Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Jantina A. ManningEmail author
  • Sharad KumarEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101703


Historical Background

NEDD4 (neural precursor cell expressed developmentally downregulated 4) was first identified in a screen for genes that are downregulated during development of the mouse brain (Kumar et al. 1992). Further characterization showed that mouse NEDD4 is a HECT type of ubiquitin ligase, comprising three WW domains (involved in protein-protein interactions) and a C2 calcium/phospholipid binding domain (Staub et al. 1996; Kumar et al. 1997). Discovery of the HECT domain gave the initial clues as to the function of NEDD4, as this domain was first identified in the papilloma virus oncoprotein E6-associated protein (E6-AP) and shown to be involved in the ubiquitination of p53 (Boase and Kumar 2015). The HECT family of ubiquitin ligases is found in all eukaryotic organisms, with NEDD4 the founding member of the NEDD4 family of HECT ligases, which contains nine human proteins (Scheffner...

This is a preview of subscription content, log in to check access.


  1. Boase NA, Kumar S. NEDD4: The founding member of a family of ubiquitin-protein ligases. Gene. 2015;557:113–22.  https://doi.org/10.1016/j.gene.2014.12.020.CrossRefPubMedGoogle Scholar
  2. Bustos F, de la Vega E, Cabezas F, Thompson J, Cornelison DD, Olwin BB, et al. NEDD4 regulates PAX7 levels promoting activation of the differentiation program in skeletal muscle precursors. Stem Cells. 2015;33:3138–51.  https://doi.org/10.1002/stem.2125.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Camera D, Coleman HA, Parkington HC, Jenkins TA, Pow DV, Boase N, et al. Learning, memory and long-term potentiation are altered in Nedd4 heterozygous mice. Behav Brain Res. 2016;303:176–81.  https://doi.org/10.1016/j.bbr.2016.01.054.CrossRefPubMedGoogle Scholar
  4. Canal M, Martin-Flores N, Perez-Sisques L, Romani-Aumedes J, Altas B, Man HY, et al. Loss of NEDD4 contributes to RTP801 elevation and neuron toxicity: implications for Parkinson’s disease. Oncotarget. 2016.  https://doi.org/10.18632/oncotarget.11020.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cao XR, Lill NL, Boase N, Shi PP, Croucher DR, Shan H, et al. Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal. 2008;1:ra5.  https://doi.org/10.1126/scisignal.1160940.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chesarino NM, McMichael TM, Yount JS. E3 ubiquitin ligase NEDD4 promotes influenza virus infection by decreasing levels of the antiviral protein IFITM3. PLoS Pathog. 2015;11:e1005095.  https://doi.org/10.1371/journal.ppat.1005095.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Christie KJ, Martinez JA, Zochodne DW. Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: Linkage to PTEN. Mol Cell Neurosci. 2012;50:179–92.  https://doi.org/10.1016/j.mcn.2012.04.006.CrossRefPubMedGoogle Scholar
  8. D’Cruz R, Plant PJ, Pablo LA, Lin S, Chackowicz J, Correa J, et al. PDLIM7 is a novel target of the ubiquitin ligase Nedd4-1 in skeletal muscle. Biochem J. 2016;473:267–76.  https://doi.org/10.1042/BJ20150222.CrossRefPubMedGoogle Scholar
  9. Foot NJ, Leong YA, Dorstyn LE, Dalton HE, Ho K, Zhao L, et al. Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis. Blood. 2011;117:638–46.  https://doi.org/10.1182/blood-2010-07-295287.CrossRefPubMedGoogle Scholar
  10. Fouladkou F, Lu C, Jiang C, Zhou L, She Y, Walls JR, et al. The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1. J Biol Chem. 2010;285:6770–80.  https://doi.org/10.1074/jbc.M109.082347.CrossRefPubMedGoogle Scholar
  11. Guo H, Qiao G, Ying H, Li Z, Zhao Y, Liang Y, et al. E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity. Cell Rep. 2012;1:472–82.  https://doi.org/10.1016/j.celrep.2012.04.008.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Kawabe H, Neeb A, Dimova K, Young Jr SM, Takeda M, Katsurabayashi S, et al. Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron. 2010;65:358–72.  https://doi.org/10.1016/j.neuron.2010.01.007.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Kumar S, Harvey KF, Kinoshita M, Copeland NG, Noda M, Jenkins NA. cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Genomics. 1997;40:435–43.  https://doi.org/10.1006/geno.1996.4582.CrossRefPubMedGoogle Scholar
