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FLASH GENE
Symbol NEDD4L contributors: mct/npt/pgu - updated : 08-12-2016
HGNC name neural precursor cell expressed, developmentally down-regulated 4-like
HGNC id 7728
Location 18q21.31      Physical location : 55.711.618 - 56.068.772
Synonym name
  • ubiquitin-protein ligase NEDD4-like
  • ubiquitin-protein ligase Rsp5
  • Synonym symbol(s) KIAA0439, RSP5, NEDD18, NEDL3, hNedd4-2, FLJ33870
    EC.number 6.3.2.-
    DNA
    TYPE functioning gene
    STRUCTURE 357.15 kb     30 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    SE57-1 18q21 CTCL tumor antigen se57-1 TCF4 18q21.1 transcription factor 4 TXNL 18q21.2 thioredoxin-like, 32kDa WDR7 18q21.1-q22 WD repeat domain 7 MGC33608 18q21.31 hypothetical protein MGC33608 SIAT8C 18q21.2 sialyltransferase 8C (alpha2,3Galbeta1,4GlcNAcalpha 2,8-sialyltransferase) ONECUT2 18q21.1-q21.2 one cut domain, family member 2 FECH 18q21.2 ferrochelatase (protoporphyria) NARS 18q21.2-q21.3 asparaginyl-tRNA synthetase ATP8B1 18q21 ATPase, Class I, type 8B, member 1 LOC284288 18q21.31 similar to Ribosomal protein L24-like LOC388476 18 similar to Nonhistone chromosomal protein HMG-14 (High-mobility group nucleosome binding domain 1) NEDD4L 18q21.2 neural precursor cell expressed, developmentally down-regulated 4-like HAK 18q21.31-q21.32 heart alpha-kinase MALT1 18q21 mucosa associated lymphoid tissue lymphoma translocation gene 1 FLJ10697 LOC390858 18 similar to RIKEN cDNA 5330437I02 gene LOC388477 18 LOC388477 LOC90701 18q21.32 similar to signal peptidase complex (18kD) GRP 18q21.31 gastrin-releasing peptide RAX 18q21.31 retina and anterior neural fold homeobox CPLX4 18q21.32 complexin 4 LMAN1 18q21.3-q22 lectin, mannose-binding, 1 FLJ30681 18q21.32 KIAA1983 protein LOC219542 18q21.32 similar to 40S ribosomal protein S26 LOC390859 18 similar to Chain A, Crystal Structure Of The R463a Mutant Of Human Glutamate Dehydrogenase LOC390860 18 similar to 60S acidic ribosomal protein P0 (L10E) PMAIP1 18q21.32 phorbol-12-myristate-13-acetate-induced protein 1 LOC147072 18q21.32 similar to nuclear factor (erythroid-derived 2)-like 3; NF-E2-related factor 3 LOC388478 18 similar to serologically defined colon cancer antigen 3 LOC284289 18q21.32 similar to TERA protein LOC388479 18 similar to 40S ribosomal protein S3a LOC342784 18q21.32 similar to TFIIH basal transcription factor complex p62 subunit (Basic transcription factor 62 kDa subunit) (BTF2-p62) (General transcription factor IIH polypeptide 1) MC4R 18q21.32 melanocortin 4 receptor MRPS5P4 18q21 mitochondrial ribosomal protein S5 pseudogene LOC220147 18q21.32 similar to C-terminal binding protein 2 isoform 2; ribeye
    RNA
    TRANSCRIPTS type
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    31 initiation site 8378 - 967 heart skeletal muscle 2009 19364400
    variant g
    31 initiation site 8388 - 854 other tissues 2009 19364400
    also called NEDD4LA, or variant f
    30 initiation site 8318 - 947 other tissues 2009 19364400
    variant h
    31 - 8473 - 975 - 2009 19364400
    also called NEDD4L variant j
    30 - 8413 - 955 - 2009 19364400
    also called NEDD4-2C6 and NEDL3, variant d
    30 - 8300 - 854 - 2009 19364400
    also called NEDD4L variant a
    31 - 8436 - 854 - 2009 19364400
    variant b
    29 - 8346 - 834 - 2009 19364400
    also called NEDD4L variant c
    31 - 8406 - 834 - 2009 19364400
    also called NEDD4L variant k
    - - - - - - 2008 19664597
  • may interact with other isoforms in a dominant-negative fashion
  • evolutionarily new isoform i, is a candidate gene for hypertension
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   lowly
    Cardiovascularheart    
    Digestiveliver   highly
    Reproductivemale systemprostate  highly
    Respiratoryrespiratory tractlarynx  highly
    Urinarykidneynephron  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Lymphoid    
    Muscularstriatumcardiac  
    Muscularstriatumskeletal  
    Nervouscentral   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a HECT domain (homologous to the E6-AP carboxyl terminus) and ubiquitin-binding site located in the HECT domain that plays a role in the regulation of polyubiquitin chain length
  • a C2 domain that binds phosphoinositides particularly PI(3)P, which is enriched on endosomal membranes (Klos Dehring 2008)and has a Ca2+-dependent association with cellular membranes
  • four WW domains
  • HOMOLOGY
    interspecies homolog to yeast S.cerevisiae Rsp5
    homolog to murine Nedd 4.2
    Homologene
    FAMILY
  • NEDD4 gene family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    text C2 domain is necessary for translocating NEDD4L to the plasma membrane to effectively interact with cell surface SCNN1A, SCNN1B, SCNN1C
    basic FUNCTION
  • playing a role in the regulation of ENaC function (negative regulation of epithelial sodium channel)
  • ubiquitin-protein ligase (ubiquitination)
  • major inactivating enzyme for SCNN1A in urinary tubular cells
  • in response to Ca2+, may be mobilized to the apical membrane via its C2 domain, where it binds SCNN1A via NEDD4L-WW:SCNN1A-PY motif interactions, leading to ubiquitination of the channel by the NEDD4L-HECT domain, with subsequent channel endocytosis and lysosomal degradation
