Full text data of NEDD4L
NEDD4L
(KIAA0439, NEDL3)
[Confidence: low (only semi-automatic identification from reviews)]
E3 ubiquitin-protein ligase NEDD4-like; 6.3.2.- (NEDD4.2; Nedd4-2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
E3 ubiquitin-protein ligase NEDD4-like; 6.3.2.- (NEDD4.2; Nedd4-2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q96PU5
ID NED4L_HUMAN Reviewed; 975 AA.
AC Q96PU5; O43165; Q3LSM7; Q7Z5F1; Q7Z5F2; Q7Z5N3; Q8N5A7; Q8WUU9;
read moreAC Q9BW58; Q9H2W4; Q9NT88;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 2.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=E3 ubiquitin-protein ligase NEDD4-like;
DE EC=6.3.2.-;
DE AltName: Full=NEDD4.2;
DE AltName: Full=Nedd4-2;
GN Name=NEDD4L; Synonyms=KIAA0439, NEDL3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND ALTERNATIVE SPLICING.
RX PubMed=11840194; DOI=10.1038/sj.ejhg.5200747;
RA Chen H., Ross C.A., Wang N., Huo Y., MacKinnon D.F., Potash J.B.,
RA Simpson S.G., McMahon F.J., DePaulo J.R. Jr., McInnis M.G.;
RT "NEDD4L on human chromosome 18q21 has multiple forms of transcripts
RT and is a homologue of the mouse Nedd4-2 gene.";
RL Eur. J. Hum. Genet. 9:922-930(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INTERACTION WITH SCNN1A;
RP SCNN1B AND SCNN1G.
RC TISSUE=Kidney;
RX PubMed=14556380; DOI=10.1016/S1631-0691(03)00154-9;
RA Malbert-Colas L., Nicolas G., Galand C., Lecomte M.-C., Dhermy D.;
RT "Identification of new partners of the epithelial sodium channel alpha
RT subunit.";
RL C. R. Biol. 326:615-624(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4; 6 AND 7), TISSUE SPECIFICITY,
RP AND INDUCTION.
RC TISSUE=Prostate;
RX PubMed=14615060; DOI=10.1016/j.mce.2003.08.009;
RA Qi H., Grenier J., Fournier A., Labrie C.;
RT "Androgens differentially regulate the expression of NEDD4L
RT transcripts in LNCaP human prostate cancer cells.";
RL Mol. Cell. Endocrinol. 210:51-62(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RA Okamoto Y., Miyazaki K., Sakamoto M., Kato C., Nakagawara A.;
RT "Homo sapiens NEDD4-like ubiquitin ligase 3.";
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8).
RA Qi H., Labrie C.;
RT "NEDD4L transcripts expressed in human prostate cells.";
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D.,
RA Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S.,
RA Bloom T., Bugalter B., Butler J., Cook A., DeCaprio D., Engels R.,
RA Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T.,
RA Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E.,
RA Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H.,
RA O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
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] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 101-975 (ISOFORM 5).
RC TISSUE=Skin, and Uterus;
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 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8).
RC TISSUE=Brain;
RX PubMed=9455477; DOI=10.1093/dnares/4.5.307;
RA Ishikawa K., Nagase T., Nakajima D., Seki N., Ohira M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VIII.
RT 78 new cDNA clones from brain which code for large proteins in
RT vitro.";
RL DNA Res. 4:307-313(1997).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 52-975 (ISOFORM 3).
RC TISSUE=Testis;
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 [11]
RP PROTEIN SEQUENCE OF 448-462, INTERACTION WITH YWHAB; YWHAG; YWHAE;
RP YWHAQ AND YWHAH, PHOSPHORYLATION AT SER-448, MUTAGENESIS OF SER-448,
RP AND MASS SPECTROMETRY.
RX PubMed=15677482; DOI=10.1074/jbc.M412884200;
RA Ichimura T., Yamamura H., Sasamoto K., Tominaga Y., Taoka M.,
RA Kakiuchi K., Shinkawa T., Takahashi N., Shimada S., Isobe T.;
RT "14-3-3 proteins modulate the expression of epithelial Na+ channels by
RT phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase.";
RL J. Biol. Chem. 280:13187-13194(2005).
RN [12]
RP INTERACTION WITH EPSTEIN-BARR VIRUS LMP2A.
RX PubMed=11046148; DOI=10.1128/MCB.20.22.8526-8535.2000;
RA Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G.,
RA Ingham R., Ernberg I., Pawson T.;
RT "Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3
RT protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases.";
RL Mol. Cell. Biol. 20:8526-8535(2000).
RN [13]
RP INTERACTION WITH SGK1 AND SCNN1A, AND PHOSPHORYLATION.
RX PubMed=11696533; DOI=10.1074/jbc.C100623200;
RA Snyder P.M., Olson D.R., Thomas B.C.;
RT "Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated
RT inhibition of the epithelial Na+ channel.";
RL J. Biol. Chem. 277:5-8(2002).
RN [14]
RP INTERACTION WITH NDFIP1.
RX PubMed=11748237; DOI=10.1074/jbc.M110443200;
RA Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S.;
RT "N4WBP5, a potential target for ubiquitination by the Nedd4 family of
RT proteins, is a novel Golgi-associated protein.";
RL J. Biol. Chem. 277:9307-9317(2002).
RN [15]
RP FUNCTION.
RX PubMed=12911626;
RA Boehmer C., Henke G., Schniepp R., Palmada M., Rothstein J.D.,
RA Broeer S., Lang F.;
RT "Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase
RT Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms
RT SGK1/3 and protein kinase B.";
RL J. Neurochem. 86:1181-1188(2003).
RN [16]
RP FUNCTION, MUTAGENESIS OF CYS-942, AND INTERACTION WITH SCN5A.
RX PubMed=15217910; DOI=10.1161/01.RES.0000136816.05109.89;
RA van Bemmelen M.X., Rougier J.-S., Gavillet B., Apotheloz F.,
RA Daidie D., Tateyama M., Rivolta I., Thomas M.A., Kass R.S., Staub O.,
RA Abriel H.;
RT "Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2
RT mediated ubiquitination.";
RL Circ. Res. 95:284-291(2004).
RN [17]
RP FUNCTION, INTERACTION WITH CLCN5, AND INDUCTION.
RX PubMed=15489223; DOI=10.1074/jbc.M411491200;
RA Hryciw D.H., Ekberg J., Lee A., Lensink I.L., Kumar S., Guggino W.B.,
RA Cook D.I., Pollock C.A., Poronnik P.;
RT "Nedd4-2 functionally interacts with ClC-5: involvement in
RT constitutive albumin endocytosis in proximal tubule cells.";
RL J. Biol. Chem. 279:54996-55007(2004).
RN [18]
RP PHOSPHORYLATION AT SER-342; THR-367 AND SER-448.
RX PubMed=15328345; DOI=10.1074/jbc.M407858200;
RA Snyder P.M., Olson D.R., Kabra R., Zhou R., Steines J.C.;
RT "cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the
RT epithelial Na(+) channel through convergent phosphorylation of Nedd4-
RT 2.";
RL J. Biol. Chem. 279:45753-45758(2004).
RN [19]
RP FUNCTION.
RX PubMed=15040001; DOI=10.1002/jcp.10430;
RA Henke G., Maier G., Wallisch S., Boehmer C., Lang F.;
RT "Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin
RT ligase Nedd4-2 and the serum and glucocorticoid inducible kinase
RT SGK1.";
RL J. Cell. Physiol. 199:194-199(2004).
RN [20]
RP INTERACTION WITH SCN2A; SCN3A AND SCN5A.
RX PubMed=15548568; DOI=10.1152/ajpcell.00460.2004;
RA Rougier J.-S., van Bemmelen M.X., Bruce M.C., Jespersen T.,
RA Gavillet B., Apotheloz F., Cordonier S., Staub O., Rotin D.,
RA Abriel H.;
RT "Molecular determinants of voltage-gated sodium channel regulation by
RT the Nedd4/Nedd4-like proteins.";
RL Am. J. Physiol. 288:C692-C701(2005).
RN [21]
RP FUNCTION, INTERACTION WITH SMAD2; SMAD3; SMAD6 AND SMAD7, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=15496141; DOI=10.1042/BJ20040738;
RA Kuratomi G., Komuro A., Goto K., Shinozaki M., Miyazawa K.,
RA Miyazono K., Imamura T.;
RT "NEDD4-2 (neural precursor cell expressed, developmentally down-
RT regulated 4-2) negatively regulates TGF-beta (transforming growth
RT factor-beta) signalling by inducing ubiquitin-mediated degradation of
RT Smad2 and TGF-beta type I receptor.";
RL Biochem. J. 386:461-470(2005).
RN [22]
RP FUNCTION.
RX PubMed=15576372; DOI=10.1074/jbc.M411053200;
RA Zhou R., Snyder P.M.;
RT "Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated
RT kinase (SGK) ubiquitination and degradation.";
RL J. Biol. Chem. 280:4518-4523(2005).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [24]
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 [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-318; SER-342; SER-446;
RP SER-449; SER-464; SER-479 AND SER-487, AND MASS 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 [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [28]
RP INTERACTION WITH NPC2, AND TISSUE SPECIFICITY.
