Full text data of NEDD4
NEDD4
(KIAA0093, NEDD4-1)
[Confidence: low (only semi-automatic identification from reviews)]
E3 ubiquitin-protein ligase NEDD4; 6.3.2.- (Cell proliferation-inducing gene 53 protein; Neural precursor cell expressed developmentally down-regulated protein 4; NEDD-4)
E3 ubiquitin-protein ligase NEDD4; 6.3.2.- (Cell proliferation-inducing gene 53 protein; Neural precursor cell expressed developmentally down-regulated protein 4; NEDD-4)
UniProt
P46934
ID NEDD4_HUMAN Reviewed; 1319 AA.
AC P46934; A1KY35; A6ND72; A7MD29; B4E2R7; B7ZM59; B7ZM60; B9EGN5;
read moreAC D6RF89;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 4.
DT 22-JAN-2014, entry version 143.
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 MASS
RP SPECTROMETRY.
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 MASS
RP SPECTROMETRY.
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 PDBsum; 2KPZ; -.
DR PDBsum; 2KQ0; -.
DR PDBsum; 2M3O; -.
DR PDBsum; 2XBB; -.
DR PDBsum; 2XBF; -.
DR PDBsum; 3B7Y; -.
DR PDBsum; 4BBN; -.
DR PDBsum; 4BE8; -.
DR ProteinModelPortal; P46934; -.
DR SMR; P46934; 517-571, 611-642, 768-798, 841-875, 888-932, 938-1312.
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; 261260094; -.
DR PaxDb; P46934; -.
DR PRIDE; P46934; -.
DR DNASU; 4734; -.
DR Ensembl; ENST00000338963; ENSP00000345530; ENSG00000069869.
DR Ensembl; ENST00000435532; ENSP00000410613; ENSG00000069869.
DR Ensembl; ENST00000506154; ENSP00000422705; ENSG00000069869.
DR Ensembl; ENST00000508342; ENSP00000424827; ENSG00000069869.
DR GeneID; 4734; -.
DR KEGG; hsa:4734; -.
DR UCSC; uc002adj.3; human.
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 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: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: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; IMP: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: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:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
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 cascade; 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: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: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 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
//
ID NEDD4_HUMAN Reviewed; 1319 AA.
AC P46934; A1KY35; A6ND72; A7MD29; B4E2R7; B7ZM59; B7ZM60; B9EGN5;
read moreAC D6RF89;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 4.
DT 22-JAN-2014, entry version 143.
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 MASS
RP SPECTROMETRY.
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 MASS
RP SPECTROMETRY.
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 PDBsum; 2KPZ; -.
DR PDBsum; 2KQ0; -.
DR PDBsum; 2M3O; -.
DR PDBsum; 2XBB; -.
DR PDBsum; 2XBF; -.
DR PDBsum; 3B7Y; -.
DR PDBsum; 4BBN; -.
DR PDBsum; 4BE8; -.
DR ProteinModelPortal; P46934; -.
DR SMR; P46934; 517-571, 611-642, 768-798, 841-875, 888-932, 938-1312.
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; 261260094; -.
DR PaxDb; P46934; -.
DR PRIDE; P46934; -.
DR DNASU; 4734; -.
DR Ensembl; ENST00000338963; ENSP00000345530; ENSG00000069869.
DR Ensembl; ENST00000435532; ENSP00000410613; ENSG00000069869.
DR Ensembl; ENST00000506154; ENSP00000422705; ENSG00000069869.
DR Ensembl; ENST00000508342; ENSP00000424827; ENSG00000069869.
DR GeneID; 4734; -.
DR KEGG; hsa:4734; -.
DR UCSC; uc002adj.3; human.
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 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: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: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; IMP: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: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:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
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 cascade; 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: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: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 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
//
MIM
602278
*RECORD*
*FIELD* NO
602278
*FIELD* TI
*602278 NEURAL PRECURSOR CELL EXPRESSED, DEVELOPMENTALLY DOWNREGULATED 4;
NEDD4
;;KIAA0093
read more*FIELD* TX
CLONING
Kumar et al. (1992) identified Nedd4 as one of a group of mouse genes
that show developmentally regulated expression in mouse embryonic brain.
