ID NED4L_MOUSE Reviewed; 1004 AA. AC Q8CFI0; Q8BRT9; Q8BS42; Q99PK2; DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot. DT 30-AUG-2005, sequence version 2. DT 27-MAR-2024, entry version 185. DE RecName: Full=E3 ubiquitin-protein ligase NEDD4-like; DE EC=2.3.2.26 {ECO:0000250|UniProtKB:P46934}; DE EC=2.3.2.36 {ECO:0000250|UniProtKB:P46934}; DE AltName: Full=HECT-type E3 ubiquitin transferase NED4L; DE AltName: Full=NEDD4.2; DE AltName: Full=Nedd4-2; GN Name=Nedd4l; Synonyms=Kiaa0439, Nedd4b; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, FUNCTION, AND RP MUTAGENESIS OF CYS-971. RC STRAIN=C57BL/6J; RX PubMed=11149908; DOI=10.1096/fj.00-0191com; RA Kamynina E., Debonneville C., Bens M., Vandewalle A., Staub O.; RT "A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ RT channel."; RL FASEB J. 15:204-214(2001). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), INTERACTION WITH SCNN1A; RP SCNN1B AND SCNN1G, AND FUNCTION. RC TISSUE=Brain; RX PubMed=12424229; DOI=10.1096/fj.02-0497fje; RA Fotia A.B., Dinudom A., Shearwin K.E., Koch J.-P., Korbmacher C., RA Cook D.I., Kumar S.; RT "The role of individual Nedd4-2 (KIAA0439) WW domains in binding and RT regulating epithelial sodium channels."; RL FASEB J. 17:70-72(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC STRAIN=FVB/N; TISSUE=Kidney, and Mammary gland; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 44-1004 (ISOFORM 3). RC STRAIN=C57BL/6J; TISSUE=Cerebellum; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [5] RP FUNCTION, INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G, PHOSPHORYLATION AT RP SER-371 AND SER-477, AND MUTAGENESIS OF SER-371 AND SER-477. RX PubMed=11742982; DOI=10.1093/emboj/20.24.7052; RA Debonneville C., Flores S.Y., Kamynina E., Plant P.J., Tauxe C., RA Thomas M.A., Muenster C., Chraiebi A., Pratt J.H., Horisberger J.-D., RA Pearce D., Loffing J., Staub O.; RT "Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell RT surface expression."; RL EMBO J. 20:7052-7059(2001). RN [6] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=11244092; DOI=10.1074/jbc.c000906200; RA Harvey K.F., Dinudom A., Cook D.I., Kumar S.; RT "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial RT sodium channel."; RL J. Biol. Chem. 276:8597-8601(2001). RN [7] RP INTERACTION WITH NDFIP2, AND SUBCELLULAR LOCATION. RX PubMed=12050153; DOI=10.1074/jbc.m203018200; RA Konstas A.-A., Shearwin-Whyatt L.M., Fotia A.B., Degger B., Riccardi D., RA Cook D.I., Korbmacher C., Kumar S.; RT "Regulation of the epithelial sodium channel by N4WBP5A, a novel RT Nedd4/Nedd4-2-interacting protein."; RL J. Biol. Chem. 277:29406-29416(2002). RN [8] RP FUNCTION, AND INTERACTION WITH SCN1A; SCN2A; SCN3A; SCN5A; SCN8A; SCN9A; RP SCN10A; SCNN1A; SCNN1B AND SCNN1G. RX PubMed=15123669; DOI=10.1074/jbc.m402820200; RA Fotia A.B., Ekberg J., Adams D.J., Cook D.I., Poronnik P., Kumar S.; RT "Regulation of neuronal voltage-gated sodium channels by the ubiquitin- RT protein ligases Nedd4 and Nedd4-2."; RL J. Biol. Chem. 279:28930-28935(2004). RN [9] RP INTERACTION WITH UBE2E3. RX PubMed=14993279; DOI=10.1128/mcb.24.6.2397-2409.2004; RA Debonneville C., Staub O.; RT "Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2- RT dependent regulation of the epithelial Na+ channel."; RL Mol. Cell. Biol. 24:2397-2409(2004). RN [10] RP PHOSPHORYLATION AT SER-477. RX PubMed=15958725; DOI=10.1681/asn.2004100828; RA Flores S.Y., Loffing-Cueni D., Kamynina E., Daidie D., Gerbex C., RA Chabanel S., Dudler J., Loffing J., Staub O.; RT "Aldosterone-induced serum and glucocorticoid-induced kinase 1 expression RT is accompanied by nedd4-2 phosphorylation and increased na+ transport in RT cortical collecting duct cells."; RL J. Am. Soc. Nephrol. 