B7Y; -.
DR   PDBsum; 4BBN; -.
DR   PDBsum; 4BE8; -.
DR   PDBsum; 4N7F; -.
DR   PDBsum; 4N7H; -.
DR   ProteinModelPortal; P46934; -.
DR   SMR; P46934; 517-571, 611-642, 768-798, 841-875, 888-932, 938-1312.
DR   BioGrid; 110811; 259.
DR   DIP; DIP-29815N; -.
DR   IntAct; P46934; 27.
DR   MINT; MINT-86457; -.
DR   STRING; 9606.ENSP00000345530; -.
DR   TCDB; 8.A.30.1.2; the nedd4-family interacting protein-2 (nedd4) family.
DR   PhosphoSite; P46934; -.
DR   DMDM; 313104311; -.
DR   PaxDb; P46934; -.
DR   PRIDE; P46934; -.
DR   DNASU; 4734; -.
DR   Ensembl; ENST00000338963; ENSP00000345530; ENSG00000069869. [P46934-3]
DR   Ensembl; ENST00000435532; ENSP00000410613; ENSG00000069869. [P46934-4]
DR   Ensembl; ENST00000506154; ENSP00000422705; ENSG00000069869. [P46934-2]
DR   Ensembl; ENST00000508342; ENSP00000424827; ENSG00000069869. [P46934-1]
DR   GeneID; 4734; -.
DR   KEGG; hsa:4734; -.
DR   UCSC; uc002adi.3; human. [P46934-3]
DR   UCSC; uc002adj.3; human. [P46934-1]
DR   UCSC; uc002adl.3; human. [P46934-4]
DR   UCSC; uc010ugj.2; human. [P46934-2]
DR   CTD; 4734; -.
DR   GeneCards; GC15M056119; -.
DR   HGNC; HGNC:7727; NEDD4.
DR   HPA; CAB001991; -.
DR   HPA; HPA039883; -.
DR   MIM; 602278; gene.
DR   neXtProt; NX_P46934; -.
DR   PharmGKB; PA31533; -.
DR   eggNOG; COG5021; -.
DR   HOVERGEN; HBG004134; -.
DR   KO; K10591; -.
DR   OMA; YRRILSV; -.
DR   OrthoDB; EOG7RFTGT; -.
DR   PhylomeDB; P46934; -.
DR   TreeFam; TF323658; -.
DR   Reactome; REACT_111102; Signal Transduction.
DR   Reactome; REACT_6900; Immune System.
DR   SignaLink; P46934; -.
DR   UniPathway; UPA00143; -.
DR   ChiTaRS; NEDD4; human.
DR   EvolutionaryTrace; P46934; -.
DR   GeneWiki; NEDD4; -.
DR   GenomeRNAi; 4734; -.
DR   NextBio; 18250; -.
DR   PRO; PR:P46934; -.
DR   Bgee; P46934; -.
DR   CleanEx; HS_NEDD4; -.
DR   Genevestigator; P46934; -.
DR   GO; GO:0016327; C:apicolateral plasma membrane; TAS:BHF-UCL.
DR   GO; GO:0005938; C:cell cortex; IDA:BHF-UCL.
DR   GO; GO:0000785; C:chromatin; IDA:BHF-UCL.
DR   GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR   GO; GO:0005829; C:cytosol; ISS:BHF-UCL.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IBA:RefGenome.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0000151; C:ubiquitin ligase complex; ISS:BHF-UCL.
DR   GO; GO:0031698; F:beta-2 adrenergic receptor binding; IDA:UniProtKB.
DR   GO; GO:0050815; F:phosphoserine binding; ISS:BHF-UCL.
DR   GO; GO:0050816; F:phosphothreonine binding; ISS:BHF-UCL.
DR   GO; GO:0070064; F:proline-rich region binding; IPI:UniProtKB.
DR   GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB.
DR   GO; GO:0070063; F:RNA polymerase binding; IPI:BHF-UCL.
DR   GO; GO:0019871; F:sodium channel inhibitor activity; IDA:BHF-UCL.
DR   GO; GO:0043130; F:ubiquitin binding; IDA:BHF-UCL.
DR   GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:BHF-UCL.
DR   GO; GO:0002250; P:adaptive immune response; IEA:Ensembl.
DR   GO; GO:0048514; P:blood vessel morphogenesis; IEA:Ensembl.
DR   GO; GO:0034644; P:cellular response to UV; IMP:BHF-UCL.
DR   GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR   GO; GO:0044111; P:development involved in symbiotic interaction; IMP:UniProtKB.
DR   GO; GO:0003197; P:endocardial cushion development; IEA:Ensembl.
DR   GO; GO:0042921; P:glucocorticoid receptor signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0007041; P:lysosomal transport; IDA:UniProtKB.
DR   GO; GO:0010766; P:negative regulation of sodium ion transport; IDA:UniProtKB.
DR   GO; GO:0010768; P:negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage; IMP:BHF-UCL.