Kumar et al. (1997) showed that Nedd4 is expressed in various other
embryonic tissues and persists in most adult tissues. Using antibody
raised against a fusion protein, they demonstrated that the Nedd4
protein is localized to the cellular cytoplasm. Kumar et al. (1997)
reported that the human NEDD4 protein has 86% amino acid identity with
the mouse protein. It has homology to ubiquitin-protein ligases and
contains 4 protein-protein interaction (WW) domains and a
calcium/phospholipid binding domain.
By sequencing clones obtained from a size-fractionated human immature
myeloid cell line cDNA library, Nagase et al. (1995) cloned NEDD4, which
they designated KIAA0093. The deduced protein has a C2 domain and is
homologous with mouse Nedd4, with which it shares 84% identity. Northern
blot analysis detected NEDD4 in all tissues and cell lines examined,
except brain.
Imhof and McDonnell (1996) identified NEDD4, which they symbolized RPF1,
as the human homolog of yeast RSP5.
MAPPING
Using a human-rodent hybrid panel, Nagase et al. (1995) mapped the NEDD4
gene to chromosome 15. By homology and by fluorescence in situ
hybridization, Kumar et al. (1997) mapped the NEDD4 gene to chromosome
15q. By interspecific backcross analysis, they mapped the mouse Nedd4
gene to mouse chromosome 9.
GENE FUNCTION
Imhof and McDonnell (1996) found that both human NEDD4 and yeast RSP5
potentiate hormone-dependent activation of transcription by the human
progesterone and glucocorticoid receptors. They used mutant proteins to
show that neither the ubiquitin-protein ligase activity nor the WW
domains are absolutely required for the potentiation of the steroid
receptors.
In Xenopus oocyte studies, Abriel et al. (1999) demonstrated that
overexpression of wildtype NEDD4 together with epithelial sodium channel
(ENaC; see SCNN1A, 600228) inhibited activity of the channel;
catalytically inactive NEDD4 stimulated it. These effects were dependent
on the presence of C-terminal PY motifs of ENaC, and changes in channel
activity were due entirely to alterations in ENaC numbers at the plasma
membrane. Abriel et al. (1999) concluded that NEDD4 is a negative
regulator of ENaC and suggested that loss of NEDD4 binding sites in ENaC
observed in Liddle syndrome (177200 and see, e.g., 600760.0001) might
explain the increase in channel number at the cell surface, increased
sodium resorption by the distal nephron, and hence hypertension in that
disorder.
Using Far Western assays, Harvey et al. (2001) found that the WW domains
of NEDD4 bind with strong affinity to all 3 subunits of the epithelial
sodium channel (ENaC): SCNN1A (600228), SCNN1B (600760), and SCNN1G
(600761). They concluded that both NEDD4 and the related gene KIAA0439
(NEDD4L; 606384) may play a role in the regulation of ENaC function.
RNA polymerase II (RNAPII; see 180660) becomes ubiquitinated and
degraded in response to DNA damage. Anindya et al. (2007) identified
NEDD4 as an E3 ubiquitin ligase and found that it associated with and
ubiquitinated RNAPII in response to ultraviolet-induced DNA damage in
human cells. NEDD4-dependent RNAPII ubiquitination could be
reconstituted in vitro in the presence of purified UBA1 (UBE1; 314370)
and UBCH7 (UBE2L3; 603721) and epitope-tagged ubiquitin (see 191339).
Anindya et al. (2007) found that DNA lesions obstructed RNAPII
progression and that transcriptional arrest at these lesions triggered
NEDD4 recruitment and RNAPII ubiquitination.
PTEN (601728) is a dual specificity phosphatase involved in
downregulating cellular survival and growth responses. Wang et al.
(2007) showed that human NEDD4 interacted with and destabilized PTEN by
catalyzing its polyubiquitination.
Trotman et al. (2007) showed that NEDD4 could also positively regulate
PTEN through monoubiquitination of PTEN in human and mouse cells.
