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Q96PU5 (NED4L_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 123. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase NEDD4-like

EC=6.3.2.-
Alternative name(s):
NEDD4.2
Nedd4-2
Gene names
Name:NEDD4L
Synonyms:KIAA0439, NEDL3
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length975 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2. Ref.15 Ref.16 Ref.17 Ref.19 Ref.21 Ref.22 Ref.30

Enzyme regulation

Activated by NDFIP1- and NDFIP2-binding.

Pathway

Protein modification; protein ubiquitination.

Subunit structure

Interacts with UBE2E3 By similarity. Interacts with NDFIP1 and NDFIP2 By similarity; this interaction activates the E3 ubiquitin-protein ligase. Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A and CLCN5. Interacts with SMAD2, SMAD3, SMAD6 and SMAD7. The phosphorylated form interacts with 14-3-3 proteins. Interacts with Epstein-Barr virus LMP2A. Interacts with TNK2. Interacts with WNK1. Interacts with SGK1. Interacts (via C2 domain) with NPC2. Ref.2 Ref.11 Ref.12 Ref.13 Ref.14 Ref.16 Ref.17 Ref.20 Ref.21 Ref.28 Ref.30 Ref.32 Ref.33 Ref.34

Subcellular location

Cytoplasm. Note: May be recruited to exosomes by NDFIP1. Ref.21 Ref.24

Tissue specificity

Ubiquitously expressed, with highest levels in prostate, pancreas and kidney. Ref.3 Ref.21 Ref.28

Induction

By androgens in prostate, and by albumin in kidney. Ref.3 Ref.17

Post-translational modification

Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation. Ref.11 Ref.13 Ref.18 Ref.32 Ref.34

Auto-ubiquitinated.

Sequence similarities

Contains 1 C2 domain.

Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.

Contains 4 WW domains.

Sequence caution

The sequence BAA23711.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

The sequence BAA23711.1 differs from that shown. Reason: Probable cloning artifact.

Ontologies

Keywords
   Biological processHost-virus interaction
Ubl conjugation pathway
   Cellular componentCytoplasm
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainRepeat
   Molecular functionLigase
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processcellular sodium ion homeostasis

Non-traceable author statement PubMed 11244092. Source: UniProtKB

excretion

Non-traceable author statement PubMed 11244092. Source: UniProtKB

gene expression

Traceable author statement. Source: Reactome

ion transmembrane transport

Traceable author statement. Source: Reactome

negative regulation of potassium ion transmembrane transport

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

negative regulation of potassium ion transmembrane transporter activity

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

negative regulation of protein localization to cell surface

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

negative regulation of sodium ion transmembrane transport

Inferred from direct assay Ref.16. Source: BHF-UCL

negative regulation of sodium ion transmembrane transporter activity

Inferred from direct assay Ref.16. Source: BHF-UCL

negative regulation of systemic arterial blood pressure

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Traceable author statement. Source: Reactome

negative regulation of transforming growth factor beta receptor signaling pathway

Traceable author statement. Source: Reactome

positive regulation of cation channel activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of caveolin-mediated endocytosis

Inferred from sequence or structural similarity PubMed 22879586. Source: BHF-UCL

positive regulation of endocytosis

Non-traceable author statement PubMed 11244092. Source: UniProtKB

positive regulation of protein catabolic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of sodium ion transport