RX PubMed=19664597; DOI=10.1016/j.bbrc.2009.07.158;
RA Araki N., Ishigami T., Ushio H., Minegishi S., Umemura M., Miyagi Y.,
RA Aoki I., Morinaga H., Tamura K., Toya Y., Uchino K., Umemura S.;
RT "Identification of NPC2 protein as interaction molecule with C2 domain
RT of human Nedd4L.";
RL Biochem. Biophys. Res. Commun. 388:290-296(2009).
RN [29]
RP ACTIVATION BY NDFIP1 AND NDFIP2, AND AUTOUBIQUITINATION.
RX PubMed=19343052; DOI=10.1038/embor.2009.30;
RA Mund T., Pelham H.R.;
RT "Control of the activity of WW-HECT domain E3 ubiquitin ligases by
RT NDFIP proteins.";
RL EMBO Rep. 10:501-507(2009).
RN [30]
RP FUNCTION AS A UBIQUITIN-PROTEIN LIGASE FOR TNK2, AND INTERACTION WITH
RP TNK2.
RX PubMed=19144635; DOI=10.1074/jbc.M806877200;
RA Chan W., Tian R., Lee Y.-F., Sit S.T., Lim L., Manser E.;
RT "Down-regulation of active ACK1 is mediated by association with the E3
RT ubiquitin ligase Nedd4-2.";
RL J. Biol. Chem. 284:8185-8194(2009).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-446, 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 [32]
RP PHOSPHORYLATION AT SER-342 AND SER-449, AND INTERACTION WITH WNK1.
RX PubMed=20525693; DOI=10.1074/jbc.M110.103432;
RA Heise C.J., Xu B.E., Deaton S.L., Cha S.K., Cheng C.J., Earnest S.,
RA Sengupta S., Juang Y.C., Stippec S., Xu Y., Zhao Y., Huang C.L.,
RA Cobb M.H.;
RT "Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial
RT sodium channel are regulated by multiple with no lysine (WNK) family
RT members.";
RL J. Biol. Chem. 285:25161-25167(2010).
RN [33]
RP 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 [34]
RP PHOSPHORYLATION BY SGK1, AND INTERACTION WITH SGK1.
RX PubMed=20730100; DOI=10.1371/journal.pone.0012163;
RA Wiemuth D., Lott J.S., Ly K., Ke Y., Teesdale-Spittle P., Snyder P.M.,
RA McDonald F.J.;
RT "Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1)
RT with the WW-domains of Nedd4-2 is required for epithelial sodium
RT channel regulation.";
RL PLoS ONE 5:E12163-E12163(2010).
RN [35]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479 AND SER-483, AND
RP MASS SPECTROMETRY.
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 [36]
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 [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479; SER-483 AND
RP SER-487, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [38]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [39]
RP VARIANTS LEU-355 AND ARG-497.
RX PubMed=15140763; DOI=10.1152/ajprenal.00353.2003;
RA Fouladkou F., Alikhani-Koopaei R., Vogt B., Flores S.Y.,
RA Malbert-Colas L., Lecomte M.-C., Loffing J., Frey F.J., Frey B.M.,
RA Staub O.;
RT "A naturally occurring human Nedd4-2 variant displays impaired ENaC
RT regulation in Xenopus laevis oocytes.";
RL Am. J. Physiol. 287:F550-F561(2004).
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 Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1
CC ubiquitination and proteasome-dependent degradation. Promotes
CC ubiquitination and internalization of various plasma membrane
CC channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8,
CC Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of
CC SGK1 and TNK2.
CC -!- ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with UBE2E3 (By similarity). Interacts with
CC NDFIP1 and NDFIP2 (By similarity); this interaction activates the
CC E3 ubiquitin-protein ligase. Interacts via its WW domains with
CC SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A,
CC SCN10A and CLCN5. Interacts with SMAD2, SMAD3, SMAD6 and SMAD7.
CC The phosphorylated form interacts with 14-3-3 proteins. Interacts
CC with Epstein-Barr virus LMP2A. Interacts with TNK2. Interacts with
CC WNK1. Interacts with SGK1. Interacts (via C2 domain) with NPC2.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=May be recruited to exosomes
CC by NDFIP1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=1; Synonyms=Nedd4-2c;
CC IsoId=Q96PU5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96PU5-2; Sequence=VSP_015448;
CC Note=No experimental confirmation available;
CC Name=3; Synonyms=NEDD4Le;
CC IsoId=Q96PU5-3; Sequence=VSP_015447;
CC Note=No experimental confirmation available;
CC Name=4; Synonyms=NEDD4La, NEDD4Lb, NEDD4Lf;
CC IsoId=Q96PU5-4; Sequence=VSP_015444;
CC Name=5; Synonyms=NEDD4Ld;
CC IsoId=Q96PU5-5; Sequence=VSP_043848;
CC Name=6; Synonyms=NEDD4Lh;
CC IsoId=Q96PU5-6; Sequence=VSP_015446, VSP_043848;
CC Name=7; Synonyms=NEDD4Lg;
CC IsoId=Q96PU5-7; Sequence=VSP_015446;
CC Name=8;
CC IsoId=Q96PU5-9; Sequence=VSP_015444, VSP_043848;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with highest levels in
CC prostate, pancreas and kidney.
CC -!- INDUCTION: By androgens in prostate, and by albumin in kidney.
CC -!- PTM: Phosphorylated by SGK1 or PKA; which impairs interaction with
CC SCNN. Interaction with YWHAH inhibits dephosphorylation.
CC -!- PTM: Auto-ubiquitinated.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein
CC ligase) domain.
CC -!- SIMILARITY: Contains 4 WW domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA23711.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=BAA23711.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF210730; AAG43524.1; -; mRNA.
DR EMBL; AF385931; AAM46208.1; -; mRNA.
DR EMBL; AY312514; AAP75706.1; -; mRNA.
DR EMBL; AY112983; AAM76728.1; -; mRNA.
DR EMBL; AY112984; AAM76729.1; -; mRNA.
DR EMBL; AY112985; AAM76730.1; -; mRNA.
DR EMBL; AB071179; BAB69424.1; -; mRNA.
DR EMBL; DQ181796; ABA10330.1; -; mRNA.
DR EMBL; AC015988; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC090236; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC107896; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471096; EAW63065.1; -; Genomic_DNA.
DR EMBL; BC000621; AAH00621.2; -; mRNA.
DR EMBL; BC019345; AAH19345.1; -; mRNA.
DR EMBL; BC032597; AAH32597.1; -; mRNA.
DR EMBL; AB007899; BAA23711.1; ALT_INIT; mRNA.
DR EMBL; AL137469; CAB70754.1; -; mRNA.
DR PIR; T46412; T46412.
DR RefSeq; NP_001138436.1; NM_001144964.1.
DR RefSeq; NP_001138437.1; NM_001144965.1.
DR RefSeq; NP_001138438.1; NM_001144966.2.
DR RefSeq; NP_001138439.1; NM_001144967.2.
DR RefSeq; NP_001138440.1; NM_001144968.1.
DR RefSeq; NP_001138441.1; NM_001144969.1.
DR RefSeq; NP_001138442.1; NM_001144970.2.
DR RefSeq; NP_001138443.1; NM_001144971.1.
DR RefSeq; NP_001230889.1; NM_001243960.1.
DR RefSeq; NP_056092.2; NM_015277.5.
DR UniGene; Hs.185677; -.
DR PDB; 2LAJ; NMR; -; A=496-535.
DR PDB; 2LB2; NMR; -; A=386-420.
DR PDB; 2LTY; NMR; -; A=385-417.
DR PDB; 2NSQ; X-ray; 1.85 A; A=1-154.
DR PDB; 2ONI; X-ray; 2.20 A; A=594-967.
DR PDB; 3JVZ; X-ray; 3.30 A; C/D=596-975.
DR PDB; 3JW0; X-ray; 3.10 A; C/D=596-975.
DR PDBsum; 2LAJ; -.
DR PDBsum; 2LB2; -.
DR PDBsum; 2LTY; -.
DR PDBsum; 2NSQ; -.
DR PDBsum; 2ONI; -.
DR PDBsum; 3JVZ; -.
DR PDBsum; 3JW0; -.
DR ProteinModelPortal; Q96PU5; -.
DR SMR; Q96PU5; 6-154, 193-252, 386-420, 496-966.
DR DIP; DIP-41935N; -.
DR IntAct; Q96PU5; 20.
DR MINT; MINT-148327; -.
DR PhosphoSite; Q96PU5; -.
DR DMDM; 73921204; -.
DR PaxDb; Q96PU5; -.
DR PRIDE; Q96PU5; -.
DR DNASU; 23327; -.
DR Ensembl; ENST00000256830; ENSP00000256830; ENSG00000049759.
DR Ensembl; ENST00000356462; ENSP00000348847; ENSG00000049759.
DR Ensembl; ENST00000357895; ENSP00000350569; ENSG00000049759.