Monoubiquitinated PTEN was stabilized by its accumulation in cell
nuclei, and it retained its ability to antagonize AKT (AKT1; 164730) and
cause apoptosis.
Using in situ hybridization and immunohistochemical analysis,
Drinjakovic et al. (2010) found that Nedd4 mRNA and protein were
expressed throughout developing Xenopus brain and retina. In retina,
Nedd4 expression was enriched in the dendritic inner and outer plexiform
layers and at retinal ganglion cell growth cones. Morpholino-based
knockdown of Nedd4 in Xenopus oocytes or expression of a
dominant-negative Nedd4 mutant showed that Nedd4 was not required for
guidance of retinal ganglion cells to the tectum, but that it was
required for axon terminal branching and arborization at the tectum.
Nedd4 functioned at the growth cone by directing proteasome-mediated
degradation of Pten, which tended to oppose axon branching via
inhibition of PI3 kinase (see 171833) signaling. Immunoprecipitation
analysis revealed that Xenopus Nedd4 and Pten interacted directly in
transfected HEK293 cells. Knockdown of Pten along with Nedd4 in Xenopus
embryos restored retinal ganglion cell axon branching. Proteasomal
degradation of Pten in Xenopus growth cones appeared to involve netrin-1
(NTN1; 601614).
By affinity chromatography of rat brain synaptosome extracts, Kawabe et
al. (2010) identified Tnik (610005) among 15 proteins that interacted
with immobilized Nedd4. Rap2a (179540) coimmunoprecipitated with Nedd4
and Tnik, but only following protein crosslinking. In vitro
ubiquitination experiments revealed that Nedd4 monoubiquitinated Rap2a,
but not Tnik or any other Ras (HRAS; 190020)-related small GTPase
examined. Tnik was required for Nedd4 ubiquitination of Rap2a, and Rap2a
monoubiquitination blocked Rap2a/Tnik signaling.
Using unbiased phenotypic screens as an alternative to target-based
approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole
(NAB) that strongly and selectively protected diverse cell types from
alpha-synuclein toxicity. Three chemical genetic screens in wildtype
yeast cells established that NAB promoted endosomal transport events
dependent on the E3 ubiquitin ligase Rsp5. These same steps were
perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded
that NAB identifies a druggable node in the biology of alpha-synuclein
that can correct multiple aspects of its underlying pathology, including
dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle
trafficking.
Chung et al. (2013) exploited mutation correction of iPS cells and
conserved proteotoxic mechanisms from yeast to humans to discover and
reverse phenotypic responses to alpha-synuclein (163890), a key protein
involved in Parkinson disease (see 168600). Chung et al. (2013)
generated cortical neurons from iPS cells of patients harboring
alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of
developing PD dementia. Genetic modifiers from unbiased screens in a
yeast model of alpha-synuclein toxicity led to identification of early
pathogenic phenotypes in patient neurons, including nitrosative stress,
accumulation of endoplasmic reticulum-associated degradation substrates,
and ER stress. A small molecule, NAB2, identified in a yeast screen, and
NEDD4, the ubiquitin ligase that it affects, reversed pathologic
phenotypes in these neurons.
MOLECULAR GENETICS
For discussion of an association between variation in the NEDD4 gene and
keloid formation, see 148100.
ANIMAL MODEL
Kawabe et al. (2010) found that Nedd4 -/- mouse embryos died in late
gestation. At embryonic day 11.5, Nedd4 -/- embryos showed retarded
development, and almost half showed subcutaneous bleeding. Cortical
neurons cultured from Nedd4 -/- embryos were smaller than wildtype and
exhibited reduced dendrite extension and arborization. Targeted deletion
of Nedd4 to cerebrum resulted in mice with smaller cerebrum size and
reduced apical dendrite branching. Synapses of Nedd4 -/- neurons
provided altered electrophysiologic data that appeared to be due to a
reduced number of functionally normal synapses. Expression of
dominant-negative Rap2a or Tnik mutants rescued dendrite morphology in
Nedd4 -/- embryos. Kawabe et al. (2010) concluded that NEDD4 positively
regulates dendrite extension by blocking RAP2A/TNIK signaling.