Inferred from electronic annotation. Source: Ensembl

proteasome-mediated ubiquitin-dependent protein catabolic process

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

protein K48-linked ubiquitination

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

protein monoubiquitination

Inferred from electronic annotation. Source: Ensembl

protein ubiquitination

Non-traceable author statement PubMed 11244092. Source: UniProtKB

protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

regulation of ion transmembrane transport

Inferred from direct assay PubMed 17289006. Source: BHF-UCL

regulation of membrane depolarization

Inferred from direct assay Ref.16. Source: BHF-UCL

regulation of membrane potential

Inferred from direct assay PubMed 17289006. Source: BHF-UCL

regulation of membrane repolarization

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

regulation of potassium ion transmembrane transporter activity

Inferred from direct assay PubMed 17289006. Source: BHF-UCL

regulation of protein catabolic process

Non-traceable author statement PubMed 11244092. Source: UniProtKB

regulation of tight junction assembly

Inferred from electronic annotation. Source: Ensembl

response to metal ion

Inferred from direct assay PubMed 11244092. Source: UniProtKB

response to salt stress

Inferred from electronic annotation. Source: Ensembl

sodium ion transport

Non-traceable author statement PubMed 11244092. Source: UniProtKB

transcription initiation from RNA polymerase II promoter

Traceable author statement. Source: Reactome

transcription, DNA-templated

Traceable author statement. Source: Reactome

transforming growth factor beta receptor signaling pathway

Traceable author statement. Source: Reactome

transmembrane transport

Traceable author statement. Source: Reactome

ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

Inferred from electronic annotation. Source: Ensembl

ventricular cardiac muscle cell action potential

Inferred from sequence or structural similarity PubMed 22879586. Source: BHF-UCL

viral life cycle

Traceable author statement. Source: Reactome

viral process

Traceable author statement. Source: Reactome

water homeostasis

Non-traceable author statement PubMed 11244092. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

cytosol

Traceable author statement. Source: Reactome

intracellular

Inferred by curator PubMed 11244092. Source: UniProtKB

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Molecular_functionion channel binding

Inferred from physical interaction Ref.16PubMed 21463633. Source: BHF-UCL

potassium channel inhibitor activity

Inferred from direct assay PubMed 21463633. Source: BHF-UCL

potassium channel regulator activity

Inferred from direct assay PubMed 17289006. Source: BHF-UCL

sodium channel inhibitor activity

Inferred from direct assay Ref.16. Source: BHF-UCL

sodium channel regulator activity

Inferred from direct assay PubMed 11244092. Source: UniProtKB

ubiquitin-protein ligase activity

Non-traceable author statement PubMed 11244092. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 8 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q96PU5-1)

Also known as: Nedd4-2c;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q96PU5-2)

The sequence of this isoform differs from the canonical sequence as follows:
     356-419: Missing.
Note: No experimental confirmation available.
Isoform 3 (identifier: Q96PU5-3)

Also known as: NEDD4Le;

The sequence of this isoform differs from the canonical sequence as follows:
     356-459: Missing.
Note: No experimental confirmation available.
Isoform 4 (identifier: Q96PU5-4)

Also known as: NEDD4La; NEDD4Lb; NEDD4Lf;

The sequence of this isoform differs from the canonical sequence as follows:
     1-121: Missing.
Isoform 5 (identifier: Q96PU5-5)

Also known as: NEDD4Ld;

The sequence of this isoform differs from the canonical sequence as follows:
     356-375: Missing.
Isoform 6 (identifier: Q96PU5-6)

Also known as: NEDD4Lh;

The sequence of this isoform differs from the canonical sequence as follows:
     1-16: MATGLGEPVYGLSEDE → MRRLAFEQ
     356-375: Missing.
Isoform 7 (identifier: Q96PU5-7)

Also known as: NEDD4Lg;

The sequence of this isoform differs from the canonical sequence as follows:
     1-16: MATGLGEPVYGLSEDE → MRRLAFEQ
Isoform 8 (identifier: Q96PU5-9)

The sequence of this isoform differs from the canonical sequence as follows:
     1-121: Missing.
     356-375: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.38
Chain2 – 975974E3 ubiquitin-protein ligase NEDD4-like
PRO_0000120323

Regions

Domain7 – 109103C2
Domain193 – 22634WW 1
Domain385 – 41834WW 2
Domain497 – 53034WW 3
Domain548 – 58134WW 4
Domain640 – 974335HECT

Sites

Active site9421Glycyl thioester intermediate

Amino acid modifications

Modified residue21N-acetylalanine Ref.38
Modified residue3181Phosphothreonine Ref.26
Modified residue3421Phosphoserine; by WNK1 and WNK4 Ref.18 Ref.26 Ref.32
Modified residue3671Phosphothreonine; by SGK1 Probable
Modified residue4461Phosphoserine Ref.26 Ref.31
Modified residue4481Phosphoserine; by PKA and SGK1 Ref.11 Ref.18
Modified residue4491Phosphoserine; by WNK1 and WNK4 Ref.26 Ref.32
Modified residue4641Phosphoserine Ref.26
Modified residue4791Phosphoserine Ref.23 Ref.26 Ref.35 Ref.37
Modified residue4831Phosphoserine Ref.35 Ref.37
Modified residue4871Phosphoserine Ref.26 Ref.37