DR Ensembl; ENST00000382850; ENSP00000372301; ENSG00000049759.
DR Ensembl; ENST00000400345; ENSP00000383199; ENSG00000049759.
DR Ensembl; ENST00000431212; ENSP00000389406; ENSG00000049759.
DR Ensembl; ENST00000435432; ENSP00000393395; ENSG00000049759.
DR Ensembl; ENST00000456173; ENSP00000405440; ENSG00000049759.
DR Ensembl; ENST00000456986; ENSP00000411947; ENSG00000049759.
DR Ensembl; ENST00000586263; ENSP00000468546; ENSG00000049759.
DR GeneID; 23327; -.
DR KEGG; hsa:23327; -.
DR UCSC; uc002lgy.3; human.
DR CTD; 23327; -.
DR GeneCards; GC18P055711; -.
DR HGNC; HGNC:7728; NEDD4L.
DR HPA; HPA024618; -.
DR MIM; 606384; gene.
DR neXtProt; NX_Q96PU5; -.
DR PharmGKB; PA31534; -.
DR eggNOG; COG5021; -.
DR HOVERGEN; HBG004134; -.
DR KO; K13305; -.
DR OMA; EQRDDME; -.
DR OrthoDB; EOG7RFTGT; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; Q96PU5; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; NEDD4L; human.
DR EvolutionaryTrace; Q96PU5; -.
DR GeneWiki; NEDD4L; -.
DR GenomeRNAi; 23327; -.
DR NextBio; 45240; -.
DR PRO; PR:Q96PU5; -.
DR ArrayExpress; Q96PU5; -.
DR Bgee; Q96PU5; -.
DR Genevestigator; Q96PU5; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0019870; F:potassium channel inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; NAS:UniProtKB.
DR GO; GO:0006883; P:cellular sodium ion homeostasis; NAS:UniProtKB.
DR GO; GO:0007588; P:excretion; NAS:UniProtKB.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:1901380; P:negative regulation of potassium ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:1901017; P:negative regulation of potassium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:2000009; P:negative regulation of protein localization to cell surface; IDA:BHF-UCL.
DR GO; GO:1902306; P:negative regulation of sodium ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:2001259; P:positive regulation of cation channel activity; IEA:Ensembl.
DR GO; GO:2001288; P:positive regulation of caveolin-mediated endocytosis; ISS:BHF-UCL.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; IEA:Ensembl.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:BHF-UCL.
DR GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0003254; P:regulation of membrane depolarization; IDA:BHF-UCL.
DR GO; GO:0060306; P:regulation of membrane repolarization; IDA:BHF-UCL.
DR GO; GO:0042176; P:regulation of protein catabolic process; NAS:UniProtKB.
DR GO; GO:2000810; P:regulation of tight junction assembly; IEA:Ensembl.
DR GO; GO:0086005; P:regulation of ventricular cardiac muscle cell action potential; ISS:BHF-UCL.
DR GO; GO:0010038; P:response to metal ion; IDA:UniProtKB.
DR GO; GO:0009651; P:response to salt stress; IEA:Ensembl.
DR GO; GO:0006814; P:sodium ion transport; NAS:UniProtKB.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043162; P:ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway; IEA:Ensembl.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR GO; GO:0030104; P:water homeostasis; NAS:UniProtKB.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR024928; E3_ub_ligase_SMURF1.
DR InterPro; IPR000569; HECT.
DR InterPro; IPR001202; WW_dom.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 4.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR PRINTS; PR00360; C2DOMAIN.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 4.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 4.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 4.
DR PROSITE; PS50020; WW_DOMAIN_2; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Host-virus interaction; Ligase;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 975 E3 ubiquitin-protein ligase NEDD4-like.
FT /FTId=PRO_0000120323.
FT DOMAIN 7 109 C2.
FT DOMAIN 193 226 WW 1.
FT DOMAIN 385 418 WW 2.
FT DOMAIN 497 530 WW 3.
FT DOMAIN 548 581 WW 4.
FT DOMAIN 640 974 HECT.
FT ACT_SITE 942 942 Glycyl thioester intermediate.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 318 318 Phosphothreonine.
FT MOD_RES 342 342 Phosphoserine; by WNK1 and WNK4.
FT MOD_RES 367 367 Phosphothreonine; by SGK1 (Probable).
FT MOD_RES 446 446 Phosphoserine.
FT MOD_RES 448 448 Phosphoserine; by PKA and SGK1.
FT MOD_RES 449 449 Phosphoserine; by WNK1 and WNK4.
FT MOD_RES 464 464 Phosphoserine.
FT MOD_RES 479 479 Phosphoserine.
FT MOD_RES 483 483 Phosphoserine.
FT MOD_RES 487 487 Phosphoserine.
FT VAR_SEQ 1 121 Missing (in isoform 4 and isoform 8).
FT /FTId=VSP_015444.
FT VAR_SEQ 1 16 MATGLGEPVYGLSEDE -> MRRLAFEQ (in isoform
FT 6 and isoform 7).
FT /FTId=VSP_015446.
FT VAR_SEQ 356 459 Missing (in isoform 3).
FT /FTId=VSP_015447.
FT VAR_SEQ 356 419 Missing (in isoform 2).
FT /FTId=VSP_015448.
FT VAR_SEQ 356 375 Missing (in isoform 5, isoform 6 and
FT isoform 8).
FT /FTId=VSP_043848.
FT VARIANT 355 355 P -> L (common polymorphism; impaired
FT ability to inhibit SCNN).
FT /FTId=VAR_023415.
FT VARIANT 497 497 S -> R.
FT /FTId=VAR_023416.
FT MUTAGEN 448 448 S->A: Abolishes interaction with 1433F.
FT MUTAGEN 942 942 C->S: Abolishes activity.
FT CONFLICT 52 52 A -> P (in Ref. 3; AAM76729/AAM76730).
FT CONFLICT 188 188 E -> K (in Ref. 2; AAP75706).
FT STRAND 9 11
FT TURN 16 18
FT STRAND 20 31
FT STRAND 43 51
FT TURN 52 55
FT STRAND 56 62
FT STRAND 73 82
FT TURN 84 86
FT STRAND 87 95
FT STRAND 98 100
FT STRAND 103 111
FT STRAND 129 132
FT STRAND 145 152
FT STRAND 391 396
FT TURN 397 399
FT STRAND 400 405
FT TURN 406 409
FT STRAND 410 414
FT HELIX 417 419
FT STRAND 503 508
FT TURN 509 511
FT STRAND 512 517
FT TURN 518 521
FT STRAND 522 526
FT HELIX 528 534
FT HELIX 594 607
FT STRAND 612 614
FT STRAND 616 622
FT HELIX 624 626
FT HELIX 627 637
FT HELIX 641 645
FT STRAND 646 652
FT STRAND 653 655
FT HELIX 660 675
FT HELIX 678 680
FT STRAND 681 687
FT TURN 688 690
FT STRAND 693 695
FT HELIX 699 702
FT HELIX 706 723
FT STRAND 728 731
FT HELIX 733 739
FT HELIX 746 749
FT TURN 750 752
FT HELIX 754 765
FT HELIX 769 771
FT STRAND 774 781
FT STRAND 784 791
FT HELIX 794 796
FT TURN 801 803
FT HELIX 804 816
FT TURN 817 819
FT HELIX 821 834
FT HELIX 837 840
FT HELIX 845 853
FT HELIX 860 865
FT STRAND 868 870
FT HELIX 878 889
FT HELIX 892 903
FT HELIX 913 915
FT STRAND 926 929
FT STRAND 933 935
FT STRAND 938 940
FT HELIX 941 943
FT STRAND 945 948
FT HELIX 954 965
SQ SEQUENCE 975 AA; 111932 MW; 2C958625B4A1AB3F CRC64;
MATGLGEPVY GLSEDEGESR ILRVKVVSGI DLAKKDIFGA SDPYVKLSLY VADENRELAL
VQTKTIKKTL NPKWNEEFYF RVNPSNHRLL FEVFDENRLT RDDFLGQVDV PLSHLPTEDP
TMERPYTFKD FLLRPRSHKS RVKGFLRLKM AYMPKNGGQD EENSDQRDDM EHGWEVVDSN
DSASQHQEEL PPPPLPPGWE EKVDNLGRTY YVNHNNRTTQ WHRPSLMDVS SESDNNIRQI
NQEAAHRRFR SRRHISEDLE PEPSEGGDVP EPWETISEEV NIAGDSLGLA LPPPPASPGS
RTSPQELSEE LSRRLQITPD SNGEQFSSLI QREPSSRLRS CSVTDAVAEQ GHLPPPSAPA
GRARSSTVTG GEEPTPSVAY VHTTPGLPSG WEERKDAKGR TYYVNHNNRT TTWTRPIMQL
AEDGASGSAT NSNNHLIEPQ IRRPRSLSSP TVTLSAPLEG AKDSPVRRAV KDTLSNPQSP
QPSPYNSPKP QHKVTQSFLP PGWEMRIAPN GRPFFIDHNT KTTTWEDPRL KFPVHMRSKT
SLNPNDLGPL PPGWEERIHL DGRTFYIDHN SKITQWEDPR LQNPAITGPA VPYSREFKQK
YDYFRKKLKK PADIPNRFEM KLHRNNIFEE SYRRIMSVKR PDVLKARLWI EFESEKGLDY
GGVAREWFFL LSKEMFNPYY GLFEYSATDN YTLQINPNSG LCNEDHLSYF TFIGRVAGLA
VFHGKLLDGF FIRPFYKMML GKQITLNDME SVDSEYYNSL KWILENDPTE LDLMFCIDEE
NFGQTYQVDL KPNGSEIMVT NENKREYIDL VIQWRFVNRV QKQMNAFLEG FTELLPIDLI
KIFDENELEL LMCGLGDVDV NDWRQHSIYK NGYCPNHPVI QWFWKAVLLM DAEKRIRLLQ
FVTGTSRVPM NGFAELYGSN GPQLFTIEQW GSPEKLPRAH TCFNRLDLPP YETFEDLREK
LLMAVENAQG FEGVD
//
ID NED4L_HUMAN Reviewed; 975 AA.