  14. 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. 1992;185:1155–61.CrossRefPubMedGoogle Scholar
  15. Li JJ, Ferry Jr RJ, Diao S, Xue B, Bahouth SW, Liao FF. Nedd4 haploinsufficient mice display moderate insulin resistance, enhanced lipolysis, and protection against high-fat diet-induced obesity. Endocrinology. 2015;156:1283–91.  https://doi.org/10.1210/en.2014-1909.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD, et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ. 2013;20:503–14.  https://doi.org/10.1038/cdd.2012.147.CrossRefPubMedGoogle Scholar
  17. Liu Y, Oppenheim RW, Sugiura Y, Lin W. Abnormal development of the neuromuscular junction in Nedd4-deficient mice. Dev Biol. 2009;330:153–66.  https://doi.org/10.1016/j.ydbio.2009.03.023.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Murdaca J, Treins C, Monthouel-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E, et al. Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. J Biol Chem. 2004;279:26754–61.  https://doi.org/10.1074/jbc.M311802200.CrossRefPubMedGoogle Scholar
  19. Nagpal P, Plant PJ, Correa J, Bain A, Takeda M, Kawabe H, et al. The ubiquitin ligase Nedd4-1 participates in denervation-induced skeletal muscle atrophy in mice. PLoS One. 2012;7:e46427.  https://doi.org/10.1371/journal.pone.0046427.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, et al. Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function. EMBO J. 2011;30:3259–73.  https://doi.org/10.1038/emboj.2011.234.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Rodrigues EM, Scudder SL, Goo MS, Patrick GN. Abeta-induced synaptic alterations require the E3 ubiquitin ligase Nedd4-1. J Neurosci. 2016;36:1590–5.  https://doi.org/10.1523/JNEUROSCI.2964-15.2016.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol. 2009;10:398–409.  https://doi.org/10.1038/nrm2690.CrossRefPubMedGoogle Scholar
  23. Scheffner M, Kumar S. Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects. Biochim Biophys Acta. 2014;1843:61–74.  https://doi.org/10.1016/j.bbamcr.2013.03.024.CrossRefPubMedGoogle Scholar
  24. Shi Y, Wang J, Chandarlapaty S, Cross J, Thompson C, Rosen N, et al. PTEN is a protein tyrosine phosphatase for IRS1. Nat Struct Mol Biol. 2014;21:522–7.  https://doi.org/10.1038/nsmb.2828.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, et al. WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle’s syndrome. EMBO J. 1996;15:2371–80.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007;128:129–39.  https://doi.org/10.1016/j.cell.2006.11.039.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Wiszniak S, Harvey N, Schwarz Q. Cell autonomous roles of Nedd4 in craniofacial bone formation. Dev Biol. 2016;410:98–107.  https://doi.org/10.1016/j.ydbio.2015.12.001.CrossRefPubMedGoogle Scholar
  28. Yang B, Gay DL, MacLeod MK, Cao X, Hala T, Sweezer EM, et al. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nat Immunol. 2008;9:1356–63.  https://doi.org/10.1038/ni.1670.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Zhang Y, Goodfellow R, Li Y, Yang S, Winters CJ, Thiel KW, et al. NEDD4 ubiquitin ligase is a putative oncogene in endometrial cancer that activates IGF-1R/PI3K/Akt signaling. Gynecol Oncol. 2015;139:127–33.  https://doi.org/10.1016/j.ygyno.2015.07.098.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Zou X, Levy-Cohen G, Blank M. Molecular functions of NEDD4 E3 ubiquitin ligases in cancer. Biochim Biophys Acta. 2015;1856:91–106.  https://doi.org/10.1016/j.bbcan.2015.06.005.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Cancer Biology, SA PathologyUniversity of South AustraliaAdelaideAustralia
  2. 2.Centre for Cancer Biology, University of South AustraliaAdelaideAustralia