Natural variations

Alternative sequence1 – 121121Missing in isoform 4 and isoform 8.
VSP_015444
Alternative sequence1 – 1616MATGL…LSEDE → MRRLAFEQ in isoform 6 and isoform 7.
VSP_015446
Alternative sequence356 – 459104Missing in isoform 3.
VSP_015447
Alternative sequence356 – 41964Missing in isoform 2.
VSP_015448
Alternative sequence356 – 37520Missing in isoform 5, isoform 6 and isoform 8.
VSP_043848
Natural variant3551P → L Common polymorphism; impaired ability to inhibit SCNN. Ref.39
VAR_023415
Natural variant4971S → R. Ref.39
VAR_023416

Experimental info

Mutagenesis4481S → A: Abolishes interaction with 1433F. Ref.11
Mutagenesis9421C → S: Abolishes activity. Ref.16
Sequence conflict521A → P in AAM76729. Ref.3
Sequence conflict521A → P in AAM76730. Ref.3
Sequence conflict1881E → K in AAP75706. Ref.2

Secondary structure

................................................................................................................. 975
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Nedd4-2c) [UniParc].

Last modified August 30, 2005. Version 2.
Checksum: 2C958625B4A1AB3F

FASTA975111,932
        10         20         30         40         50         60 
MATGLGEPVY GLSEDEGESR ILRVKVVSGI DLAKKDIFGA SDPYVKLSLY VADENRELAL 

        70         80         90        100        110        120 
VQTKTIKKTL NPKWNEEFYF RVNPSNHRLL FEVFDENRLT RDDFLGQVDV PLSHLPTEDP 

       130        140        150        160        170        180 
TMERPYTFKD FLLRPRSHKS RVKGFLRLKM AYMPKNGGQD EENSDQRDDM EHGWEVVDSN 

       190        200        210        220        230        240 
DSASQHQEEL PPPPLPPGWE EKVDNLGRTY YVNHNNRTTQ WHRPSLMDVS SESDNNIRQI 

       250        260        270        280        290        300 
NQEAAHRRFR SRRHISEDLE PEPSEGGDVP EPWETISEEV NIAGDSLGLA LPPPPASPGS 

       310        320        330        340        350        360 
RTSPQELSEE LSRRLQITPD SNGEQFSSLI QREPSSRLRS CSVTDAVAEQ GHLPPPSAPA 

       370        380        390        400        410        420 
GRARSSTVTG GEEPTPSVAY VHTTPGLPSG WEERKDAKGR TYYVNHNNRT TTWTRPIMQL 

       430        440        450        460        470        480 
AEDGASGSAT NSNNHLIEPQ IRRPRSLSSP TVTLSAPLEG AKDSPVRRAV KDTLSNPQSP 

       490        500        510        520        530        540 
QPSPYNSPKP QHKVTQSFLP PGWEMRIAPN GRPFFIDHNT KTTTWEDPRL KFPVHMRSKT 

       550        560        570        580        590        600 
SLNPNDLGPL PPGWEERIHL DGRTFYIDHN SKITQWEDPR LQNPAITGPA VPYSREFKQK 

       610        620        630        640        650        660 
YDYFRKKLKK PADIPNRFEM KLHRNNIFEE SYRRIMSVKR PDVLKARLWI EFESEKGLDY 

       670        680        690        700        710        720 
GGVAREWFFL LSKEMFNPYY GLFEYSATDN YTLQINPNSG LCNEDHLSYF TFIGRVAGLA 

       730        740        750        760        770        780 
VFHGKLLDGF FIRPFYKMML GKQITLNDME SVDSEYYNSL KWILENDPTE LDLMFCIDEE 

       790        800        810        820        830        840 
NFGQTYQVDL KPNGSEIMVT NENKREYIDL VIQWRFVNRV QKQMNAFLEG FTELLPIDLI 

       850        860        870        880        890        900 
KIFDENELEL LMCGLGDVDV NDWRQHSIYK NGYCPNHPVI QWFWKAVLLM DAEKRIRLLQ 

       910        920        930        940        950        960 
FVTGTSRVPM NGFAELYGSN GPQLFTIEQW GSPEKLPRAH TCFNRLDLPP YETFEDLREK 

       970 
LLMAVENAQG FEGVD 

« Hide

Isoform 2 [UniParc].

Checksum: CE04AAED677AA506
Show »

FASTA911104,922
Isoform 3 (NEDD4Le) [UniParc].

Checksum: 5E2AB9B510060D4A
Show »

FASTA871100,752
Isoform 4 (NEDD4La) (NEDD4Lb) (NEDD4Lf) [UniParc].