AC Q96PU5; O43165; Q3LSM7; Q7Z5F1; Q7Z5F2; Q7Z5N3; Q8N5A7; Q8WUU9;
read moreAC Q9BW58; Q9H2W4; Q9NT88;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 2.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=E3 ubiquitin-protein ligase NEDD4-like;
DE EC=6.3.2.-;
DE AltName: Full=NEDD4.2;
DE AltName: Full=Nedd4-2;
GN Name=NEDD4L; Synonyms=KIAA0439, NEDL3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND ALTERNATIVE SPLICING.
RX PubMed=11840194; DOI=10.1038/sj.ejhg.5200747;
RA Chen H., Ross C.A., Wang N., Huo Y., MacKinnon D.F., Potash J.B.,
RA Simpson S.G., McMahon F.J., DePaulo J.R. Jr., McInnis M.G.;
RT "NEDD4L on human chromosome 18q21 has multiple forms of transcripts
RT and is a homologue of the mouse Nedd4-2 gene.";
RL Eur. J. Hum. Genet. 9:922-930(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INTERACTION WITH SCNN1A;
RP SCNN1B AND SCNN1G.
RC TISSUE=Kidney;
RX PubMed=14556380; DOI=10.1016/S1631-0691(03)00154-9;
RA Malbert-Colas L., Nicolas G., Galand C., Lecomte M.-C., Dhermy D.;
RT "Identification of new partners of the epithelial sodium channel alpha
RT subunit.";
RL C. R. Biol. 326:615-624(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4; 6 AND 7), TISSUE SPECIFICITY,
RP AND INDUCTION.
RC TISSUE=Prostate;
RX PubMed=14615060; DOI=10.1016/j.mce.2003.08.009;
RA Qi H., Grenier J., Fournier A., Labrie C.;
RT "Androgens differentially regulate the expression of NEDD4L
RT transcripts in LNCaP human prostate cancer cells.";
RL Mol. Cell. Endocrinol. 210:51-62(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RA Okamoto Y., Miyazaki K., Sakamoto M., Kato C., Nakagawara A.;
RT "Homo sapiens NEDD4-like ubiquitin ligase 3.";
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8).
RA Qi H., Labrie C.;
RT "NEDD4L transcripts expressed in human prostate cells.";
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D.,
RA Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S.,
RA Bloom T., Bugalter B., Butler J., Cook A., DeCaprio D., Engels R.,
RA Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T.,
RA Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E.,
RA Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H.,
RA O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
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] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 101-975 (ISOFORM 5).
RC TISSUE=Skin, and Uterus;
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 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8).
RC TISSUE=Brain;
RX PubMed=9455477; DOI=10.1093/dnares/4.5.307;
RA Ishikawa K., Nagase T., Nakajima D., Seki N., Ohira M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VIII.
RT 78 new cDNA clones from brain which code for large proteins in
RT vitro.";
RL DNA Res. 4:307-313(1997).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 52-975 (ISOFORM 3).
RC TISSUE=Testis;
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 [11]
RP PROTEIN SEQUENCE OF 448-462, INTERACTION WITH YWHAB; YWHAG; YWHAE;
RP YWHAQ AND YWHAH, PHOSPHORYLATION AT SER-448, MUTAGENESIS OF SER-448,
RP AND MASS SPECTROMETRY.
RX PubMed=15677482; DOI=10.1074/jbc.M412884200;
RA Ichimura T., Yamamura H., Sasamoto K., Tominaga Y., Taoka M.,
RA Kakiuchi K., Shinkawa T., Takahashi N., Shimada S., Isobe T.;
RT "14-3-3 proteins modulate the expression of epithelial Na+ channels by
RT phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase.";
RL J. Biol. Chem. 280:13187-13194(2005).
RN [12]
RP INTERACTION WITH EPSTEIN-BARR VIRUS LMP2A.
RX PubMed=11046148; DOI=10.1128/MCB.20.22.8526-8535.2000;
RA Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G.,
RA Ingham R., Ernberg I., Pawson T.;
RT "Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3
RT protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases.";
RL Mol. Cell. Biol. 20:8526-8535(2000).
RN [13]
RP INTERACTION WITH SGK1 AND SCNN1A, AND PHOSPHORYLATION.
RX PubMed=11696533; DOI=10.1074/jbc.C100623200;
RA Snyder P.M., Olson D.R., Thomas B.C.;
RT "Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated
RT inhibition of the epithelial Na+ channel.";
RL J. Biol. Chem. 277:5-8(2002).
RN [14]
RP INTERACTION WITH NDFIP1.
RX PubMed=11748237; DOI=10.1074/jbc.M110443200;
RA Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S.;
RT "N4WBP5, a potential target for ubiquitination by the Nedd4 family of
RT proteins, is a novel Golgi-associated protein.";
RL J. Biol. Chem. 277:9307-9317(2002).
RN [15]
RP FUNCTION.
RX PubMed=12911626;
RA Boehmer C., Henke G., Schniepp R., Palmada M., Rothstein J.D.,
RA Broeer S., Lang F.;
RT "Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase
RT Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms
RT SGK1/3 and protein kinase B.";
RL J. Neurochem. 86:1181-1188(2003).
RN [16]
RP FUNCTION, MUTAGENESIS OF CYS-942, AND INTERACTION WITH SCN5A.
RX PubMed=15217910; DOI=10.1161/01.RES.0000136816.05109.89;
RA van Bemmelen M.X., Rougier J.-S., Gavillet B., Apotheloz F.,
RA Daidie D., Tateyama M., Rivolta I., Thomas M.A., Kass R.S., Staub O.,
RA Abriel H.;
RT "Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2
RT mediated ubiquitination.";
RL Circ. Res. 95:284-291(2004).
RN [17]
RP FUNCTION, INTERACTION WITH CLCN5, AND INDUCTION.
RX PubMed=15489223; DOI=10.1074/jbc.M411491200;
RA Hryciw D.H., Ekberg J., Lee A., Lensink I.L., Kumar S., Guggino W.B.,
RA Cook D.I., Pollock C.A., Poronnik P.;
RT "Nedd4-2 functionally interacts with ClC-5: involvement in
RT constitutive albumin endocytosis in proximal tubule cells.";
RL J. Biol. Chem. 279:54996-55007(2004).
RN [18]
RP PHOSPHORYLATION AT SER-342; THR-367 AND SER-448.
RX PubMed=15328345; DOI=10.1074/jbc.M407858200;
RA Snyder P.M., Olson D.R., Kabra R., Zhou R., Steines J.C.;
RT "cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the
RT epithelial Na(+) channel through convergent phosphorylation of Nedd4-
RT 2.";
RL J. Biol. Chem. 279:45753-45758(2004).
RN [19]
RP FUNCTION.
RX PubMed=15040001; DOI=10.1002/jcp.10430;
RA Henke G., Maier G., Wallisch S., Boehmer C., Lang F.;
RT "Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin
RT ligase Nedd4-2 and the serum and glucocorticoid inducible kinase
RT SGK1.";
RL J. Cell. Physiol. 199:194-199(2004).
RN [20]
RP INTERACTION WITH SCN2A; SCN3A AND SCN5A.
RX PubMed=15548568; DOI=10.1152/ajpcell.00460.2004;
RA Rougier J.-S., van Bemmelen M.X., Bruce M.C., Jespersen T.,
RA Gavillet B., Apotheloz F., Cordonier S., Staub O., Rotin D.,
RA Abriel H.;
RT "Molecular determinants of voltage-gated sodium channel regulation by
RT the Nedd4/Nedd4-like proteins.";
RL Am. J. Physiol. 288:C692-C701(2005).
RN [21]
RP FUNCTION, INTERACTION WITH SMAD2; SMAD3; SMAD6 AND SMAD7, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=15496141; DOI=10.1042/BJ20040738;
RA Kuratomi G., Komuro A., Goto K., Shinozaki M., Miyazawa K.,
RA Miyazono K., Imamura T.;
RT "NEDD4-2 (neural precursor cell expressed, developmentally down-
RT regulated 4-2) negatively regulates TGF-beta (transforming growth
RT factor-beta) signalling by inducing ubiquitin-mediated degradation of
RT Smad2 and TGF-beta type I receptor.";
RL Biochem. J. 386:461-470(2005).
