Alternative titles; symbols
HGNC Approved Gene Symbol: NEDD4
Cytogenetic location: 15q21.3 Genomic coordinates (GRCh38): 15:55,826,917-55,993,612 (from NCBI)
Kumar et al. (1992) identified Nedd4 as one of a group of mouse genes that show developmentally regulated expression in embryonic brain. Kumar et al. (1997) showed that Nedd4 is expressed in various other embryonic tissues and persists in most adult tissues. Using antibody raised against a fusion protein, they demonstrated that the Nedd4 protein is localized to the cellular cytoplasm. Kumar et al. (1997) reported that the human NEDD4 protein has 86% amino acid identity with the mouse protein. It has homology to ubiquitin-protein ligases and contains 4 protein-protein interaction (WW) domains and a calcium/phospholipid binding domain.
By sequencing clones obtained from a size-fractionated human immature myeloid cell line cDNA library, Nagase et al. (1995) cloned NEDD4, which they designated KIAA0093. The deduced protein has a C2 domain and is homologous with mouse Nedd4, with which it shares 84% identity. Northern blot analysis detected NEDD4 in all tissues and cell lines examined, except brain.
Imhof and McDonnell (1996) identified NEDD4, which they symbolized RPF1, as the human homolog of yeast RSP5.
Using a human-rodent hybrid panel, Nagase et al. (1995) mapped the NEDD4 gene to chromosome 15. By homology and by fluorescence in situ hybridization, Kumar et al. (1997) mapped the NEDD4 gene to chromosome 15q. By interspecific backcross analysis, they mapped the mouse Nedd4 gene to chromosome 9.
Imhof and McDonnell (1996) found that both human NEDD4 and yeast Rsp5 potentiate hormone-dependent activation of transcription by the human progesterone and glucocorticoid receptors. They used mutant proteins to show that neither the ubiquitin-protein ligase activity nor the WW domains are absolutely required for the potentiation of the steroid receptors.
In Xenopus oocyte studies, Abriel et al. (1999) demonstrated that overexpression of wildtype NEDD4 together with epithelial sodium channel (ENaC; see SCNN1A, 600228) inhibited activity of the channel; catalytically inactive NEDD4 stimulated it. These effects were dependent on the presence of C-terminal PY motifs of ENaC, and changes in channel activity were due entirely to alterations in ENaC numbers at the plasma membrane. Abriel et al. (1999) concluded that NEDD4 is a negative regulator of ENaC and suggested that loss of NEDD4 binding sites in ENaC observed in Liddle syndrome (177200 and see, e.g., 600760.0001) might explain the increase in channel number at the cell surface, increased sodium resorption by the distal nephron, and hence hypertension in that disorder.
Using Far Western assays, Harvey et al. (2001) found that the WW domains of NEDD4 bind with strong affinity to all 3 subunits of the epithelial sodium channel (ENaC): SCNN1A (600228), SCNN1B (600760), and SCNN1G (600761). They concluded that both NEDD4 and the related gene KIAA0439 (NEDD4L; 606384) may play a role in the regulation of ENaC function.
RNA polymerase II (RNAPII; see 180660) becomes ubiquitinated and degraded in response to DNA damage. Anindya et al. (2007) identified NEDD4 as an E3 ubiquitin ligase and found that it associated with and ubiquitinated RNAPII in response to ultraviolet-induced DNA damage in human cells. NEDD4-dependent RNAPII ubiquitination could be reconstituted in vitro in the presence of purified UBA1 (UBE1; 314370) and UBCH7 (UBE2L3; 603721) and epitope-tagged ubiquitin (see 191339). Anindya et al. (2007) found that DNA lesions obstructed RNAPII progression and that transcriptional arrest at these lesions triggered NEDD4 recruitment and RNAPII ubiquitination.
PTEN (601728) is a dual specificity phosphatase involved in downregulating cellular survival and growth responses. Wang et al. (2007) showed that human NEDD4 interacted with and destabilized PTEN by catalyzing its polyubiquitination.
Trotman et al. (2007) showed that NEDD4 could also positively regulate PTEN through monoubiquitination of PTEN in human and mouse cells. Monoubiquitinated PTEN was stabilized by its accumulation in cell nuclei, and it retained its ability to antagonize AKT (AKT1; 164730) and cause apoptosis.