*FIELD* RF
1. Abriel, H.; Loffing, J.; Rebhun, J. F.; Pratt, J. H.; Schild, L.;
Horisberger, J.-D.; Rotin, D.; Staub, O.: Defective regulation of
the epithelial Na(+) channel by Nedd4 in Liddle's syndrome. J. Clin.
Invest. 103: 667-673, 1999.
2. Anindya, R.; Aygun, O.; Svejstrup, J. Q.: Damage-induced ubiquitylation
of human RNA polymerase II by the ubiquitin ligase Nedd4, but not
Cockayne syndrome proteins or BRCA1. Molec. Cell 28: 386-397, 2007.
3. Chung, C. Y.; Khurana, V.; Auluck, P. K.; Tardiff, D. F.; Mazzulli,
J. R.; Soldner, F.; Baru, V.; Lou, Y.; Freyzon, Y.; Cho, S.; Mungenast,
A. E.; Muffat, J.; and 10 others: Identification and rescue of
alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342:
983-987, 2013.
4. Drinjakovic, J.; Jung, H.; Campbell, D. S.; Strochlic, L.; Dwivedy,
A.; Holt, C. E.: E3 ligase Nedd4 promotes axon branching by downregulating
PTEN. Neuron 65: 341-357, 2010.
5. Harvey, K. F.; Dinudom, A.; Cook, D. I.; Kumar, S.: The Nedd4-like
protein KIAA0439 is a potential regulator of the epithelial sodium
channel. J. Biol. Chem. 276: 8597-8601, 2001.
6. Imhof, M. O.; McDonnell, D. P.: Yeast RSP5 and its human homolog
hRPF1 potentiate hormone-dependent activation of transcription by
human progesterone and glucocorticoid receptors. Molec. Cell. Biol. 16:
2594-2605, 1996.
7. Kawabe, H.; Neeb, A.; Dimova, K.; Young, S. M., Jr.; Takeda, M.;
Katsurabayashi, S.; Mitkovski, M.; Malakhova, O. A.; Zhang, D.-E.;
Umikawa, M.; Kariya, K.; Goebbels, S.; Nave, K.-A.; Rosenmund, C.;
Jahn, O.; Rhee, J.; Brose, N.: Regulation of Rap2A by the ubiquitin
ligase Nedd4-1 controls neurite development. Neuron 65: 358-372,
2010.
8. Kumar, S.; Harvey, K. F.; Kinoshita, M.; Copeland, N. G.; Noda,
M.; Jenkins, N. A.: cDNA cloning, expression analysis, and mapping
of the mouse Nedd4 gene. Genomics 40: 435-443, 1997. Note: Erratum:
Genomics 44: 156 only, 1997.
9. Kumar, S.; Tomooka, Y.; Noda, M.: Identification of a set of genes
with developmentally down-regulated expression in the mouse brain. Biochem.
Biophys. Res. Commun. 185: 1155-1161, 1992.
10. Nagase, T; Miyajima, N; Tanaka, A.; Sazuka, T.; Seki, N.; Sato,
S.; Tabata, S.; Ishikawa, K.; Kawarabayashi, Y.; Kotani, H.; Nomura,
N.: Prediction of the coding sequences of unidentified human genes.
III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced
by analysis of cDNA clones from human cell line KG-1. DNA Res. 2:
37-43, 1995.
11. Tardiff, D. F.; Jui, N. T.; Khurana, V.; Tambe, M. A.; Thompson,
M. L.; Chung, C. Y.; Kamadurai, H. B.; Kim, H. T.; Lancaster, A. K.;
Caldwell, K. A.; Caldwell, G. A.; Rochet, J.-C.; Buchwald, S. L.;
Lindquist, S.: Yeast reveal a 'druggable' Rsp5/Nedd4 network that
ameliorates alpha-synuclein toxicity in neurons. Science 342: 979-983,
2013.