16:2279-2287(2005). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-508, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-478; SER-493; SER-508; RP SER-512 AND SER-516, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Pancreas, RC Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [13] RP DEVELOPMENTAL STAGE. RX PubMed=27694961; DOI=10.1038/ng.3676; RG Deciphering Developmental Disorders study; RA Broix L., Jagline H., Ivanova L.E., Schmucker S., Drouot N., RA Clayton-Smith J., Pagnamenta A.T., Metcalfe K.A., Isidor B., Louvier U.W., RA Poduri A., Taylor J.C., Tilly P., Poirier K., Saillour Y., Lebrun N., RA Stemmelen T., Rudolf G., Muraca G., Saintpierre B., Elmorjani A., Moise M., RA Weirauch N.B., Guerrini R., Boland A., Olaso R., Masson C., Tripathy R., RA Keays D., Beldjord C., Nguyen L., Godin J., Kini U., Nischke P., RA Deleuze J.F., Bahi-Buisson N., Sumara I., Hinckelmann M.V., Chelly J.; RT "Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway RT deregulation and cause periventricular nodular heterotopia."; RL Nat. Genet. 48:1349-1358(2016). RN [14] RP STRUCTURE BY NMR OF 221-254; 414-447 AND 525-560. RA Kowalski K., Merkel A.L., Booker G.W.; RT "Solution structures of WW domains of NEDD4-2."; RL Submitted (OCT-2005) to the PDB data bank. CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates the CC polyubiquitination of lysine and cysteine residues on target proteins CC and is thereby implicated in the regulation of various signaling CC pathways including autophagy, innate immunity or DNA repair. Inhibits CC TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and CC proteasome-dependent degradation. Downregulates autophagy and cell CC growth by ubiquitinating and reducing cellular ULK1 or ASCT2 levels. CC Promotes ubiquitination and internalization of various plasma membrane CC channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, CC SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, CC KCNQ3/Kv7.3 or CLC5 (PubMed:15123669). Promotes ubiquitination and CC degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this CC ubiquitination is enhanced in the presence of NDFIP1. Plays a role in CC dendrite formation by melanocytes (By similarity). Involved in the CC regulation of TOR signaling (By similarity). Ubiquitinates and CC regulates protein levels of NTRK1 once this one is activated by NGF. CC Plays a role in antiviral innate immunity by catalyzing 'Lys-29'-linked CC cysteine ubiquitination of TRAF3, resulting in enhanced 'Lys-48' and CC 'Lys-63'-linked ubiquitination of TRAF3 (By similarity). CC {ECO:0000250|UniProtKB:Q96PU5, ECO:0000269|PubMed:11149908, CC ECO:0000269|PubMed:11244092, ECO:0000269|PubMed:11742982, CC ECO:0000269|PubMed:12424229, ECO:0000269|PubMed:15123669}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.26; Evidence={ECO:0000250|UniProtKB:Q96PU5}; CC -!- CATALYTIC ACTIVITY: CC Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + CC [acceptor protein]-L-cysteine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + [acceptor protein]-S-ubiquitinyl-L-cysteine.; EC=2.3.2.36; CC Evidence={ECO:0000250|UniProtKB:Q96PU5}; CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding. CC {ECO:0000250|UniProtKB:Q96PU5}. CC -!- PATHWAY: Protein modification; protein ubiquitination. {ECO:0000305}. CC -!