DR   GO; GO:0030948; P:negative regulation of vascular endothelial growth factor receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0007528; P:neuromuscular junction development; IEA:Ensembl.
DR   GO; GO:0031175; P:neuron projection development; IEP:BHF-UCL.
DR   GO; GO:0003151; P:outflow tract morphogenesis; IEA:Ensembl.
DR   GO; GO:0046824; P:positive regulation of nucleocytoplasmic transport; IDA:BHF-UCL.
DR   GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IMP:BHF-UCL.
DR   GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI.
DR   GO; GO:0050847; P:progesterone receptor signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR   GO; GO:0006513; P:protein monoubiquitination; IEA:Ensembl.
DR   GO; GO:0006622; P:protein targeting to lysosome; IDA:UniProtKB.
DR   GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR   GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR   GO; GO:0032801; P:receptor catabolic process; IDA:UniProtKB.
DR   GO; GO:0031623; P:receptor internalization; IDA:UniProtKB.
DR   GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS: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:0050807; P:regulation of synapse organization; IEA:Ensembl.
DR   GO; GO:0051592; P:response to calcium ion; TAS:BHF-UCL.
DR   GO; GO:0042110; P:T cell activation; IEA:Ensembl.
DR   GO; GO:0019089; P:transmission of virus; IMP:BHF-UCL.
DR   GO; GO:0043162; P:ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway; IMP:BHF-UCL.
DR   Gene3D; 2.60.40.150; -; 1.
DR   InterPro; IPR000008; C2_dom.
DR   InterPro; IPR000569; HECT.
DR   InterPro; IPR001202; WW_dom.
DR   Pfam; PF00632; HECT; 1.
DR   Pfam; PF00397; WW; 4.
DR   SMART; SM00119; HECTc; 1.
DR   SMART; SM00456; WW; 4.
DR   SUPFAM; SSF51045; SSF51045; 4.
DR   SUPFAM; SSF56204; SSF56204; 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; Cell membrane; Complete proteome;
KW   Cytoplasm; Host-virus interaction; Ligase; Membrane; Neurogenesis;
KW   Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW   Ubl conjugation; Ubl conjugation pathway.
FT   CHAIN         1   1319       E3 ubiquitin-protein ligase NEDD4.
FT                                /FTId=PRO_0000120319.
FT   DOMAIN      610    643       WW 1.
FT   DOMAIN      767    800       WW 2.
FT   DOMAIN      840    873       WW 3.
FT   DOMAIN      892    925       WW 4.
FT   DOMAIN      984   1318       HECT.
FT   REGION      578    981       Mediates interaction with TNIK (By
FT                                similarity).
FT   COMPBIAS     68    215       Ser-rich.
FT   ACT_SITE   1286   1286       Glycyl thioester intermediate (By
FT                                similarity).
FT   MOD_RES     648    648       Phosphothreonine (By similarity).
FT   MOD_RES     670    670       Phosphoserine (By similarity).
FT   MOD_RES     747    747       Phosphoserine.
FT   VAR_SEQ       1    419       Missing (in isoform 4).
FT                                /FTId=VSP_038256.
FT   VAR_SEQ     420    516       SACLPSSQNVDCQININGELERPHSQMNKNHGILRRSISLG
FT                                GAYPNISCLSSLKHNCSKGGPSQLLIKFASGNEGKVDNLSR
FT                                DSNRDCTNELSNSCK -> MATCAVEVFGLLEDEENSRIVR
FT                                VRVIAGIGLAKKDILGASDPYVRVTLYDPMNGVLTSVQTKT
FT                                IKKSLNPKWNEEILFRVHPQQHRLLFEVFDENRL (in
FT                                isoform 4).
FT                                /FTId=VSP_038257.
FT   VAR_SEQ     517    588       Missing (in isoform 3).
FT                                /FTId=VSP_038258.
FT   VAR_SEQ     589    604       Missing (in isoform 2).
FT                                /FTId=VSP_038259.
FT   VARIANT      33     33       M -> V (in dbSNP:rs1912403).
FT                                /FTId=VAR_061985.
FT   VARIANT     627    627       Y -> H (in a breast cancer sample;
FT                                somatic mutation).
FT                                /FTId=VAR_036472.
FT   VARIANT     679    679       R -> Q (in dbSNP:rs2303580).
FT                                /FTId=VAR_047909.
FT   VARIANT     698    698       N -> S (in dbSNP:rs2303579).
FT                                /FTId=VAR_047910.
FT   CONFLICT     59     59       A -> T (in Ref. 5; AL832063).
FT   CONFLICT    407    407       N -> H (in Ref. 5; AL832063).
FT   CONFLICT    620    620       Q -> R (in Ref. 4; AAT52215 and 8;
FT                                AAI44285).
FT   CONFLICT    863    863       T -> I (in Ref. 8; AAI36606/AAI44285).
FT   CONFLICT   1199   1199       L -> P (in Ref. 3; BAG65229).
FT   CONFLICT   1268   1268       S -> L (in Ref. 5; AL832063).