12. Trotman, L. C.; Wang, X.; Alimont, A.; Chen, Z.; Teruya-Feldstein,
J.; Yang, H.; Pavletich, N. P.; Carver, B. S.; Cordon-Cardo, C.; Erdjument-Bromage,
H.; Tempst, P.; Chi, S.-G.; Kim, H.-J.; Misteli, T.; Jiang, X.; Pandolfi,
P. P.: Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128:
141-156, 2007.
13. Wang, X.; Trotman, L. C.; Koppie, T.; Alimonti, A.; Chen, Z.;
Gao, Z.; Wang, J.; Erdjument-Bromage, H.; Tempst, P.; Cordon-Cardo,
C.; Pandolfi, P. P.; Jiang, X.: NEDD4-1 is a proto-oncogenic ubiquitin
ligase for PTEN. Cell 128: 129-139, 2007.
*FIELD* CN
Ada Hamosh - updated: 12/5/2013
Patricia A. Hartz - updated: 8/25/2011
Marla J. F. O'Neill - updated: 9/24/2010
Patricia A. Hartz - updated: 12/26/2007
Patricia A. Hartz - updated: 11/29/2007
Marla J. F. O'Neill - updated: 7/13/2005
Dawn Watkins-Chow - updated: 10/19/2001
*FIELD* CD
Rebekah S. Rasooly: 1/26/1998
*FIELD* ED
alopez: 12/06/2013
alopez: 12/5/2013
terry: 8/3/2012
alopez: 6/26/2012
terry: 6/26/2012
mgross: 10/13/2011
terry: 8/25/2011
wwang: 9/24/2010
terry: 9/24/2010
wwang: 6/11/2008
wwang: 12/26/2007
mgross: 11/29/2007
wwang: 7/19/2005
terry: 7/13/2005
carol: 10/19/2001
psherman: 10/21/1998
carol: 1/28/1998
carol: 1/27/1998
*RECORD*
*FIELD* NO
602278
*FIELD* TI
*602278 NEURAL PRECURSOR CELL EXPRESSED, DEVELOPMENTALLY DOWNREGULATED 4;
NEDD4
;;KIAA0093
read more*FIELD* TX
CLONING
Kumar et al. (1992) identified Nedd4 as one of a group of mouse genes
that show developmentally regulated expression in mouse embryonic brain.
Kumar et al. (1997) showed that Nedd4 is expressed in various other
embryonic tissues and persists in most adult tissues. Using antibody
raised against a fusion protein, they demonstrated that the Nedd4
protein is localized to the cellular cytoplasm. Kumar et al. (1997)
reported that the human NEDD4 protein has 86% amino acid identity with
the mouse protein. It has homology to ubiquitin-protein ligases and
contains 4 protein-protein interaction (WW) domains and a
calcium/phospholipid binding domain.
By sequencing clones obtained from a size-fractionated human immature
myeloid cell line cDNA library, Nagase et al. (1995) cloned NEDD4, which
they designated KIAA0093. The deduced protein has a C2 domain and is
homologous with mouse Nedd4, with which it shares 84% identity. Northern
blot analysis detected NEDD4 in all tissues and cell lines examined,
except brain.
Imhof and McDonnell (1996) identified NEDD4, which they symbolized RPF1,
as the human homolog of yeast RSP5.
MAPPING
Using a human-rodent hybrid panel, Nagase et al. (1995) mapped the NEDD4
gene to chromosome 15. By homology and by fluorescence in situ
hybridization, Kumar et al. (1997) mapped the NEDD4 gene to chromosome
15q. By interspecific backcross analysis, they mapped the mouse Nedd4
gene to mouse chromosome 9.
GENE FUNCTION
Imhof and McDonnell (1996) found that both human NEDD4 and yeast RSP5
potentiate hormone-dependent activation of transcription by the human
progesterone and glucocorticoid receptors. They used mutant proteins to
show that neither the ubiquitin-protein ligase activity nor the WW
domains are absolutely required for the potentiation of the steroid
receptors.