RN [22]
RP FUNCTION.
RX PubMed=15576372; DOI=10.1074/jbc.M411053200;
RA Zhou R., Snyder P.M.;
RT "Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated
RT kinase (SGK) ubiquitination and degradation.";
RL J. Biol. Chem. 280:4518-4523(2005).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [24]
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 [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-318; SER-342; SER-446;
RP SER-449; SER-464; SER-479 AND SER-487, AND MASS 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 [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [28]
RP INTERACTION WITH NPC2, AND TISSUE SPECIFICITY.
RX PubMed=19664597; DOI=10.1016/j.bbrc.2009.07.158;
RA Araki N., Ishigami T., Ushio H., Minegishi S., Umemura M., Miyagi Y.,
RA Aoki I., Morinaga H., Tamura K., Toya Y., Uchino K., Umemura S.;
RT "Identification of NPC2 protein as interaction molecule with C2 domain
RT of human Nedd4L.";
RL Biochem. Biophys. Res. Commun. 388:290-296(2009).
RN [29]
RP ACTIVATION BY NDFIP1 AND NDFIP2, AND AUTOUBIQUITINATION.
RX PubMed=19343052; DOI=10.1038/embor.2009.30;
RA Mund T., Pelham H.R.;
RT "Control of the activity of WW-HECT domain E3 ubiquitin ligases by
RT NDFIP proteins.";
RL EMBO Rep. 10:501-507(2009).
RN [30]
RP FUNCTION AS A UBIQUITIN-PROTEIN LIGASE FOR TNK2, AND INTERACTION WITH
RP TNK2.
RX PubMed=19144635; DOI=10.1074/jbc.M806877200;
RA Chan W., Tian R., Lee Y.-F., Sit S.T., Lim L., Manser E.;
RT "Down-regulation of active ACK1 is mediated by association with the E3
RT ubiquitin ligase Nedd4-2.";
RL J. Biol. Chem. 284:8185-8194(2009).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-446, 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 [32]
RP PHOSPHORYLATION AT SER-342 AND SER-449, AND INTERACTION WITH WNK1.
RX PubMed=20525693; DOI=10.1074/jbc.M110.103432;
RA Heise C.J., Xu B.E., Deaton S.L., Cha S.K., Cheng C.J., Earnest S.,
RA Sengupta S., Juang Y.C., Stippec S., Xu Y., Zhao Y., Huang C.L.,
RA Cobb M.H.;
RT "Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial
RT sodium channel are regulated by multiple with no lysine (WNK) family
RT members.";
RL J. Biol. Chem. 285:25161-25167(2010).
RN [33]
RP 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 [34]
RP PHOSPHORYLATION BY SGK1, AND INTERACTION WITH SGK1.
RX PubMed=20730100; DOI=10.1371/journal.pone.0012163;
RA Wiemuth D., Lott J.S., Ly K., Ke Y., Teesdale-Spittle P., Snyder P.M.,
RA McDonald F.J.;
RT "Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1)
RT with the WW-domains of Nedd4-2 is required for epithelial sodium
RT channel regulation.";
RL PLoS ONE 5:E12163-E12163(2010).
RN [35]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479 AND SER-483, AND
RP MASS SPECTROMETRY.
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 [36]
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 [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479; SER-483 AND
RP SER-487, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [38]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [39]
RP VARIANTS LEU-355 AND ARG-497.
RX PubMed=15140763; DOI=10.1152/ajprenal.00353.2003;
RA Fouladkou F., Alikhani-Koopaei R., Vogt B., Flores S.Y.,
RA Malbert-Colas L., Lecomte M.-C., Loffing J., Frey F.J., Frey B.M.,
RA Staub O.;
RT "A naturally occurring human Nedd4-2 variant displays impaired ENaC
RT regulation in Xenopus laevis oocytes.";
RL Am. J. Physiol. 287:F550-F561(2004).
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 Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1
CC ubiquitination and proteasome-dependent degradation. Promotes
CC ubiquitination and internalization of various plasma membrane
CC channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8,
CC Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of
CC SGK1 and TNK2.
CC -!- ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with UBE2E3 (By similarity). Interacts with
CC NDFIP1 and NDFIP2 (By similarity); this interaction activates the
CC E3 ubiquitin-protein ligase. Interacts via its WW domains with
CC SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A,
CC SCN10A and CLCN5. Interacts with SMAD2, SMAD3, SMAD6 and SMAD7.
CC The phosphorylated form interacts with 14-3-3 proteins. Interacts
CC with Epstein-Barr virus LMP2A. Interacts with TNK2. Interacts with
CC WNK1. Interacts with SGK1. Interacts (via C2 domain) with NPC2.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=May be recruited to exosomes
CC by NDFIP1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=1; Synonyms=Nedd4-2c;
CC IsoId=Q96PU5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96PU5-2; Sequence=VSP_015448;
CC Note=No experimental confirmation available;
CC Name=3; Synonyms=NEDD4Le;
CC IsoId=Q96PU5-3; Sequence=VSP_015447;
CC Note=No experimental confirmation available;
CC Name=4; Synonyms=NEDD4La, NEDD4Lb, NEDD4Lf;
CC IsoId=Q96PU5-4; Sequence=VSP_015444;
CC Name=5; Synonyms=NEDD4Ld;
CC IsoId=Q96PU5-5; Sequence=VSP_043848;
CC Name=6; Synonyms=NEDD4Lh;
CC IsoId=Q96PU5-6; Sequence=VSP_015446, VSP_043848;
CC Name=7; Synonyms=NEDD4Lg;
CC IsoId=Q96PU5-7; Sequence=VSP_015446;
CC Name=8;
CC IsoId=Q96PU5-9; Sequence=VSP_015444, VSP_043848;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with highest levels in
CC prostate, pancreas and kidney.
CC -!- INDUCTION: By androgens in prostate, and by albumin in kidney.
CC -!- PTM: Phosphorylated by SGK1 or PKA; which impairs interaction with
CC SCNN. Interaction with YWHAH inhibits dephosphorylation.
CC -!- PTM: Auto-ubiquitinated.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein
CC ligase) domain.
CC -!- SIMILARITY: Contains 4 WW domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA23711.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=BAA23711.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF210730; AAG43524.1; -; mRNA.
DR EMBL; AF385931; AAM46208.1; -; mRNA.
DR EMBL; AY312514; AAP75706.1; -; mRNA.
DR EMBL; AY112983; AAM76728.1; -; mRNA.
DR EMBL; AY112984; AAM76729.1; -; mRNA.
DR EMBL; AY112985; AAM76730.1; -; mRNA.
DR EMBL; AB071179; BAB69424.1; -; mRNA.
DR EMBL; DQ181796; ABA10330.1; -; mRNA.
DR EMBL; AC015988; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC090236; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC107896; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471096; EAW63065.1; -; Genomic_DNA.
DR EMBL; BC000621; AAH00621.2; -; mRNA.
DR EMBL; BC019345; AAH19345.1; -; mRNA.
DR EMBL; BC032597; AAH32597.1; -; mRNA.
DR EMBL; AB007899; BAA23711.1; ALT_INIT; mRNA.
DR EMBL; AL137469; CAB70754.1; -; mRNA.
DR PIR; T46412; T46412.
DR RefSeq; NP_001138436.1; NM_001144964.1.
DR RefSeq; NP_001138437.1; NM_001144965.1.
DR RefSeq; NP_001138438.1; NM_001144966.2.
DR RefSeq; NP_001138439.1; NM_001144967.2.
DR RefSeq; NP_001138440.1; NM_001144968.1.
DR RefSeq; NP_001138441.1; NM_001144969.1.
DR RefSeq; NP_001138442.1; NM_001144970.2.
DR RefSeq; NP_001138443.1; NM_001144971.1.
DR RefSeq; NP_001230889.1; NM_001243960.1.
DR RefSeq; NP_056092.2; NM_015277.5.
DR UniGene; Hs.185677; -.
DR PDB; 2LAJ; NMR; -; A=496-535.
DR PDB; 2LB2; NMR; -; A=386-420.
DR PDB; 2LTY; NMR; -; A=385-417.
DR PDB; 2NSQ; X-ray; 1.85 A; A=1-154.
DR PDB; 2ONI; X-ray; 2.20 A; A=594-967.
DR PDB; 3JVZ; X-ray; 3.30 A; C/D=596-975.
DR PDB; 3JW0; X-ray; 3.10 A; C/D=596-975.
DR PDBsum; 2LAJ; -.
DR PDBsum; 2LB2; -.
DR PDBsum; 2LTY; -.
DR PDBsum; 2NSQ; -.
DR PDBsum; 2ONI; -.
DR PDBsum; 3JVZ; -.
DR PDBsum; 3JW0; -.