FT   STRAND      520    528
FT   STRAND      546    549
FT   STRAND      561    569
FT   STRAND      846    850
FT   TURN        852    854
FT   STRAND      856    860
FT   TURN        861    864
FT   STRAND      865    869
FT   TURN        871    873
FT   HELIX       941    951
FT   STRAND      956    958
FT   STRAND      960    966
FT   HELIX       968    970
FT   HELIX       971    979
FT   HELIX       985    989
FT   STRAND      990    996
FT   HELIX      1004   1019
FT   HELIX      1022   1024
FT   STRAND     1025   1031
FT   STRAND     1037   1039
FT   HELIX      1043   1046
FT   HELIX      1050   1066
FT   STRAND     1071   1073
FT   HELIX      1077   1083
FT   HELIX      1090   1094
FT   HELIX      1098   1109
FT   HELIX      1113   1115
FT   STRAND     1118   1125
FT   STRAND     1128   1135
FT   HELIX      1138   1140
FT   TURN       1145   1147
FT   HELIX      1148   1160
FT   HELIX      1162   1164
FT   HELIX      1165   1175
FT   TURN       1176   1178
FT   HELIX      1181   1184
FT   HELIX      1189   1197
FT   HELIX      1204   1209
FT   STRAND     1211   1214
FT   STRAND     1219   1221
FT   HELIX      1222   1233
FT   HELIX      1236   1247
FT   STRAND     1248   1250
FT   HELIX      1257   1259
FT   STRAND     1263   1266
FT   STRAND     1269   1273
FT   STRAND     1282   1284
FT   HELIX      1285   1287
FT   STRAND     1289   1292
FT   HELIX      1298   1310
SQ   SEQUENCE   1319 AA;  149114 MW;  D56EBBC50A34F13B CRC64;
     MAQSLRLHFA ARRSNTYPLS ETSGDDLDSH VHMCFKRPTR ISTSNVVQMK LTPRQTALAP
     LIKENVQSQE RSSVPSSENV NKKSSCLQIS LQPTRYSGYL QSSNVLADSD DASFTCILKD
     GIYSSAVVDN ELNAVNDGHL VSSPAICSGS LSNFSTSDNG SYSSNGSDFG SCASITSGGS
     YTNSVISDSS SYTFPPSDDT FLGGNLPSDS TSNRSVPNRN TTPCEIFSRS TSTDPFVQDD
     LEHGLEIMKL PVSRNTKIPL KRYSSLVIFP RSPSTTRPTS PTSLCTLLSK GSYQTSHQFI
     ISPSEIAHNE DGTSAKGFLS TAVNGLRLSK TICTPGEVRD IRPLHRKGSL QKKIVLSNNT
     PRQTVCEKSS EGYSCVSVHF TQRKAATLDC ETTNGDCKPE MSEIKLNSDS EYIKLMHRTS
     ACLPSSQNVD CQININGELE RPHSQMNKNH GILRRSISLG GAYPNISCLS SLKHNCSKGG
     PSQLLIKFAS GNEGKVDNLS RDSNRDCTNE LSNSCKTRDD FLGQVDVPLY PLPTENPRLE
     RPYTFKDFVL HPRSHKSRVK GYLRLKMTYL PKTSGSEDDN AEQAEELEPG WVVLDQPDAA
     CHLQQQQEPS PLPPGWEERQ DILGRTYYVN HESRRTQWKR PTPQDNLTDA ENGNIQLQAQ
     RAFTTRRQIS EETESVDNRE SSENWEIIRE DEATMYSNQA FPSPPPSSNL DVPTHLAEEL
     NARLTIFGNS AVSQPASSSN HSSRRGSLQA YTFEEQPTLP VLLPTSSGLP PGWEEKQDER
     GRSYYVDHNS RTTTWTKPTV QATVETSQLT SSQSSAGPQS QASTSDSGQQ VTQPSEIEQG
     FLPKGWEVRH APNGRPFFID HNTKTTTWED PRLKIPAHLR GKTSLDTSND LGPLPPGWEE
     RTHTDGRIFY INHNIKRTQW EDPRLENVAI TGPAVPYSRD YKRKYEFFRR KLKKQNDIPN
     KFEMKLRRAT VLEDSYRRIM GVKRADFLKA RLWIEFDGEK GLDYGGVARE WFFLISKEMF
     NPYYGLFEYS ATDNYTLQIN PNSGLCNEDH LSYFKFIGRV AGMAVYHGKL LDGFFIRPFY
     KMMLHKPITL HDMESVDSEY YNSLRWILEN DPTELDLRFI IDEELFGQTH QHELKNGGSE
     IVVTNKNKKE YIYLVIQWRF VNRIQKQMAA FKEGFFELIP QDLIKIFDEN ELELLMCGLG
     DVDVNDWREH TKYKNGYSAN HQVIQWFWKA VLMMDSEKRI RLLQFVTGTS RVPMNGFAEL
     YGSNGPQSFT VEQWGTPEKL PRAHTCFNRL DLPPYESFEE LWDKLQMAIE NTQGFDGVD
//
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