Using in situ hybridization and immunohistochemical analysis, Drinjakovic et al. (2010) found that Nedd4 mRNA and protein were expressed throughout developing Xenopus brain and retina. In retina, Nedd4 expression was enriched in the dendritic inner and outer plexiform layers and at retinal ganglion cell growth cones. Morpholino-based knockdown of Nedd4 in Xenopus oocytes or expression of a dominant-negative Nedd4 mutant showed that Nedd4 was not required for guidance of retinal ganglion cells to the tectum, but that it was required for axon terminal branching and arborization at the tectum. Nedd4 functioned at the growth cone by directing proteasome-mediated degradation of Pten, which tended to oppose axon branching via inhibition of PI3 kinase (see 171833) signaling. Immunoprecipitation analysis revealed that Xenopus Nedd4 and Pten interacted directly in transfected HEK293 cells. Knockdown of Pten along with Nedd4 in Xenopus embryos restored retinal ganglion cell axon branching. Proteasomal degradation of Pten in Xenopus growth cones appeared to involve netrin-1 (NTN1; 601614).
By affinity chromatography of rat brain synaptosome extracts, Kawabe et al. (2010) identified Tnik (610005) among 15 proteins that interacted with immobilized Nedd4. Rap2a (179540) coimmunoprecipitated with Nedd4 and Tnik, but only following protein crosslinking. In vitro ubiquitination experiments revealed that Nedd4 monoubiquitinated Rap2a, but not Tnik or any other Ras (HRAS; 190020)-related small GTPase examined. Tnik was required for Nedd4 ubiquitination of Rap2a, and Rap2a monoubiquitination blocked Rap2a/Tnik signaling.
Using unbiased phenotypic screens as an alternative to target-based approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-synuclein toxicity. Three chemical genetic screens in wildtype yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5. These same steps were perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded that NAB identifies a druggable node in the biology of alpha-synuclein that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle trafficking.
Chung et al. (2013) exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein (163890), a key protein involved in Parkinson disease (see 168600). Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons.
Using pull-down and coimmunoprecipitation experiments in mouse and human cells, Noyes et al. (2016) showed that the cytoplasmic domain of LDLRAD3 (617986) interacted with the E3 ubiquitin ligases ITCH (606409), NEDD4, and NEDD4L. Mutation analysis showed that the WW domains of the ligases interacted with the polyproline sequences in LDLRAD3. Expression of LDLRAD3 in HEK293 cells led to increased ITCH and NEDD4 protein degradation in association with increased ITCH and NEDD4 autoubiquitination. Inhibitor experiments revealed that ubiquitinated ITCH was degraded by the proteasome. Mutation experiments suggested that the second polyproline motif of LDLRAD3 was more important than the first for LDLRAD3-mediated ITCH ubiquitination and degradation.
For discussion of an association between variation in the NEDD4 gene and keloid formation, see 148100.
Kawabe et al. (2010) found that Nedd4 -/- mouse embryos died in late gestation. At embryonic day 11.5, Nedd4 -/- embryos showed retarded development, and almost half showed subcutaneous bleeding. Cortical neurons cultured from Nedd4 -/- embryos were smaller than wildtype and exhibited reduced dendrite extension and arborization. Targeted deletion of Nedd4 to cerebrum resulted in mice with smaller cerebrum size and reduced apical dendrite branching. Synapses of Nedd4 -/- neurons provided altered electrophysiologic data that appeared to be due to a reduced number of functionally normal synapses. Expression of dominant-negative Rap2a or Tnik mutants rescued dendrite morphology in Nedd4 -/- embryos. Kawabe et al. (2010) concluded that NEDD4 positively regulates dendrite extension by blocking RAP2A/TNIK signaling.