Checksum: 00C74E1661F52E7F
Show »

FASTA85498,181
Isoform 5 (NEDD4Ld) [UniParc].

Checksum: A8BB278A37F6A6B5
Show »

FASTA955110,022
Isoform 6 (NEDD4Lh) [UniParc].

Checksum: F107E5A8E0C3BB8D
Show »

FASTA947109,404
Isoform 7 (NEDD4Lg) [UniParc].

Checksum: 9786AC67C8CD165F
Show »

FASTA967111,314
Isoform 8 [UniParc].

Checksum: 47C33C4FB577C3DB
Show »

FASTA83496,271

References

« Hide 'large scale' references
[1]"NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene."
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.
Eur. J. Hum. Genet. 9:922-930(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), ALTERNATIVE SPLICING.
[2]"Identification of new partners of the epithelial sodium channel alpha subunit."
Malbert-Colas L., Nicolas G., Galand C., Lecomte M.-C., Dhermy D.
C. R. Biol. 326:615-624(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G.
Tissue: Kidney.
[3]"Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells."
Qi H., Grenier J., Fournier A., Labrie C.
Mol. Cell. Endocrinol. 210:51-62(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4; 6 AND 7), TISSUE SPECIFICITY, INDUCTION.
Tissue: Prostate.
[4]"Homo sapiens NEDD4-like ubiquitin ligase 3."
Okamoto Y., Miyazaki K., Sakamoto M., Kato C., Nakagawara A.
Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
[5]"NEDD4L transcripts expressed in human prostate cells."
Qi H., Labrie C.
Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8).
[6]"DNA sequence and analysis of human chromosome 18."
Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J. expand/collapse author list , Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.
Nature 437:551-555(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 101-975 (ISOFORM 5).
Tissue: Skin and Uterus.
[9]"Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro."
Ishikawa K., Nagase T., Nakajima D., Seki N., Ohira M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 4:307-313(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8).
Tissue: Brain.
[10]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 52-975 (ISOFORM 3).
Tissue: Testis.
[11]"14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase."
Ichimura T., Yamamura H., Sasamoto K., Tominaga Y., Taoka M., Kakiuchi K., Shinkawa T., Takahashi N., Shimada S., Isobe T.
J. Biol. Chem. 280:13187-13194(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 448-462, INTERACTION WITH YWHAB; YWHAG; YWHAE; YWHAQ AND YWHAH, PHOSPHORYLATION AT SER-448, MUTAGENESIS OF SER-448, IDENTIFICATION BY MASS SPECTROMETRY.
[12]"Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases."
Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G., Ingham R., Ernberg I., Pawson T.
Mol. Cell. Biol. 20:8526-8535(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EPSTEIN-BARR VIRUS LMP2A.
[13]"Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel."
Snyder P.M., Olson D.R., Thomas B.C.
J. Biol. Chem. 277:5-8(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SGK1 AND SCNN1A, PHOSPHORYLATION.
[14]"N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein."
Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S.
J. Biol. Chem. 277:9307-9317(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NDFIP1.
[15]"Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B."
Boehmer C., Henke G., Schniepp R., Palmada M., Rothstein J.D., Broeer S., Lang F.
J. Neurochem. 86:1181-1188(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[16]"Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination."
van Bemmelen M.X., Rougier J.-S., Gavillet B., Apotheloz F., Daidie D., Tateyama M., Rivolta I., Thomas M.A., Kass R.S., Staub O., Abriel H.
Circ. Res. 95:284-291(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF CYS-942, INTERACTION WITH SCN5A.
[17]"Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells."
Hryciw D.H., Ekberg J., Lee A., Lensink I.L., Kumar S., Guggino W.B., Cook D.I., Pollock C.A., Poronnik P.
J. Biol. Chem. 279:54996-55007(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH CLCN5, INDUCTION.
[18]"cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2."
Snyder P.M., Olson D.R., Kabra R., Zhou R., Steines J.C.
J. Biol. Chem. 279:45753-45758(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-342; THR-367 AND SER-448.
[19]"Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1."
Henke G., Maier G., Wallisch S., Boehmer C., Lang F.
J. Cell. Physiol. 199:194-199(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[20]"Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins."
Rougier J.-S., van Bemmelen M.X., Bruce M.C., Jespersen T., Gavillet B., Apotheloz F., Cordonier S., Staub O., Rotin D., Abriel H.
Am. J. Physiol. 288:C692-C701(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SCN2A; SCN3A AND SCN5A.
[21]"NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor."
Kuratomi G., Komuro A., Goto K., Shinozaki M., Miyazawa K., Miyazono K., Imamura T.