In Xenopus oocyte studies, Abriel et al. (1999) demonstrated that
overexpression of wildtype NEDD4 together with epithelial sodium channel
(ENaC; see SCNN1A, 600228) inhibited activity of the channel;
catalytically inactive NEDD4 stimulated it. These effects were dependent
on the presence of C-terminal PY motifs of ENaC, and changes in channel
activity were due entirely to alterations in ENaC numbers at the plasma
membrane. Abriel et al. (1999) concluded that NEDD4 is a negative
regulator of ENaC and suggested that loss of NEDD4 binding sites in ENaC
observed in Liddle syndrome (177200 and see, e.g., 600760.0001) might
explain the increase in channel number at the cell surface, increased
sodium resorption by the distal nephron, and hence hypertension in that
disorder.
Using Far Western assays, Harvey et al. (2001) found that the WW domains
of NEDD4 bind with strong affinity to all 3 subunits of the epithelial
sodium channel (ENaC): SCNN1A (600228), SCNN1B (600760), and SCNN1G
(600761). They concluded that both NEDD4 and the related gene KIAA0439
(NEDD4L; 606384) may play a role in the regulation of ENaC function.
RNA polymerase II (RNAPII; see 180660) becomes ubiquitinated and
degraded in response to DNA damage. Anindya et al. (2007) identified
NEDD4 as an E3 ubiquitin ligase and found that it associated with and
ubiquitinated RNAPII in response to ultraviolet-induced DNA damage in
human cells. NEDD4-dependent RNAPII ubiquitination could be
reconstituted in vitro in the presence of purified UBA1 (UBE1; 314370)
and UBCH7 (UBE2L3; 603721) and epitope-tagged ubiquitin (see 191339).
Anindya et al. (2007) found that DNA lesions obstructed RNAPII
progression and that transcriptional arrest at these lesions triggered
NEDD4 recruitment and RNAPII ubiquitination.
PTEN (601728) is a dual specificity phosphatase involved in
downregulating cellular survival and growth responses. Wang et al.
(2007) showed that human NEDD4 interacted with and destabilized PTEN by
catalyzing its polyubiquitination.
Trotman et al. (2007) showed that NEDD4 could also positively regulate
PTEN through monoubiquitination of PTEN in human and mouse cells.
Monoubiquitinated PTEN was stabilized by its accumulation in cell
nuclei, and it retained its ability to antagonize AKT (AKT1; 164730) and
cause apoptosis.
Using in situ hybridization and immunohistochemical analysis,
Drinjakovic et al. (2010) found that Nedd4 mRNA and protein were
expressed throughout developing Xenopus brain and retina. In retina,
Nedd4 expression was enriched in the dendritic inner and outer plexiform
layers and at retinal ganglion cell growth cones. Morpholino-based
knockdown of Nedd4 in Xenopus oocytes or expression of a
dominant-negative Nedd4 mutant showed that Nedd4 was not required for
guidance of retinal ganglion cells to the tectum, but that it was
required for axon terminal branching and arborization at the tectum.
Nedd4 functioned at the growth cone by directing proteasome-mediated
degradation of Pten, which tended to oppose axon branching via
inhibition of PI3 kinase (see 171833) signaling. Immunoprecipitation
analysis revealed that Xenopus Nedd4 and Pten interacted directly in
transfected HEK293 cells. Knockdown of Pten along with Nedd4 in Xenopus
embryos restored retinal ganglion cell axon branching. Proteasomal
degradation of Pten in Xenopus growth cones appeared to involve netrin-1
(NTN1; 601614).
By affinity chromatography of rat brain synaptosome extracts, Kawabe et
al. (2010) identified Tnik (610005) among 15 proteins that interacted
with immobilized Nedd4. Rap2a (179540) coimmunoprecipitated with Nedd4
and Tnik, but only following protein crosslinking. In vitro
ubiquitination experiments revealed that Nedd4 monoubiquitinated Rap2a,
but not Tnik or any other Ras (HRAS; 190020)-related small GTPase
examined. Tnik was required for Nedd4 ubiquitination of Rap2a, and Rap2a
monoubiquitination blocked Rap2a/Tnik signaling.