- SUBUNIT: Interacts with UBE2E3 (PubMed:14993279). Interacts with CC NDFIP1; this interaction activates the E3 ubiquitin-protein ligase (By CC similarity). Interacts with NDFIP2; this interaction activates the E3 CC ubiquitin-protein ligase (PubMed:12050153). Interacts (via WW domains) CC with SCNN1A (PubMed:11742982, PubMed:12424229, PubMed:15123669). CC Interacts (via WW domains) with SCNN1B (PubMed:12424229, CC PubMed:11742982). Interacts (via WW domains) with SCNN1G CC (PubMed:12424229, PubMed:11742982, PubMed:15123669). Interacts (via WW CC domains) with SCN1A (PubMed:15123669). Interacts (via WW domains) with CC SCN2A (PubMed:15123669). Interacts (via WW domains) with SCN3A CC (PubMed:15123669). Interacts (via WW domains) with SCN5A CC (PubMed:15123669). Interacts (via WW domains) with SCN8A CC (PubMed:15123669). Interacts (via WW domains) with SCN9A CC (PubMed:15123669). Interacts (via WW domains) with SCN10A CC (PubMed:15123669). Interacts (via WW domains) with CLCN5 (By CC similarity). Interacts with SMAD2 (By similarity). Interacts with SMAD3 CC (By similarity). Interacts with SMAD6 (By similarity). Interacts with CC SMAD7 (By similarity). The phosphorylated form interacts with 14-3-3 CC proteins (By similarity). Interacts with TNK2 (By similarity). CC Interacts with WNK1 (By similarity). Interacts with SGK1 (By CC similarity). Interacts (via C2 domain) with NPC2 (By similarity). CC Interacts with ARRDC4 (By similarity). Interacts with KCNQ1; promotes CC internalization of KCNQ1 (By similarity). Interacts (via domains WW1, 3 CC and 4) with USP36; the interaction inhibits ubiquitination of, at CC least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (By similarity). Interacts with CC PRRG4 (via cytoplasmic domain) (By similarity). Interacts with LDLRAD3; CC the interaction is direct (By similarity). Interacts with UBE2D2 (By CC similarity). {ECO:0000250|UniProtKB:Q96PU5, CC ECO:0000269|PubMed:11742982, ECO:0000269|PubMed:12050153, CC ECO:0000269|PubMed:12424229, ECO:0000269|PubMed:14993279, CC ECO:0000269|PubMed:15123669}. CC -!- INTERACTION: CC Q8CFI0; Q99N57: Raf1; NbExp=2; IntAct=EBI-8046183, EBI-397757; CC Q8CFI0; Q9Z2S7-3: Tsc22d3; NbExp=2; IntAct=EBI-8046183, EBI-15771036; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12050153}. Golgi CC apparatus {ECO:0000250|UniProtKB:Q96PU5}. Endosome, multivesicular body CC {ECO:0000250|UniProtKB:Q96PU5}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8CFI0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8CFI0-2; Sequence=VSP_015450; CC Name=3; CC IsoId=Q8CFI0-3; Sequence=VSP_015453; CC -!- TISSUE SPECIFICITY: Highly expressed in liver and kidney. Also CC expressed in heart, brain and lung. Isoform 1 is expressed in kidney, CC lung and gut. Isoform 3 is ubiquitously expressed. CC {ECO:0000269|PubMed:11149908, ECO:0000269|PubMed:11244092}. CC -!- DEVELOPMENTAL STAGE: In the developing brain, it is homogenously CC distributed in the cortical plate, ventricular zone and ganglionic CC eminences at 15 dpc. A peak of expression in the cortex is observed at CC 16.5 dpc. {ECO:0000269|PubMed:27694961}. CC -!- PTM: Phosphorylated; which impairs interaction with SCNN. Interaction CC with YWHAH inhibits dephosphorylation (By similarity). Aldosterone CC induces Ser-477 phosphorylation by SGK1. {ECO:0000250, CC ECO:0000269|PubMed:11742982, ECO:0000269|PubMed:15958725}. CC -!- PTM: Auto-ubiquitinated. Deubiquitinated by USP36, no effect on NEDD4L CC protein levels. Both proteins interact and regulate each other's CC ubiquitination levels. {ECO:0000250|UniProtKB:Q96PU5}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC31307.