Biochem. J. 386:461-470(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SMAD2; SMAD3; SMAD6 AND SMAD7, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[22]"Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation."
Zhou R., Snyder P.M.
J. Biol. Chem. 280:4518-4523(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[23]"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[24]"Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins."
Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J., Tan S.S.
J. Biol. Chem. 283:32621-32627(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[25]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[26]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-318; SER-342; SER-446; SER-449; SER-464; SER-479 AND SER-487, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[27]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[28]"Identification of NPC2 protein as interaction molecule with C2 domain of human Nedd4L."
Araki N., Ishigami T., Ushio H., Minegishi S., Umemura M., Miyagi Y., Aoki I., Morinaga H., Tamura K., Toya Y., Uchino K., Umemura S.
Biochem. Biophys. Res. Commun. 388:290-296(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NPC2, TISSUE SPECIFICITY.
[29]"Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins."
Mund T., Pelham H.R.
EMBO Rep. 10:501-507(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACTIVATION BY NDFIP1 AND NDFIP2, AUTOUBIQUITINATION.
[30]"Down-regulation of active ACK1 is mediated by association with the E3 ubiquitin ligase Nedd4-2."
Chan W., Tian R., Lee Y.-F., Sit S.T., Lim L., Manser E.
J. Biol. Chem. 284:8185-8194(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS A UBIQUITIN-PROTEIN LIGASE FOR TNK2, INTERACTION WITH TNK2.
[31]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-446, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[32]"Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members."
Heise C.J., Xu B.E., Deaton S.L., Cha S.K., Cheng C.J., Earnest S., Sengupta S., Juang Y.C., Stippec S., Xu Y., Zhao Y., Huang C.L., Cobb M.H.
J. Biol. Chem. 285:25161-25167(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-342 AND SER-449, INTERACTION WITH WNK1.
[33]"HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK."
Lin Q., Wang J., Childress C., Sudol M., Carey D.J., Yang W.
Mol. Cell. Biol. 30:1541-1554(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TNK2.
[34]"Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1) with the WW-domains of Nedd4-2 is required for epithelial sodium channel regulation."
Wiemuth D., Lott J.S., Ly K., Ke Y., Teesdale-Spittle P., Snyder P.M., McDonald F.J.
PLoS ONE 5:E12163-E12163(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY SGK1, INTERACTION WITH SGK1.
[35]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479 AND SER-483, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[36]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[37]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-479; SER-483 AND SER-487, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[38]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
[39]"A naturally occurring human Nedd4-2 variant displays impaired ENaC regulation in Xenopus laevis oocytes."
Fouladkou F., Alikhani-Koopaei R., Vogt B., Flores S.Y., Malbert-Colas L., Lecomte M.-C., Loffing J., Frey F.J., Frey B.M., Staub O.
Am. J. Physiol. 287:F550-F561(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS LEU-355 AND ARG-497.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF210730 mRNA. Translation: AAG43524.1.
AF385931 mRNA. Translation: AAM46208.1.
AY312514 mRNA. Translation: AAP75706.1.
AY112983 mRNA. Translation: AAM76728.1.
AY112984 mRNA. Translation: AAM76729.1.
AY112985 mRNA. Translation: AAM76730.1.
AB071179 mRNA. Translation: BAB69424.1.
DQ181796 mRNA. Translation: ABA10330.1.
AC015988 Genomic DNA. No translation available.
AC090236 Genomic DNA. No translation available.
AC107896 Genomic DNA. No translation available.
CH471096 Genomic DNA. Translation: EAW63065.1.
BC000621 mRNA. Translation: AAH00621.2.
BC019345 mRNA. Translation: AAH19345.1.
BC032597 mRNA. Translation: AAH32597.1.
AB007899 mRNA. Translation: BAA23711.1. Different initiation.
AL137469 mRNA. Translation: CAB70754.1.
PIRT46412.
RefSeqNP_001138436.1. NM_001144964.1.
NP_001138437.1. NM_001144965.1.
NP_001138438.1. NM_001144966.2.
NP_001138439.1. NM_001144967.2.
NP_001138440.1. NM_001144968.1.
NP_001138441.1. NM_001144969.1.
NP_001138442.1. NM_001144970.2.
NP_001138443.1. NM_001144971.1.
NP_001230889.1. NM_001243960.1.
NP_056092.2. NM_015277.5.
UniGeneHs.185677.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2LAJNMR-A496-535[»]
2LB2NMR-A386-420[»]
2LTYNMR-A385-417[»]
2NSQX-ray1.85A1-154[»]
2ONIX-ray2.20A594-967[»]
3JVZX-ray3.30C/D596-975[»]
3JW0X-ray3.10C/D596-975[»]
ProteinModelPortalQ96PU5.
SMRQ96PU5. Positions 6-154, 193-252, 382-966.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid116915. 159 interactions.
DIPDIP-41935N.
IntActQ96PU5. 20 interactions.
MINTMINT-148327.