  • regulator of renal sodium channels, that is shown to play a broader role as a general modulator of Smad turnover during TGF-beta signal transduction
  • regulate the epithelial Na+ channel by its ubiquitination and removal from the plasma membrane
  • may regulate TRPV6 protein abundance in intestinal epithelia by controlling TRPV6 ubiquitination (
  • may regulate TRPV6 ubiquitination and degradation at different rates by regulating their interaction (
  • can suppress the onset of cystic fibrosis symptoms by inhibiting SCNN1A in lung epithelia
  • having protective regulatory role against the development of cystic fibrosis
  • ubiquitin ligase that targets the epithelial sodium channel for degradation, and plays a role in the progression of various cancers
  • regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • member of HECT class of E3 ubiquitin ligases
  • CAV3, NEDD4L, and KCNH2 likely form a complex in the plasma membrane
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • ubiquination of RFA1
  • potent negative regulator of amiloride-sensitive epithelium sodium channel SCNN1A, SCNN1B, SCNN1G, SCNN1D
  • phosphorylated form of NEDD4L interacts with 14-3-3 proteins (interaction is dependent on SGK1-catalyzed phosphorylation at Ser-468)
  • differentially interacts with and regulates TTYH1-3, will be important for understanding mechanisms controlling Tweety proteins in physiology and disease
  • NEDD4L binds TNK2 via a conserved PPXY-containing region
  • binds the PY motif of SCNN1A C-terminals and catalyzes ubiquitination of the NH2 terminal of the protein for subsequent degradation
  • phosphorylation of the Pro-Gly-Ser-Pro motif within L1 of SCN8A is necessary for stress-induced current modulation, with positive or negative regulation depending upon the availability of the C-terminal Pro-Ser-Tyr motif to bind NEDD4L
  • NEDD4L mediated ubiquitination regulates the cell surface expression of SLC5A7
  • NEDD4, NEDD4L and ITCH mediate poly-ubiquitination of AMOT/p130
  • NDRG1 upregulates neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) and GLI-similar-3 (GLIS3)
  • CNKSR3 physically interacts with SCNN1A, B, D, NEDD4L, and SGK1 and stimulates SCNN1A, SCNN1B, SCNN1D function in a PDZ domain-dependent, aldosterone-induced manner
  • CAV3 enhances ubiquitin ligase NEDD4L interaction with mature KCNH2 channels in the plasma membrane, leading to decreased channel expression
  • RAB4A decreases the KCNH2 density at the plasma membrane by increasing the endogenous NEDD4L expression
  • WNK3 is an activator of SLC12A3, and NEDD4L is an inhibitor
  • proline-rich exons are modular cassettes that convert WNK1 into a NEDD4L substrate, thereby linking aldosterone and other NEDD4L-suppressing antinatriuretic hormones to SLC12A3 phosphorylation status
  • NDFIP1 is primarily localized in the Golgi apparatus where it recruits NEDD4L to mediate the degradation of mature KCNH2 proteins during channel trafficking to the plasma membrane
  • important negative regulatory function for NEDD4L and NDFIP1 in IgE-dependent mast cell activity
  • cell & other
    REGULATION
    inhibited by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (SGK1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of SCNN1G
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    with NDFIP1 proteins are up-regulated in stressed neurons during brain injury
    constitutional       loss of function
    in lung epithelia causes a CF-like disease, suggesting that normally this E3 ligase provides a protective function against the development of cystic fibrosis symptoms
    constitutional       loss of function
    in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of Na+Cl- cotransporter, elevation of SCNN1B/SCNN1G, but not SCNN1A
    tumoral     --over  
    negative NEDD4L expression is strongly related to the invasion and metastasis of gastric cancer
    Susceptibility
  • to essential hypertension
  • to beta-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease
  • Variant & Polymorphism SNP
  • association between several SNPs and hypertension
  • functional NEDD4L rs4149601 polymorphism influences the efficacy of beta-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection
  • Candidate gene
    Marker
  • NEDD4L expression can be used as an independent prognostic marker of gastric cancer
  • Therapy target
    SystemTypeDisorderPubmed
    miscelleaneoushypertension 
    implications of SCNN1A/NEDD4L systems might reach fruition in the discovery of molecular targets that could serve as therapeutic point of actions for the pharmaceutical management of essential hypertension in the future
    respiratoryCF (mucoviscidosis) 
    search for compounds that enhance NEDD4L activity could provide a useful approach to develop unique treatments for cystic fibrosis
    neurologyneurodegenerativealzheimer
    drugs which inhibit the interaction between SLC5A7 and NEDD4L might be useful for diseases involving decrease in acetylcholine level such as Alzheimer disease
    ANIMAL & CELL MODELS
  • specific ablation of Nedd4L in lung epithelia in mice leads to the development of cystic fibrosis-like symptoms, most likely caused by increased SCNN1A function