Gene Symbol: Nedd4l
Description: neural precursor cell expressed, developmentally down-regulated 4-like, E3 ubiquitin protein ligase
Alias: Nedd4-2, E3 ubiquitin-protein ligase NEDD4-like
Species: rat
Products:     Nedd4l

Top Publications

  1. Kimura T, Kawabe H, Jiang C, Zhang W, Xiang Y, Lu C, et al. Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease. Proc Natl Acad Sci U S A. 2011;108:3216-21 pubmed publisher
    ..Here we show that knockout of the ubiquitin ligase Nedd4L (Nedd4-2) specifically in lung epithelia (surfactant protein C-expressing type II and Clara cells) causes cystic ..
  2. Raikwar N, Vandewalle A, Thomas C. Nedd4-2 interacts with occludin to inhibit tight junction formation and enhance paracellular conductance in collecting duct epithelia. Am J Physiol Renal Physiol. 2010;299:F436-44 pubmed publisher
    ..In summary, we demonstrate that Nedd4-2 plays a role in tight junction assembly and the regulation of paracellular conductance in the collecting duct. ..
  3. Cachemaille M, Laedermann C, Pertin M, Abriel H, Gosselin R, Decosterd I. Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain. Neuroscience. 2012;227:370-80 pubmed publisher
  4. Lamothe S, Zhang S. The serum- and glucocorticoid-inducible kinases SGK1 and SGK3 regulate hERG channel expression via ubiquitin ligase Nedd4-2 and GTPase Rab11. J Biol Chem. 2013;288:15075-84 pubmed publisher
    ..These results show that SGK enhances the expression level of mature hERG channels by inhibiting Nedd4-2 as well as by promoting Rab11-mediated hERG recycling. ..
  5. Edinger R, Lebowitz J, Li H, Alzamora R, Wang H, Johnson J, et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2. J Biol Chem. 2009;284:150-7 pubmed publisher
    ..In summary, these results suggest a novel mode of ENaC regulation that occurs through IKKbeta-dependent Nedd4-2 phosphorylation at a recognized SGK1 and protein kinase A target site. ..
  6. Guo J, Wang T, Li X, Shallow H, Yang T, Li W, et al. Cell surface expression of human ether-a-go-go-related gene (hERG) channels is regulated by caveolin-3 protein via the ubiquitin ligase Nedd4-2. J Biol Chem. 2012;287:33132-41 pubmed
    ..Our data demonstrate that hERG expression in the plasma membrane is regulated by Cav3 via Nedd4-2. These findings extend our understanding of the regulation of hERG channels and cardiac electrophysiology. ..
  7. Flores S, Loffing Cueni D, Kamynina E, Daidié D, Gerbex C, Chabanel S, et al. Aldosterone-induced serum and glucocorticoid-induced kinase 1 expression is accompanied by Nedd4-2 phosphorylation and increased Na+ transport in cortical collecting duct cells. J Am Soc Nephrol. 2005;16:2279-87 pubmed
    ..Hence, these data provide evidence in cortical collecting duct cells in vitro and in vivo that Sgk1-dependent phosphorylation of Nedd4-2 is part of the aldosterone response. ..
  8. Low L, Chow Y, Li Y, Goh C, Putz U, Silke J, et al. Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response. J Biol Chem. 2015;290:7141-50 pubmed publisher
    ..These results point to Ndfip1 as a sensor protein during cell injury and Ndfip1 up-regulation as a cue for BRAT1 ubiquitination by Nedd4 E3 ligases, followed by nuclear translocation of BRAT1. ..
  9. Ekberg J, Schuetz F, Boase N, Conroy S, Manning J, Kumar S, et al. Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by ubiquitination. Novel role for Nedd4-2. J Biol Chem. 2007;282:12135-42 pubmed
    ..Furthermore, Nedd4-2 could ubiquitinate KCNQ2/3 in transfected cells. Taken together, these data suggest that Nedd4-2 is potentially an important regulator of M-current activity in the nervous system. ..