Using unbiased phenotypic screens as an alternative to target-based
approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole
(NAB) that strongly and selectively protected diverse cell types from
alpha-synuclein toxicity. Three chemical genetic screens in wildtype
yeast cells established that NAB promoted endosomal transport events
dependent on the E3 ubiquitin ligase Rsp5. These same steps were
perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded
that NAB identifies a druggable node in the biology of alpha-synuclein
that can correct multiple aspects of its underlying pathology, including
dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle
trafficking.
Chung et al. (2013) exploited mutation correction of iPS cells and
conserved proteotoxic mechanisms from yeast to humans to discover and
reverse phenotypic responses to alpha-synuclein (163890), a key protein
involved in Parkinson disease (see 168600). Chung et al. (2013)
generated cortical neurons from iPS cells of patients harboring
alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of
developing PD dementia. Genetic modifiers from unbiased screens in a
yeast model of alpha-synuclein toxicity led to identification of early
pathogenic phenotypes in patient neurons, including nitrosative stress,
accumulation of endoplasmic reticulum-associated degradation substrates,
and ER stress. A small molecule, NAB2, identified in a yeast screen, and
NEDD4, the ubiquitin ligase that it affects, reversed pathologic
phenotypes in these neurons.
MOLECULAR GENETICS
For discussion of an association between variation in the NEDD4 gene and
keloid formation, see 148100.
ANIMAL MODEL
Kawabe et al. (2010) found that Nedd4 -/- mouse embryos died in late
gestation. At embryonic day 11.5, Nedd4 -/- embryos showed retarded
development, and almost half showed subcutaneous bleeding. Cortical
neurons cultured from Nedd4 -/- embryos were smaller than wildtype and
exhibited reduced dendrite extension and arborization. Targeted deletion
of Nedd4 to cerebrum resulted in mice with smaller cerebrum size and
reduced apical dendrite branching. Synapses of Nedd4 -/- neurons
provided altered electrophysiologic data that appeared to be due to a
reduced number of functionally normal synapses. Expression of
dominant-negative Rap2a or Tnik mutants rescued dendrite morphology in
Nedd4 -/- embryos. Kawabe et al. (2010) concluded that NEDD4 positively
regulates dendrite extension by blocking RAP2A/TNIK signaling.
*FIELD* RF
1. Abriel, H.; Loffing, J.; Rebhun, J. F.; Pratt, J. H.; Schild, L.;
Horisberger, J.-D.; Rotin, D.; Staub, O.: Defective regulation of
the epithelial Na(+) channel by Nedd4 in Liddle's syndrome. J. Clin.
Invest. 103: 667-673, 1999.
2. Anindya, R.; Aygun, O.; Svejstrup, J. Q.: Damage-induced ubiquitylation
of human RNA polymerase II by the ubiquitin ligase Nedd4, but not
Cockayne syndrome proteins or BRCA1. Molec. Cell 28: 386-397, 2007.
3. Chung, C. Y.; Khurana, V.; Auluck, P. K.; Tardiff, D. F.; Mazzulli,
J. R.; Soldner, F.; Baru, V.; Lou, Y.; Freyzon, Y.; Cho, S.; Mungenast,
A. E.; Muffat, J.; and 10 others: Identification and rescue of
alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342:
983-987, 2013.
4. Drinjakovic, J.; Jung, H.; Campbell, D. S.; Strochlic, L.; Dwivedy,
A.; Holt, C. E.: E3 ligase Nedd4 promotes axon branching by downregulating
PTEN. Neuron 65: 341-357, 2010.
5. Harvey, K. F.; Dinudom, A.; Cook, D. I.; Kumar, S.: The Nedd4-like
protein KIAA0439 is a potential regulator of the epithelial sodium
channel. J. Biol. Chem. 276: 8597-8601, 2001.
6. Imhof, M. O.; McDonnell, D. P.: Yeast RSP5 and its human homolog
hRPF1 potentiate hormone-dependent activation of transcription by
human progesterone and glucocorticoid receptors. Molec. Cell. Biol. 16:
2594-2605, 1996.