DR ProteinModelPortal; Q96PU5; -.
DR SMR; Q96PU5; 6-154, 193-252, 386-420, 496-966.
DR DIP; DIP-41935N; -.
DR IntAct; Q96PU5; 20.
DR MINT; MINT-148327; -.
DR PhosphoSite; Q96PU5; -.
DR DMDM; 73921204; -.
DR PaxDb; Q96PU5; -.
DR PRIDE; Q96PU5; -.
DR DNASU; 23327; -.
DR Ensembl; ENST00000256830; ENSP00000256830; ENSG00000049759.
DR Ensembl; ENST00000356462; ENSP00000348847; ENSG00000049759.
DR Ensembl; ENST00000357895; ENSP00000350569; ENSG00000049759.
DR Ensembl; ENST00000382850; ENSP00000372301; ENSG00000049759.
DR Ensembl; ENST00000400345; ENSP00000383199; ENSG00000049759.
DR Ensembl; ENST00000431212; ENSP00000389406; ENSG00000049759.
DR Ensembl; ENST00000435432; ENSP00000393395; ENSG00000049759.
DR Ensembl; ENST00000456173; ENSP00000405440; ENSG00000049759.
DR Ensembl; ENST00000456986; ENSP00000411947; ENSG00000049759.
DR Ensembl; ENST00000586263; ENSP00000468546; ENSG00000049759.
DR GeneID; 23327; -.
DR KEGG; hsa:23327; -.
DR UCSC; uc002lgy.3; human.
DR CTD; 23327; -.
DR GeneCards; GC18P055711; -.
DR HGNC; HGNC:7728; NEDD4L.
DR HPA; HPA024618; -.
DR MIM; 606384; gene.
DR neXtProt; NX_Q96PU5; -.
DR PharmGKB; PA31534; -.
DR eggNOG; COG5021; -.
DR HOVERGEN; HBG004134; -.
DR KO; K13305; -.
DR OMA; EQRDDME; -.
DR OrthoDB; EOG7RFTGT; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; Q96PU5; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; NEDD4L; human.
DR EvolutionaryTrace; Q96PU5; -.
DR GeneWiki; NEDD4L; -.
DR GenomeRNAi; 23327; -.
DR NextBio; 45240; -.
DR PRO; PR:Q96PU5; -.
DR ArrayExpress; Q96PU5; -.
DR Bgee; Q96PU5; -.
DR Genevestigator; Q96PU5; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0019870; F:potassium channel inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; NAS:UniProtKB.
DR GO; GO:0006883; P:cellular sodium ion homeostasis; NAS:UniProtKB.
DR GO; GO:0007588; P:excretion; NAS:UniProtKB.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:1901380; P:negative regulation of potassium ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:1901017; P:negative regulation of potassium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:2000009; P:negative regulation of protein localization to cell surface; IDA:BHF-UCL.
DR GO; GO:1902306; P:negative regulation of sodium ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:2001259; P:positive regulation of cation channel activity; IEA:Ensembl.
DR GO; GO:2001288; P:positive regulation of caveolin-mediated endocytosis; ISS:BHF-UCL.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; IEA:Ensembl.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:BHF-UCL.
DR GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0003254; P:regulation of membrane depolarization; IDA:BHF-UCL.
DR GO; GO:0060306; P:regulation of membrane repolarization; IDA:BHF-UCL.
DR GO; GO:0042176; P:regulation of protein catabolic process; NAS:UniProtKB.
DR GO; GO:2000810; P:regulation of tight junction assembly; IEA:Ensembl.
DR GO; GO:0086005; P:regulation of ventricular cardiac muscle cell action potential; ISS:BHF-UCL.
DR GO; GO:0010038; P:response to metal ion; IDA:UniProtKB.
DR GO; GO:0009651; P:response to salt stress; IEA:Ensembl.
DR GO; GO:0006814; P:sodium ion transport; NAS:UniProtKB.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043162; P:ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway; IEA:Ensembl.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR GO; GO:0030104; P:water homeostasis; NAS:UniProtKB.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR024928; E3_ub_ligase_SMURF1.
DR InterPro; IPR000569; HECT.
DR InterPro; IPR001202; WW_dom.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 4.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR PRINTS; PR00360; C2DOMAIN.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 4.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 4.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 4.
DR PROSITE; PS50020; WW_DOMAIN_2; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Host-virus interaction; Ligase;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 975 E3 ubiquitin-protein ligase NEDD4-like.
FT /FTId=PRO_0000120323.
FT DOMAIN 7 109 C2.
FT DOMAIN 193 226 WW 1.
FT DOMAIN 385 418 WW 2.
FT DOMAIN 497 530 WW 3.
FT DOMAIN 548 581 WW 4.
FT DOMAIN 640 974 HECT.
FT ACT_SITE 942 942 Glycyl thioester intermediate.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 318 318 Phosphothreonine.
FT MOD_RES 342 342 Phosphoserine; by WNK1 and WNK4.
FT MOD_RES 367 367 Phosphothreonine; by SGK1 (Probable).
FT MOD_RES 446 446 Phosphoserine.
FT MOD_RES 448 448 Phosphoserine; by PKA and SGK1.
FT MOD_RES 449 449 Phosphoserine; by WNK1 and WNK4.
FT MOD_RES 464 464 Phosphoserine.
FT MOD_RES 479 479 Phosphoserine.
FT MOD_RES 483 483 Phosphoserine.
FT MOD_RES 487 487 Phosphoserine.
FT VAR_SEQ 1 121 Missing (in isoform 4 and isoform 8).
FT /FTId=VSP_015444.
FT VAR_SEQ 1 16 MATGLGEPVYGLSEDE -> MRRLAFEQ (in isoform
FT 6 and isoform 7).
FT /FTId=VSP_015446.
FT VAR_SEQ 356 459 Missing (in isoform 3).
FT /FTId=VSP_015447.
FT VAR_SEQ 356 419 Missing (in isoform 2).
FT /FTId=VSP_015448.
FT VAR_SEQ 356 375 Missing (in isoform 5, isoform 6 and
FT isoform 8).
FT /FTId=VSP_043848.
FT VARIANT 355 355 P -> L (common polymorphism; impaired
FT ability to inhibit SCNN).
FT /FTId=VAR_023415.
FT VARIANT 497 497 S -> R.
FT /FTId=VAR_023416.
FT MUTAGEN 448 448 S->A: Abolishes interaction with 1433F.
FT MUTAGEN 942 942 C->S: Abolishes activity.
FT CONFLICT 52 52 A -> P (in Ref. 3; AAM76729/AAM76730).
FT CONFLICT 188 188 E -> K (in Ref. 2; AAP75706).
FT STRAND 9 11
FT TURN 16 18
FT STRAND 20 31
FT STRAND 43 51
FT TURN 52 55
FT STRAND 56 62
FT STRAND 73 82
FT TURN 84 86
FT STRAND 87 95
FT STRAND 98 100
FT STRAND 103 111
FT STRAND 129 132
FT STRAND 145 152
FT STRAND 391 396
FT TURN 397 399
FT STRAND 400 405
FT TURN 406 409
FT STRAND 410 414
FT HELIX 417 419
FT STRAND 503 508
FT TURN 509 511
FT STRAND 512 517
FT TURN 518 521
FT STRAND 522 526
FT HELIX 528 534
FT HELIX 594 607
FT STRAND 612 614
FT STRAND 616 622
FT HELIX 624 626
FT HELIX 627 637
FT HELIX 641 645
FT STRAND 646 652
FT STRAND 653 655
FT HELIX 660 675
FT HELIX 678 680
FT STRAND 681 687
FT TURN 688 690
FT STRAND 693 695
FT HELIX 699 702
FT HELIX 706 723
FT STRAND 728 731
FT HELIX 733 739
FT HELIX 746 749
FT TURN 750 752
FT HELIX 754 765
FT HELIX 769 771
FT STRAND 774 781
FT STRAND 784 791
FT HELIX 794 796
FT TURN 801 803
FT HELIX 804 816
FT TURN 817 819
FT HELIX 821 834
FT HELIX 837 840
FT HELIX 845 853
FT HELIX 860 865
FT STRAND 868 870
FT HELIX 878 889
FT HELIX 892 903
FT HELIX 913 915
FT STRAND 926 929
FT STRAND 933 935
FT STRAND 938 940
FT HELIX 941 943
FT STRAND 945 948
FT HELIX 954 965
SQ SEQUENCE 975 AA; 111932 MW; 2C958625B4A1AB3F CRC64;
MATGLGEPVY GLSEDEGESR ILRVKVVSGI DLAKKDIFGA SDPYVKLSLY VADENRELAL
VQTKTIKKTL NPKWNEEFYF RVNPSNHRLL FEVFDENRLT RDDFLGQVDV PLSHLPTEDP
TMERPYTFKD FLLRPRSHKS RVKGFLRLKM AYMPKNGGQD EENSDQRDDM EHGWEVVDSN
DSASQHQEEL PPPPLPPGWE EKVDNLGRTY YVNHNNRTTQ WHRPSLMDVS SESDNNIRQI
NQEAAHRRFR SRRHISEDLE PEPSEGGDVP EPWETISEEV NIAGDSLGLA LPPPPASPGS
RTSPQELSEE LSRRLQITPD SNGEQFSSLI QREPSSRLRS CSVTDAVAEQ GHLPPPSAPA
GRARSSTVTG GEEPTPSVAY VHTTPGLPSG WEERKDAKGR TYYVNHNNRT TTWTRPIMQL
AEDGASGSAT NSNNHLIEPQ IRRPRSLSSP TVTLSAPLEG AKDSPVRRAV KDTLSNPQSP
QPSPYNSPKP QHKVTQSFLP PGWEMRIAPN GRPFFIDHNT KTTTWEDPRL KFPVHMRSKT
SLNPNDLGPL PPGWEERIHL DGRTFYIDHN SKITQWEDPR LQNPAITGPA VPYSREFKQK
YDYFRKKLKK PADIPNRFEM KLHRNNIFEE SYRRIMSVKR PDVLKARLWI EFESEKGLDY
GGVAREWFFL LSKEMFNPYY GLFEYSATDN YTLQINPNSG LCNEDHLSYF TFIGRVAGLA
VFHGKLLDGF FIRPFYKMML GKQITLNDME SVDSEYYNSL KWILENDPTE LDLMFCIDEE
NFGQTYQVDL KPNGSEIMVT NENKREYIDL VIQWRFVNRV QKQMNAFLEG FTELLPIDLI
KIFDENELEL LMCGLGDVDV NDWRQHSIYK NGYCPNHPVI QWFWKAVLLM DAEKRIRLLQ
FVTGTSRVPM NGFAELYGSN GPQLFTIEQW GSPEKLPRAH TCFNRLDLPP YETFEDLREK
LLMAVENAQG FEGVD
//
MIM
606384
*RECORD*
*FIELD* NO
606384
*FIELD* TI
*606384 UBIQUITIN PROTEIN LIGASE NEDD4-LIKE; NEDD4L
;;NEDD4-2;;
KIAA0439;;
RSP5, S. CEREVISIAE, HOMOLOG OF
read more*FIELD* TX
CLONING
During a large-scale analysis of human brain cDNAs, Ishikawa et al.