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF277232; AAK00809.1; -; mRNA. DR EMBL; BC039746; AAH39746.1; -; mRNA. DR EMBL; BC071210; AAH71210.1; -; mRNA. DR EMBL; AK042621; BAC31307.1; ALT_INIT; mRNA. DR CCDS; CCDS29305.1; -. [Q8CFI0-2] DR PDB; 1WR3; NMR; -; A=221-254. DR PDB; 1WR4; NMR; -; A=414-447. DR PDB; 1WR7; NMR; -; A=525-560. DR PDBsum; 1WR3; -. DR PDBsum; 1WR4; -. DR PDBsum; 1WR7; -. DR AlphaFoldDB; Q8CFI0; -. DR BMRB; Q8CFI0; -. DR SMR; Q8CFI0; -. DR DIP; DIP-48843N; -. DR IntAct; Q8CFI0; 10. DR MINT; Q8CFI0; -. DR STRING; 10090.ENSMUSP00000158026; -. DR TCDB; 8.A.30.1.1; the nedd4-family interacting protein-2 (nedd4) family. DR GlyGen; Q8CFI0; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q8CFI0; -. DR PhosphoSitePlus; Q8CFI0; -. DR EPD; Q8CFI0; -. DR jPOST; Q8CFI0; -. DR MaxQB; Q8CFI0; -. DR PaxDb; 10090-ENSMUSP00000132838; -. DR PeptideAtlas; Q8CFI0; -. DR ProteomicsDB; 253057; -. [Q8CFI0-1] DR ProteomicsDB; 253058; -. [Q8CFI0-2] DR ProteomicsDB; 253059; -. [Q8CFI0-3] DR Pumba; Q8CFI0; -. DR Antibodypedia; 5421; 332 antibodies from 33 providers. DR Ensembl; ENSMUST00000237410.2; ENSMUSP00000158044.2; ENSMUSG00000024589.19. [Q8CFI0-3] DR UCSC; uc008fen.2; mouse. [Q8CFI0-3] DR AGR; MGI:1933754; -. DR MGI; MGI:1933754; Nedd4l. DR VEuPathDB; HostDB:ENSMUSG00000024589; -. DR eggNOG; KOG0940; Eukaryota. DR GeneTree; ENSGT00940000156873; -. DR InParanoid; Q8CFI0; -. DR PhylomeDB; Q8CFI0; -. DR Reactome; R-MMU-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity. DR Reactome; R-MMU-2672351; Stimuli-sensing channels. DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR UniPathway; UPA00143; -. DR ChiTaRS; Nedd4l; mouse. DR EvolutionaryTrace; Q8CFI0; -. DR PRO; PR:Q8CFI0; -. DR Proteomes; UP000000589; Chromosome 18. DR RNAct; Q8CFI0; Protein. DR Bgee; ENSMUSG00000024589; Expressed in caudate-putamen and 271 other cell types or tissues. DR ExpressionAtlas; Q8CFI0; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell. DR GO; GO:0005771; C:multivesicular body; IEA:UniProtKB-SubCell. DR GO; GO:0019870; F:potassium channel inhibitor activity; ISO:MGI. DR GO; GO:0015459; F:potassium channel regulator activity; ISO:MGI. DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:MGI. DR GO; GO:0017080; F:sodium channel regulator activity; ISO:MGI. DR GO; GO:0044325; F:transmembrane transporter binding; ISO:MGI. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISO:MGI. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0051649; P:establishment of localization in cell; IMP:MGI. DR GO; GO:1901380; P:negative regulation of potassium ion transmembrane transport; ISO:MGI. DR GO; GO:2000009; P:negative regulation of protein localization to cell surface; ISO:MGI. DR GO; GO:1902306; P:negative regulation of sodium ion transmembrane transport; ISO:MGI. DR GO; GO:0010766; P:negative regulation of sodium ion transport; IDA:MGI. DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IMP:MGI. DR GO; GO:2001288; P:positive regulation of caveolin-mediated endocytosis; ISO:MGI. DR GO; GO:1903861; P:positive regulation of dendrite extension; ISO:MGI. DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISO:MGI. DR GO; GO:0010765; P:positive regulation of sodium ion transport; IGI:MGI. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISO:MGI. DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISO:MGI. DR GO; GO:0006513; P:protein monoubiquitination; ISO:MGI. DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB. DR GO; GO:2000810; P:regulation of bicellular tight junction assembly; IDA:MGI. DR GO; GO:0048814; P:regulation of dendrite morphogenesis; IBA:GO_Central. DR GO; GO:0003254; P:regulation of membrane depolarization; ISO:MGI. DR GO; GO:0042391; P:regulation of membrane potential; ISO:MGI. DR GO; GO:0060306; P:regulation of membrane repolarization; ISO:MGI. DR GO; GO:0034765; P:regulation of monoatomic ion transmembrane transport; ISO:MGI. DR GO; GO:0031647; P:regulation of protein stability; ISS:UniProtKB. DR GO; GO:1902305; P:regulation of sodium ion transmembrane transport; ISS:UniProtKB. DR GO; GO:0002028; P:regulation of sodium ion transport; IDA:MGI. DR GO; GO:0009651; P:response to salt stress; IMP:MGI. DR GO; GO:0006814; P:sodium ion transport; IMP:MGI. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:MGI. DR GO; GO:0086005; P:ventricular cardiac muscle cell action potential; ISO:MGI. DR CDD; cd04033; C2_NEDD4_NEDD4L; 1. DR CDD; cd00078; HECTc; 1. DR CDD; cd00201; WW; 4. DR Gene3D; 2.20.70.10; -; 3. DR Gene3D; 2.60.40.150; C2 domain; 1. DR Gene3D; 3.30.2160.10; Hect, E3 ligase catalytic domain; 1. DR Gene3D; 3.30.2410.10; Hect, E3 ligase catalytic domain; 1. DR Gene3D; 3.90.1750.10; Hect, E3 ligase catalytic domains; 1. DR InterPro; IPR000008; C2_dom. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR024928; E3_ub_ligase_SMURF1. DR InterPro; IPR000569; HECT_dom. DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase. DR InterPro; IPR001202; WW_dom. DR InterPro; IPR036020; WW_dom_sf. DR PANTHER; PTHR11254:SF310; E3 UBIQUITIN-PROTEIN LIGASE NEDD4-LIKE; 1. DR PANTHER; PTHR11254; HECT DOMAIN UBIQUITIN-PROTEIN LIGASE; 1. 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; C2 domain (Calcium/lipid-binding domain, CaLB); 1. DR SUPFAM; SSF56204; Hect, E3 ligase catalytic domain; 1. DR SUPFAM; SSF51045; WW domain; 4. DR PROSITE; PS50004; C2; 1. DR PROSITE; PS50237; HECT; 1. DR PROSITE; PS01159; WW_DOMAIN_1; 4. DR PROSITE; PS50020; WW_DOMAIN_2; 4. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Differentiation; Endosome; KW Golgi apparatus; Phosphoprotein; Reference proteome; Repeat; Transferase; KW Ubl conjugation; Ubl conjugation pathway. FT CHAIN 1..1004 FT /note="E3 ubiquitin-protein ligase NEDD4-like" FT /id="PRO_0000120324" FT DOMAIN 30..154 FT /note="C2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT DOMAIN 221..254 FT /note="WW 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 414..447 FT /note="WW 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 526..559 FT /note="WW 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 577..610 FT /note="WW 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 669..1003 FT /note="HECT" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104" FT REGION 207..230 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 272..407 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 453..523 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 272..289 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 330..402 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 453..484 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 971 FT /note="Glycyl thioester intermediate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104" FT MOD_RES 341 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96PU5" FT MOD_RES 347 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q96PU5" FT MOD_RES 371 FT /note="Phosphoserine; by WNK1 and WNK4" FT /evidence="ECO:0000269|PubMed:11742982" FT MOD_RES 396 FT /note="Phosphothreonine; by SGK1" FT /evidence="ECO:0000250|UniProtKB:Q96PU5" FT MOD_RES 475 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96PU5" FT MOD_RES 477 FT /note="Phosphoserine; by SGK1" FT /evidence="ECO:0000269|PubMed:11742982, FT ECO:0000269|PubMed:15958725" FT