Abriel, H., Loffing, J., Rebhun, J. F., Pratt, J. H., Schild, L., Horisberger, J.-D., Rotin, D., Staub, O. Defective regulation of the epithelial Na(+) channel by Nedd4 in Liddle's syndrome. J. Clin. Invest. 103: 667-673, 1999. [PubMed: 10074483] [Full Text: https://doi.org/10.1172/JCI5713]
Anindya, R., Aygun, O., Svejstrup, J. Q. Damage-induced ubiquitylation of human RNA polymerase II by the ubiquitin ligase Nedd4, but not Cockayne syndrome proteins or BRCA1. Molec. Cell 28: 386-397, 2007. [PubMed: 17996703] [Full Text: https://doi.org/10.1016/j.molcel.2007.10.008]
Chung, C. Y., Khurana, V., Auluck, P. K., Tardiff, D. F., Mazzulli, J. R., Soldner, F., Baru, V., Lou, Y., Freyzon, Y., Cho, S., Mungenast, A. E., Muffat, J., and 10 others. Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342: 983-987, 2013. [PubMed: 24158904] [Full Text: https://doi.org/10.1126/science.1245296]
Drinjakovic, J., Jung, H., Campbell, D. S., Strochlic, L., Dwivedy, A., Holt, C. E. E3 ligase Nedd4 promotes axon branching by downregulating PTEN. Neuron 65: 341-357, 2010. [PubMed: 20159448] [Full Text: https://doi.org/10.1016/j.neuron.2010.01.017]
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. [PubMed: 11244092] [Full Text: https://doi.org/10.1074/jbc.C000906200]
Imhof, M. O., McDonnell, D. P. Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors. Molec. Cell. Biol. 16: 2594-2605, 1996. [PubMed: 8649367] [Full Text: https://doi.org/10.1128/MCB.16.6.2594]
Kawabe, H., Neeb, A., Dimova, K., Young, S. M., Jr., Takeda, M., Katsurabayashi, S., Mitkovski, M., Malakhova, O. A., Zhang, D.-E., Umikawa, M., Kariya, K., Goebbels, S., Nave, K.-A., Rosenmund, C., Jahn, O., Rhee, J., Brose, N. Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron 65: 358-372, 2010. [PubMed: 20159449] [Full Text: https://doi.org/10.1016/j.neuron.2010.01.007]
Kumar, S., Harvey, K. F., Kinoshita, M., Copeland, N. G., Noda, M., Jenkins, N. A. cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Genomics 40: 435-443, 1997. Note: Erratum: Genomics 44: 156 only, 1997. [PubMed: 9073511] [Full Text: https://doi.org/10.1006/geno.1996.4582]
Kumar, S., Tomooka, Y., Noda, M. Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem. Biophys. Res. Commun. 185: 1155-1161, 1992. [PubMed: 1378265] [Full Text: https://doi.org/10.1016/0006-291x(92)91747-e]
Nagase, T, Miyajima, N, Tanaka, A., Sazuka, T., Seki, N., Sato, S., Tabata, S., Ishikawa, K., Kawarabayashi, Y., Kotani, H., Nomura, N. Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 37-43, 1995. [PubMed: 7788527] [Full Text: https://doi.org/10.1093/dnares/2.1.37]
Noyes, N. C., Hampton, B., Migliorini, M., Strickland, D. K. Regulation of Itch and Nedd4 E3 ligase activity and degradation by LRAD3. Biochemistry 55: 1204-1213, 2016. [PubMed: 26854353] [Full Text: https://doi.org/10.1021/acs.biochem.5b01218]
Tardiff, D. F., Jui, N. T., Khurana, V., Tambe, M. A., Thompson, M. L., Chung, C. Y., Kamadurai, H. B., Kim, H. T., Lancaster, A. K., Caldwell, K. A., Caldwell, G. A., Rochet, J.-C., Buchwald, S. L., Lindquist, S. Yeast reveal a 'druggable' Rsp5/Nedd4 network that ameliorates alpha-synuclein toxicity in neurons. Science 342: 979-983, 2013. [PubMed: 24158909] [Full Text: https://doi.org/10.1126/science.1245321]
Trotman, L. C., Wang, X., Alimont, A., Chen, Z., Teruya-Feldstein, J., Yang, H., Pavletich, N. P., Carver, B. S., Cordon-Cardo, C., Erdjument-Bromage, H., Tempst, P., Chi, S.-G., Kim, H.-J., Misteli, T., Jiang, X., Pandolfi, P. P. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128: 141-156, 2007. [PubMed: 17218261] [Full Text: https://doi.org/10.1016/j.cell.2006.11.040]
Wang, X., Trotman, L. C., Koppie, T., Alimonti, A., Chen, Z., Gao, Z., Wang, J., Erdjument-Bromage, H., Tempst, P., Cordon-Cardo, C., Pandolfi, P. P., Jiang, X. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128: 129-139, 2007. [PubMed: 17218260] [Full Text: https://doi.org/10.1016/j.cell.2006.11.039]