7. Kawabe, H.; Neeb, A.; Dimova, K.; Young, S. M., Jr.; Takeda, M.;
Katsurabayashi, S.; Mitkovski, M.; Malakhova, O. A.; Zhang, D.-E.;
Umikawa, M.; Kariya, K.; Goebbels, S.; Nave, K.-A.; Rosenmund, C.;
Jahn, O.; Rhee, J.; Brose, N.: Regulation of Rap2A by the ubiquitin
ligase Nedd4-1 controls neurite development. Neuron 65: 358-372,
2010.
8. Kumar, S.; Harvey, K. F.; Kinoshita, M.; Copeland, N. G.; Noda,
M.; Jenkins, N. A.: cDNA cloning, expression analysis, and mapping
of the mouse Nedd4 gene. Genomics 40: 435-443, 1997. Note: Erratum:
Genomics 44: 156 only, 1997.
9. Kumar, S.; Tomooka, Y.; Noda, M.: Identification of a set of genes
with developmentally down-regulated expression in the mouse brain. Biochem.
Biophys. Res. Commun. 185: 1155-1161, 1992.
10. Nagase, T; Miyajima, N; Tanaka, A.; Sazuka, T.; Seki, N.; Sato,
S.; Tabata, S.; Ishikawa, K.; Kawarabayashi, Y.; Kotani, H.; Nomura,
N.: Prediction of the coding sequences of unidentified human genes.
III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced
by analysis of cDNA clones from human cell line KG-1. DNA Res. 2:
37-43, 1995.
11. Tardiff, D. F.; Jui, N. T.; Khurana, V.; Tambe, M. A.; Thompson,
M. L.; Chung, C. Y.; Kamadurai, H. B.; Kim, H. T.; Lancaster, A. K.;
Caldwell, K. A.; Caldwell, G. A.; Rochet, J.-C.; Buchwald, S. L.;
Lindquist, S.: Yeast reveal a 'druggable' Rsp5/Nedd4 network that
ameliorates alpha-synuclein toxicity in neurons. Science 342: 979-983,
2013.
12. Trotman, L. C.; Wang, X.; Alimont, A.; Chen, Z.; Teruya-Feldstein,
J.; Yang, H.; Pavletich, N. P.; Carver, B. S.; Cordon-Cardo, C.; Erdjument-Bromage,
H.; Tempst, P.; Chi, S.-G.; Kim, H.-J.; Misteli, T.; Jiang, X.; Pandolfi,
P. P.: Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128:
141-156, 2007.
13. Wang, X.; Trotman, L. C.; Koppie, T.; Alimonti, A.; Chen, Z.;
Gao, Z.; Wang, J.; Erdjument-Bromage, H.; Tempst, P.; Cordon-Cardo,
C.; Pandolfi, P. P.; Jiang, X.: NEDD4-1 is a proto-oncogenic ubiquitin
ligase for PTEN. Cell 128: 129-139, 2007.
*FIELD* CN
Ada Hamosh - updated: 12/5/2013
Patricia A. Hartz - updated: 8/25/2011
Marla J. F. O'Neill - updated: 9/24/2010
Patricia A. Hartz - updated: 12/26/2007
Patricia A. Hartz - updated: 11/29/2007
Marla J. F. O'Neill - updated: 7/13/2005
Dawn Watkins-Chow - updated: 10/19/2001
*FIELD* CD
Rebekah S. Rasooly: 1/26/1998
*FIELD* ED
alopez: 12/06/2013
alopez: 12/5/2013
terry: 8/3/2012
alopez: 6/26/2012
terry: 6/26/2012
mgross: 10/13/2011
terry: 8/25/2011
wwang: 9/24/2010
terry: 9/24/2010
wwang: 6/11/2008
wwang: 12/26/2007
mgross: 11/29/2007
wwang: 7/19/2005
terry: 7/13/2005
carol: 10/19/2001
psherman: 10/21/1998
carol: 1/28/1998
carol: 1/27/1998