MOD_RES 478 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 493 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 504 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96PU5" FT MOD_RES 508 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17242355, FT ECO:0007744|PubMed:21183079" FT MOD_RES 512 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 516 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT VAR_SEQ 1..149 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11149908, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015450" FT VAR_SEQ 385..404 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:12424229, FT ECO:0000303|PubMed:16141072" FT /id="VSP_015453" FT MUTAGEN 371 FT /note="S->A: Weakly reduces phosphorylation by SGK1." FT /evidence="ECO:0000269|PubMed:11742982" FT MUTAGEN 477 FT /note="S->A: Strongly reduces phosphorylation by SGK1." FT /evidence="ECO:0000269|PubMed:11742982" FT MUTAGEN 971 FT /note="C->S: Abolishes activity." FT /evidence="ECO:0000269|PubMed:11149908" FT CONFLICT 179 FT /note="A -> G (in Ref. 1; AAK00809)" FT /evidence="ECO:0000305" FT CONFLICT 390 FT /note="R -> G (in Ref. 1; AAK00809)" FT /evidence="ECO:0000305" FT CONFLICT 403 FT /note="P -> S (in Ref. 1; AAK00809)" FT /evidence="ECO:0000305" FT CONFLICT 585 FT /note="E -> G (in Ref. 1; AAK00809)" FT /evidence="ECO:0000305" FT CONFLICT 832 FT /note="N -> T (in Ref. 1; AAK00809)" FT /evidence="ECO:0000305" FT CONFLICT 847 FT /note="N -> D (in Ref. 1; AAK00809)" FT /evidence="ECO:0000305" FT CONFLICT 949 FT /note="N -> K (in Ref. 4; BAC31307)" FT /evidence="ECO:0000305" FT STRAND 227..231 FT /evidence="ECO:0007829|PDB:1WR3" FT STRAND 233..235 FT /evidence="ECO:0007829|PDB:1WR3" FT STRAND 237..241 FT /evidence="ECO:0007829|PDB:1WR3" FT TURN 242..244 FT /evidence="ECO:0007829|PDB:1WR3" FT STRAND 247..250 FT /evidence="ECO:0007829|PDB:1WR3" FT STRAND 420..424 FT /evidence="ECO:0007829|PDB:1WR4" FT STRAND 426..428 FT /evidence="ECO:0007829|PDB:1WR4" FT STRAND 430..434 FT /evidence="ECO:0007829|PDB:1WR4" FT TURN 435..438 FT /evidence="ECO:0007829|PDB:1WR4" FT STRAND 439..443 FT /evidence="ECO:0007829|PDB:1WR4" FT STRAND 532..536 FT /evidence="ECO:0007829|PDB:1WR7" FT STRAND 542..546 FT /evidence="ECO:0007829|PDB:1WR7" FT TURN 547..550 FT /evidence="ECO:0007829|PDB:1WR7" FT STRAND 551..555 FT /evidence="ECO:0007829|PDB:1WR7" FT HELIX 557..559 FT /evidence="ECO:0007829|PDB:1WR7" SQ SEQUENCE 1004 AA; 115419 MW; 50CBB3436052AA60 CRC64; MSLCEAPVHV GDKELKYFQI PQMLSQLSLL ASHHSRGLEF SGGQGESRIL RVKVVSGIDL AKKDIFGASD PYVKLSLYVA DENRELALVQ TKTIKKTLNP KWNEEFYFRV NPSNHRLLFE VFDENRLTRD DFLGQVDVPL SHLPTEDPTM ERPYTFKDFL LRPRSHKSRV KGFLRLKMAY MPKNGGQDEE NSEQRDDMEH GWEVVDSNDS ASQHQEELPP PPLPPGWEEK VDNLGRTYYV NHNNRSTQWH RPSLMDVSSE SDNNIRQINQ EAAHRRFRSR RHISEDLEPE ASEGGGEGPE PWETISEEMN MAGDSLSLAL PPPPASPVSR TSPQELSEEV SRRLQITPDS NGEQFSSLIQ REPSSRLRSC SVTDTVAEQA HLPPPSTPTR RARSSTVTGG EEPTPSVAYV HTTPGLPSGW EERKDAKGRT YYVNHNNRTT TWTRPIMQLA EDGASGSATN SNNHLVEPQI RRPRSLSSPT VTLSAPLEGA KDSPIRRAVK DTLSNPQSPQ PSPYNSPKPQ HKVTQSFLPP GWEMRIAPNG RPFFIDHNTK TTTWEDPRLK FPVHMRSKAS LNPNDLGPLP PGWEERIHLD GRTFYIDHNS KITQWEDPRL QNPAITGPAV PYSREFKQKY DYFRKKLKKP ADIPNRFEMK LHRNNIFEES YRRIMSVKRP DVLKARLWIE FESEKGLDYG GVAREWFFLL SKEMFNPYYG LFEYSATDNY TLQINPNSGL CNEDHLSYFT FIGRVAGLAV FHGKLLDGFF IRPFYKMMLG KQITLNDMES VDSEYYNSLK WILENDPTEL DLMFCIDEEN FGQTYQVDLK PNGSEIMVTN ENKREYIDLV IQWRFVNRVQ KQMNAFLEGF TELLPIDLIK IFDENELELL MCGLGDVDVN DWRQHSIYKN GYCPNHPVIQ WFWKAVLLMD AEKRIRLLQF VTGTSRVPMN GFAELYGSNG PQLFTIEQWG SPEKLPRAHT CFNRLDLPPY ETFEDLREKL LMAVENAQGF EGVD //