More Information


  1. Harvey K, Dinudom A, Cook D, Kumar S. The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J Biol Chem. 2001;276:8597-601 pubmed
    ..We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC regulation or function in a tissue- and/or signal-specific manner to down-regulate ENaC. ..
  2. Xu D, Wang H, You G. An Essential Role of Nedd4-2 in the Ubiquitination, Expression, and Function of Organic Anion Transporter-3. Mol Pharm. 2016;13:621-30 pubmed publisher
    ..In conclusion, our results provided the first evidence that Nedd4-2 is an important regulator for OAT3 ubiquitination, expression, and transport activity. ..
  3. Gille T, Randrianarison Pellan N, Goolaerts A, Dard N, Uzunhan Y, Ferrary E, et al. Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway. Am J Respir Cell Mol Biol. 2014;50:526-37 pubmed publisher
    ..Our data strongly suggest that Nedd4-2-mediated ubiquitination of ENaC leading to endocytosis and degradation of apical Na(+) channels is a key feature of hypoxia-induced inhibition of transepithelial alveolar Na(+) transport. ..
  4. van Bemmelen M, Rougier J, Gavillet B, Apothéloz F, Daidié D, Tateyama M, et al. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. Circ Res. 2004;95:284-91 pubmed
    ..5. These results demonstrate that Na(v)1.5 can be ubiquitinated in heart tissues and that the ubiquitin-protein ligase Nedd4-2 acts on Na(v)1.5 by decreasing the channel density at the cell surface. ..
  5. Kabra R, Knight K, Zhou R, Snyder P. Nedd4-2 induces endocytosis and degradation of proteolytically cleaved epithelial Na+ channels. J Biol Chem. 2008;283:6033-9 pubmed publisher
    ..Together the data indicate that Nedd4-2 reduces ENaC surface expression by altering its trafficking at two distinct sites in the endocytic pathway, inducing endocytosis of cleaved channels and targeting them for degradation. ..
  6. Lee I, Dinudom A, Sanchez Perez A, Kumar S, Cook D. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2. J Biol Chem. 2007;282:29866-73 pubmed
    ..Together these data suggest that both Akt and Sgk are components of an insulin signaling pathway that increases Na(+) absorption by up-regulating membrane expression of ENaC via a regulatory system that involves inhibition of Nedd4-2. ..
  7. Wilkars W, Wollberg J, Mohr E, Han M, Chetkovich D, Bähring R, et al. Nedd4-2 regulates surface expression and may affect N-glycosylation of hyperpolarization-activated cyclic nucleotide-gated (HCN)-1 channels. FASEB J. 2014;28:2177-90 pubmed publisher
    ..Taken together, our data indicate that Nedd4-2 plays an important role in the regulation of HCN1 trafficking and may compete with TRIP8b(1a-4) in this process. ..
  8. Lee E, Hyun S, Chun J, Shin S, Kang S. Ubiquitylation of Fe65 adaptor protein by neuronal precursor cell expressed developmentally down regulated 4-2 (Nedd4-2) via the WW domain interaction with Fe65. Exp Mol Med. 2009;41:555-68 pubmed publisher
  9. Georgieva M, de Pablo Y, Sanchis D, Comella J, Llovera M. Ubiquitination of TrkA by Nedd4-2 regulates receptor lysosomal targeting and mediates receptor signaling. J Neurochem. 2011;117:479-93 pubmed publisher
    ..In addition, TrkA multimonoubiquitination does not interfere with the activation of signaling cascades, but rather potentiates receptor signaling leading to differentiation. ..
  10. Kamynina E, Debonneville C, Bens M, Vandewalle A, Staub O. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J. 2001;15:204-214 pubmed
    ..Thus, these results suggest that the novel suppressor protein Nedd4-2 is the regulator of ENaC and hence a potential susceptibility gene for arterial hypertension. ..
  11. Albesa M, Grilo L, Gavillet B, Abriel H. Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1. J Mol Cell Cardiol. 2011;51:90-8 pubmed publisher
    ..These results suggest that ubiquitylation of the hERG1 protein by Nedd4-2, and its subsequent down-regulation, could represent an important mechanism for modulation of the duration of the human cardiac action potential. ..
  12. Chan W, Tian R, Lee Y, Sit S, Lim L, Manser E. Down-regulation of active ACK1 is mediated by association with the E3 ubiquitin ligase Nedd4-2. J Biol Chem. 2009;284:8185-94 pubmed publisher
    ..These processes are particularly pertinent given the report of genomic amplification of the ACK1 locus in metastatic tumors. ..
  13. Shi P, Cao X, Sweezer E, Kinney T, Williams N, Husted R, et al. Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2. Am J Physiol Renal Physiol. 2008;295:F462-70 pubmed publisher
    ..The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder. ..
  14. Li T, Koshy S, Folkesson H. Involvement of {alpha}ENaC and Nedd4-2 in the conversion from lung fluid secretion to fluid absorption at birth in the rat as assayed by RNA interference analysis. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1069-78 pubmed
    ..Thus we provide evidence that ENaC and Nedd4-2 are involved in the transition from lung fluid secretion to fluid absorption near term and at birth. ..
  15. Anta B, Martín Rodríguez C, Gomis Pèrez C, Calvo L, López Benito S, Calderón García A, et al. Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3). J Biol Chem. 2016;291:19132-45 pubmed publisher
    ..2/3 channel regulation. Our results demonstrate that USP36 binds to and regulates the actions of Nedd4-2 over different substrates affecting their expression and functions. ..
  16. Lackovic J, Howitt J, Callaway J, Silke J, Bartlett P, Tan S. Differential regulation of Nedd4 ubiquitin ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke. Exp Neurol. 2012;235:326-35 pubmed publisher
  17. Jespersen T, Membrez M, Nicolas C, Pitard B, Staub O, Olesen S, et al. The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family. Cardiovasc Res. 2007;74:64-74 pubmed
    ..This mechanism may thereby be important in regulating the surface density of the KCNQ1 channels in cardiomyocytes and other cell types. ..
  18. Umemura M, Ishigami T, Tamura K, Sakai M, Miyagi Y, Nagahama K, et al. Transcriptional diversity and expression of NEDD4L gene in distal nephron. Biochem Biophys Res Commun. 2006;339:1129-37 pubmed
    The ubiquitin ligase NEDD4L participates in plasma volume and blood pressure regulation by controlling expression of the epithelial sodium channel (ENaC)...