PTM databases

PhosphoSiteQ96PU5.

Polymorphism databases

DMDM73921204.

Proteomic databases

PaxDbQ96PU5.
PRIDEQ96PU5.

Protocols and materials databases

DNASU23327.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000256830; ENSP00000256830; ENSG00000049759. [Q96PU5-3]
ENST00000356462; ENSP00000348847; ENSG00000049759. [Q96PU5-2]
ENST00000357895; ENSP00000350569; ENSG00000049759. [Q96PU5-7]
ENST00000382850; ENSP00000372301; ENSG00000049759. [Q96PU5-5]
ENST00000400345; ENSP00000383199; ENSG00000049759. [Q96PU5-1]
ENST00000431212; ENSP00000389406; ENSG00000049759. [Q96PU5-4]
ENST00000435432; ENSP00000393395; ENSG00000049759. [Q96PU5-9]
ENST00000456173; ENSP00000405440; ENSG00000049759. [Q96PU5-9]
ENST00000456986; ENSP00000411947; ENSG00000049759. [Q96PU5-4]
ENST00000586263; ENSP00000468546; ENSG00000049759. [Q96PU5-6]
GeneID23327.
KEGGhsa:23327.
UCSCuc002lgx.3. human. [Q96PU5-5]
uc002lgy.3. human. [Q96PU5-1]
uc002lgz.3. human. [Q96PU5-2]
uc002lhb.2. human. [Q96PU5-9]
uc002lhc.2. human. [Q96PU5-7]
uc002lhe.2. human. [Q96PU5-6]
uc002lhh.2. human. [Q96PU5-3]

Organism-specific databases

CTD23327.
GeneCardsGC18P055711.
HGNCHGNC:7728. NEDD4L.
HPAHPA024618.
MIM606384. gene.
neXtProtNX_Q96PU5.
PharmGKBPA31534.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5021.
HOVERGENHBG004134.
KOK13305.
OMAEQRDDME.
OrthoDBEOG7RFTGT.
PhylomeDBQ96PU5.
TreeFamTF323658.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_15518. Transmembrane transport of small molecules.
REACT_6900. Immune System.
REACT_71. Gene Expression.
SignaLinkQ96PU5.
UniPathwayUPA00143.

Gene expression databases

ArrayExpressQ96PU5.
BgeeQ96PU5.
GenevestigatorQ96PU5.

Family and domain databases

Gene3D2.60.40.150. 1 hit.
InterProIPR000008. C2_dom.
IPR024928. E3_ub_ligase_SMURF1.
IPR000569. HECT.
IPR001202. WW_dom.
[Graphical view]
PfamPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 4 hits.
[Graphical view]
PIRSFPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
PRINTSPR00360. C2DOMAIN.
SMARTSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
[Graphical view]
SUPFAMSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 4 hits.
SSF56204. SSF56204. 1 hit.
PROSITEPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSNEDD4L. human.
EvolutionaryTraceQ96PU5.
GeneWikiNEDD4L.
GenomeRNAi23327.
NextBio45240.
PROQ96PU5.
SOURCESearch...

Entry information

Entry nameNED4L_HUMAN
AccessionPrimary (citable) accession number: Q96PU5
Secondary accession number(s): O43165 expand/collapse secondary AC list , Q3LSM7, Q7Z5F1, Q7Z5F2, Q7Z5N3, Q8N5A7, Q8WUU9, Q9BW58, Q9H2W4, Q9NT88
Entry history
Integrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: August 30, 2005
Last modified: April 16, 2014
This is version 123 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 18

Human chromosome 18: entries, gene names and cross-references to MIM