(1997) cloned a partial cDNA, which they designated KIAA0439. Harvey et
al. (2001) found that the KIAA0439 protein shares 78% sequence identity
with NEDD4 (602278) and used phylogenetic analysis to cluster NEDD4-like
proteins, including KIAA0439, into 4 subgroups. By Northern blot
analysis, they detected a 4-kb KIAA0439 transcript at high levels in
liver and kidney and at lower levels in brain, heart, lung, spleen,
skeletal muscle, and testis.
Using cosmids from a human chromosome 18-specific library, Chen et al.
(2001) used exon trapping and cDNA cloning to identify a gene homologous
to NEDD4. The full-length cDNA sequence of 3,246 bp, obtained by RACE,
contains an open reading frame of 2,562 nucleotides. The deduced
854-amino acid polypeptide was predicted to contain 4 WW domains and an
HECT ubiquitin-protein ligase domain, highly conserved features in the
NEDD4 gene family. The NEDD4L gene has 97% and 62% amino acid sequence
identity to mouse Nedd4-2 and human NEDD4 genes, respectively. By
expression analysis, a 3.4-kb band was observed in heart and muscle,
while a 3.2-kb band and/or an additional 3.6-kb band were seen in other
tissues examined. An alternative splicing event involving exon 12 of 60
bp was observed, the shorter allele being predominantly present in brain
and lymphocytes, while the longer allele was strongly expressed in
kidney and placenta.
By sequence analysis of exons and intron boundaries of the NEDD4L gene
in 48 Caucasians, Dunn et al. (2002) identified a common variant
(variant 13), a G (70%) or A (30%) as the last nucleotide of a putative
exon 1, which could affect the generation of a previously unrecognized
splice isoform. They confirmed the presence of this putative isoform
(isoform I) in kidney and adrenals and established that variant 13-A
leads to the systematic use of an alternative splice site, generating a
transcript encoding a nonfunctional protein that lacks a full-length
Ca(2+)-dependent lipid-binding (C2) domain.
GENE STRUCTURE
Chen et al. (2001) determined that the NEDDL4 gene contains 30 exons
distributed over at least 356 kb.
MAPPING
Using a radiation hybrid mapping panel, Chen et al. (2001) mapped the
NEDD4L gene to chromosome 18q21.
GENE FUNCTION
Erdeniz and Rothstein (2000) found that the ubiquitination domain of
KIAA0439 shares homology with the S. cerevisiae Rsp5, a
ubiquitin-protein ligase. They analyzed Rsp5 mutant strains and
concluded that Rsp5 may be involved in the degradation of the
single-stranded DNA-binding protein Rfa1, thereby linking
ubiquitin-dependent protein degradation to the replication-recombination
machinery.
Using Far Western assays, Harvey et al. (2001) found that the WW domains
(see 602307) of KIAA0439 bind with strong affinity to all 3 subunits of
the epithelial sodium channel (ENaC): SCNN1A (600228), SCNN1B (600760),
and SCNN1G (600761). Using whole-cell patch-clamp experiments, they
demonstrated that a recombinant KIAA0439 protein acts as a
dominant-negative mutant that interferes with the sodium-dependent
feedback inhibition of ENaC. Harvey et al. (2001) concluded that
KIAA0439 may play a role in the regulation of ENaC function. By
targeting the ENaC for degradation, NEDD4L is a significant determinant
of sodium reabsorption in the distal nephron.
Due to the potential role of NEDD4L in regulating the epithelial sodium
channel, Chen et al. (2001) proposed it a candidate gene for a rare form
of autosomal dominant orthostatic hypotensive disorder (143850) mapped
to 18q21.
TGF-beta (TGFB1; 190180) signaling activates the transcription factors
SMAD2 (601366) and SMAD3 (603109) through phosphorylation at their C
termini. Further phosphorylation of activated SMAD2 and SMAD3 at a
linker region marks the activated SMAD proteins for proteasome-mediated
destruction. Gao et al. (2009) found that NEDD4L bound to SMAD2 and
SMAD3 that were phosphorylated at the linker region and targeted them
for degradation. By doing so, NEDD4L limited the active half-life of
SMAD2 and SMAD3 and reduced the amplitude and duration of TGF-beta gene
responses. In mouse embryonic stem cells, Nedd4l limited the induction
of mesodermal fates by Smad2- and Smad3-activating factors. Gao et al.
(2009) concluded that NEDD4L is the principal ubiquitin ligase that
selectively targets activated SMAD2 and SMAD3 for destruction.
MOLECULAR GENETICS
Since the NEDD4L gene mapped to the region of 18q21 showing linkage
evidence for a susceptibility locus for bipolar affective disorder
(125480), Chen et al. (2001) screened the NEDD4L gene for mutations in 3
unrelated bipolar I probands and their parents, but no mutations were
detected.
Dunn et al. (2002) stated that individuals homozygous for variant 13-A
of the NEDD4L gene are predicted to have a decrease in the amount of
C2-domain NEDD4L, produced from expression of isoform I. They suggested
that variant 13 is a likely candidate single nucleotide polymorphism for
association with phenotypes relevant to orthostatic hypotension and
essential hypertension. Differential function of NEDD4L isoforms could
prove significant in blood pressure regulation through an effect on
ENaC-dependent sodium reabsorption.
For discussion of a possible association between variation in the NEDD4L
gene and diabetic nephropathy in African Americans, see MVCD1 (603933).
*FIELD* RF
1. Chen, H.; Ross, C. A.; Wang, N.; Huo, Y.; MacKinnon, D. F.; Potash,
J. B.; Simpson, S. G.; McMahon, F. J.; DePaulo, J. R., Jr.; McInnis,
M. G.: NEDD4L on human chromosome 18q21 has multiple forms of transcripts
and is a homologue of the mouse Nedd4-2 gene. Europ. J. Hum. Genet. 9:
922-930, 2001.
2. Dunn, D. M.; Ishigami, T.; Pankow, J.; von Niederhausern, A.; Alder,
J.; Hunt, S. C.; Leppert, M. F.; Lalouel, J.-M.; Weiss, R. B.: Common
variant of human NEDD4L activates a cryptic splice site to form a
frameshifted transcript. J. Hum. Genet. 47: 665-676, 2002.
3. Erdeniz, N.; Rothstein, R.: Rsp5, a ubiquitin-protein ligase,
is involved in degradation of the single-stranded-DNA binding protein
Rfa1 in Saccharomyces cerevisiae. Molec. Cell. Biol. 20: 224-232,
2000.
4. Gao, S.; Alarcon, C.; Sapkota, G.; Rahman, S.; Chen, P.-Y.; Goerner,
N.; Macias, M. J.; Erdjument-Bromage, H.; Tempst, P.; Massague, J.
: Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta
signaling. Molec. Cell 36: 457-468, 2009.
