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FLASH GENE

Symbol

NEDD4L

contributors: mct/npt/pgu - updated : 08-12-2017

HGNC name	neural precursor cell expressed, developmentally down-regulated 4-like
HGNC id	7728

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001144968 31 initiation site 8378 NP_001138440 - 967 heart skeletal muscle 2009 19364400 variant g NM_001144965 31 initiation site 8388 NP_001138437 - 854 other tissues 2009 19364400 also called NEDD4LA, or variant f NM_001144969 30 initiation site 8318 NP_001138441 - 947 other tissues 2009 19364400 variant h NM_001144967 31 - 8473 NP_001138439 - 975 - 2009 19364400 also called NEDD4L variant j NM_015277 30 - 8413 NP_056092 - 955 - 2009 19364400 also called NEDD4-2C6 and NEDL3, variant d NM_001144966 30 - 8300 NP_001138438 - 854 - 2009 19364400 also called NEDD4L variant a NM_001144964 31 - 8436 NP_001138436 - 854 - 2009 19364400 variant b NM_001144970 29 - 8346 NP_001138442 - 834 - 2009 19364400 also called NEDD4L variant c NM_001144971 31 - 8406 NP_001138443 - 834 - 2009 19364400 also called NEDD4L variant k NEDD4L variant i - - - - - - 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)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic spleen       lowly Cardiovascular heart         Digestive liver       highly Reproductive male system prostate     highly Respiratory respiratory tract larynx     highly Urinary kidney nephron     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid         Muscular striatum cardiac     Muscular striatum skeletal     Nervous central

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
	USP36 binds to and regulates the actions of NEDD4L over different substrates affecting their expression and functions
	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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed miscelleaneous hypertension   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 respiratory CF (mucoviscidosis)   search for compounds that enhance NEDD4L activity could provide a useful approach to develop unique treatments for cystic fibrosis neurology neurodegenerative alzheimer 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