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. Ishikawa, K.; Nagase, T.; Nakajima, D.; Seki, N.; Ohira, M.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of
the coding sequences of unidentified human genes. VIII. 78 new cDNA
clones from brain which code for large proteins in vitro. DNA Res. 4:
307-313, 1997.
*FIELD* CN
Patricia A. Hartz - updated: 9/28/2010
Marla J. F. O'Neill - updated: 8/25/2010
Victor A. McKusick - updated: 2/10/2003
Michael B. Petersen - updated: 8/20/2002
*FIELD* CD
Dawn Watkins-Chow: 10/11/2001
*FIELD* ED
mgross: 09/28/2010
terry: 9/28/2010
wwang: 8/27/2010
terry: 8/25/2010
wwang: 6/11/2008
mgross: 9/1/2006
carol: 2/19/2003
tkritzer: 2/14/2003
terry: 2/10/2003
alopez: 8/20/2002
carol: 3/14/2002
carol: 12/12/2001
carol: 10/23/2001
carol: 10/11/2001
*RECORD*
*FIELD* NO
606384
*FIELD* TI
*606384 UBIQUITIN PROTEIN LIGASE NEDD4-LIKE; NEDD4L
;;NEDD4-2;;
KIAA0439;;
RSP5, S. CEREVISIAE, HOMOLOG OF
read more*FIELD* TX
CLONING
During a large-scale analysis of human brain cDNAs, Ishikawa et al.
(1997) cloned a partial cDNA, which they designated KIAA0439. Harvey et
al. (2001) found that the KIAA0439 protein shares 78% sequence identity
with NEDD4 (602278) and used phylogenetic analysis to cluster NEDD4-like
proteins, including KIAA0439, into 4 subgroups. By Northern blot
analysis, they detected a 4-kb KIAA0439 transcript at high levels in
liver and kidney and at lower levels in brain, heart, lung, spleen,
skeletal muscle, and testis.
Using cosmids from a human chromosome 18-specific library, Chen et al.
(2001) used exon trapping and cDNA cloning to identify a gene homologous
to NEDD4. The full-length cDNA sequence of 3,246 bp, obtained by RACE,
contains an open reading frame of 2,562 nucleotides. The deduced
854-amino acid polypeptide was predicted to contain 4 WW domains and an
HECT ubiquitin-protein ligase domain, highly conserved features in the
NEDD4 gene family. The NEDD4L gene has 97% and 62% amino acid sequence
identity to mouse Nedd4-2 and human NEDD4 genes, respectively. By
expression analysis, a 3.4-kb band was observed in heart and muscle,
while a 3.2-kb band and/or an additional 3.6-kb band were seen in other
tissues examined. An alternative splicing event involving exon 12 of 60
bp was observed, the shorter allele being predominantly present in brain
and lymphocytes, while the longer allele was strongly expressed in
kidney and placenta.
By sequence analysis of exons and intron boundaries of the NEDD4L gene
in 48 Caucasians, Dunn et al. (2002) identified a common variant
(variant 13), a G (70%) or A (30%) as the last nucleotide of a putative
exon 1, which could affect the generation of a previously unrecognized
splice isoform. They confirmed the presence of this putative isoform
(isoform I) in kidney and adrenals and established that variant 13-A
leads to the systematic use of an alternative splice site, generating a
transcript encoding a nonfunctional protein that lacks a full-length
Ca(2+)-dependent lipid-binding (C2) domain.
GENE STRUCTURE
Chen et al. (2001) determined that the NEDDL4 gene contains 30 exons
distributed over at least 356 kb.
MAPPING
Using a radiation hybrid mapping panel, Chen et al. (2001) mapped the
NEDD4L gene to chromosome 18q21.
GENE FUNCTION
Erdeniz and Rothstein (2000) found that the ubiquitination domain of
KIAA0439 shares homology with the S. cerevisiae Rsp5, a
ubiquitin-protein ligase. They analyzed Rsp5 mutant strains and
concluded that Rsp5 may be involved in the degradation of the
single-stranded DNA-binding protein Rfa1, thereby linking
ubiquitin-dependent protein degradation to the replication-recombination
machinery.
Using Far Western assays, Harvey et al. (2001) found that the WW domains
(see 602307) of KIAA0439 bind with strong affinity to all 3 subunits of
the epithelial sodium channel (ENaC): SCNN1A (600228), SCNN1B (600760),
and SCNN1G (600761). Using whole-cell patch-clamp experiments, they
demonstrated that a recombinant KIAA0439 protein acts as a
dominant-negative mutant that interferes with the sodium-dependent
feedback inhibition of ENaC. Harvey et al. (2001) concluded that
KIAA0439 may play a role in the regulation of ENaC function. By
targeting the ENaC for degradation, NEDD4L is a significant determinant
of sodium reabsorption in the distal nephron.
Due to the potential role of NEDD4L in regulating the epithelial sodium
channel, Chen et al. (2001) proposed it a candidate gene for a rare form
of autosomal dominant orthostatic hypotensive disorder (143850) mapped
to 18q21.
TGF-beta (TGFB1; 190180) signaling activates the transcription factors
SMAD2 (601366) and SMAD3 (603109) through phosphorylation at their C
termini. Further phosphorylation of activated SMAD2 and SMAD3 at a
linker region marks the activated SMAD proteins for proteasome-mediated
destruction. Gao et al. (2009) found that NEDD4L bound to SMAD2 and
SMAD3 that were phosphorylated at the linker region and targeted them
for degradation. By doing so, NEDD4L limited the active half-life of
SMAD2 and SMAD3 and reduced the amplitude and duration of TGF-beta gene
responses. In mouse embryonic stem cells, Nedd4l limited the induction
of mesodermal fates by Smad2- and Smad3-activating factors. Gao et al.
(2009) concluded that NEDD4L is the principal ubiquitin ligase that
selectively targets activated SMAD2 and SMAD3 for destruction.
MOLECULAR GENETICS
Since the NEDD4L gene mapped to the region of 18q21 showing linkage
evidence for a susceptibility locus for bipolar affective disorder
(125480), Chen et al. (2001) screened the NEDD4L gene for mutations in 3
unrelated bipolar I probands and their parents, but no mutations were
detected.
Dunn et al. (2002) stated that individuals homozygous for variant 13-A
of the NEDD4L gene are predicted to have a decrease in the amount of
C2-domain NEDD4L, produced from expression of isoform I. They suggested
that variant 13 is a likely candidate single nucleotide polymorphism for
association with phenotypes relevant to orthostatic hypotension and
essential hypertension. Differential function of NEDD4L isoforms could
prove significant in blood pressure regulation through an effect on
ENaC-dependent sodium reabsorption.
For discussion of a possible association between variation in the NEDD4L
gene and diabetic nephropathy in African Americans, see MVCD1 (603933).
*FIELD* RF
1. Chen, H.; Ross, C. A.; Wang, N.; Huo, Y.; MacKinnon, D. F.; Potash,
J. B.; Simpson, S. G.; McMahon, F. J.; DePaulo, J. R., Jr.; McInnis,
M. G.: NEDD4L on human chromosome 18q21 has multiple forms of transcripts
and is a homologue of the mouse Nedd4-2 gene. Europ. J. Hum. Genet. 9:
922-930, 2001.
2. Dunn, D. M.; Ishigami, T.; Pankow, J.; von Niederhausern, A.; Alder,
J.; Hunt, S. C.; Leppert, M. F.; Lalouel, J.-M.; Weiss, R. B.: Common
variant of human NEDD4L activates a cryptic splice site to form a
frameshifted transcript. J. Hum. Genet. 47: 665-676, 2002.
3. Erdeniz, N.; Rothstein, R.: Rsp5, a ubiquitin-protein ligase,
is involved in degradation of the single-stranded-DNA binding protein
Rfa1 in Saccharomyces cerevisiae. Molec. Cell. Biol. 20: 224-232,
2000.
4. Gao, S.; Alarcon, C.; Sapkota, G.; Rahman, S.; Chen, P.-Y.; Goerner,
N.; Macias, M. J.; Erdjument-Bromage, H.; Tempst, P.; Massague, J.
: Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta
signaling. Molec. Cell 36: 457-468, 2009.
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. Ishikawa, K.; Nagase, T.; Nakajima, D.; Seki, N.; Ohira, M.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of
the coding sequences of unidentified human genes. VIII. 78 new cDNA
clones from brain which code for large proteins in vitro. DNA Res. 4:
307-313, 1997.
*FIELD* CN
Patricia A. Hartz - updated: 9/28/2010
Marla J. F. O'Neill - updated: 8/25/2010
Victor A. McKusick - updated: 2/10/2003
Michael B. Petersen - updated: 8/20/2002
*FIELD* CD
Dawn Watkins-Chow: 10/11/2001
*FIELD* ED
mgross: 09/28/2010
terry: 9/28/2010
wwang: 8/27/2010
terry: 8/25/2010
wwang: 6/11/2008
mgross: 9/1/2006
carol: 2/19/2003
tkritzer: 2/14/2003
terry: 2/10/2003
alopez: 8/20/2002
carol: 3/14/2002
carol: 12/12/2001
carol: 10/23/2001
carol: 10/11/2001