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Gene Review

NEDD4L  -  neural precursor cell expressed,...

Homo sapiens

Synonyms: E3 ubiquitin-protein ligase NEDD4-like, KIAA0439, NEDD4-2, NEDD4.2, NEDL3, ...
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Disease relevance of NEDD4L


High impact information on NEDD4L

  • They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4-2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, beta-catenin, nuclear factor kappaB) [4].
  • The binding of Nedd4-2 to TrkA through a PPXY motif leads to the ubiquitination and downregulation of TrkA [5].
  • Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression [6].
  • Here we show by expression studies in Xenopus laevis oocytes that the aldosterone-induced Sgk1 kinase interacts with the ubiquitin protein ligase Nedd4-2 in a PY motif-dependent manner and phosphorylates Nedd4-2 on Ser444 and, to a lesser extent, Ser338 [6].
  • This disproportionate increase in cleavage was reproduced by expression of a dominant-negative Nedd4-2 or mutation of ENaC ubiquitination sites, interventions that disrupt ENaC endocytosis and lysosomal degradation [7].

Chemical compound and disease context of NEDD4L

  • A search for transcripts whose levels increase following androgen treatment of LNCaP human prostate cancer cells led to the isolation of three new NEDD4L transcripts designated NEDD4Lf, NEDD4Lg and NEDD4Lh [1].

Biological context of NEDD4L


Anatomical context of NEDD4L

  • We found that this interaction preserved the activity of the Sgk1-stimulated ENaC-dependent Na+ current while disrupting the interaction decreased ENaC density on the Xenopus laevis oocytes surface possibly by enhancing Nedd4-2-mediated ubiquitination that leads to ENaC degradation [8].
  • Coexpression, in Fischer rat thyroid epithelia, of ENaC and Nedd4-2 cDNAs leads to a significant reduction in amiloride-sensitive currents, confirming a role in Na+ transport regulation [9].
  • Immunohistochemistry in human small intestine revealed SGK1 colocalization with Nedd4-2 in villus enterocytes [10].
  • In summary, these results suggest a novel mechanism for ENaC regulation in which AMPK promotes ENaC-Nedd4-2 interaction, thereby inhibiting ENaC by increasing Nedd4-2-dependent ENaC retrieval from the plasma membrane [11].
  • Nedd4-2 is expressed in the mouse collecting duct, and overexpression of Nedd4-2 reduces endogenous ENaC activity in a collecting duct cell line [12].

Associations of NEDD4L with chemical compounds

  • NEDD4L contains the WW and HECT domains seen in the NEDD4 gene family, but lacks the C2 domain in the N-terminus [13].
  • These data provide new information on the structure and expression profile of NEDD4L-derived transcripts and identify specific isoforms of the NEDD4L ubiquitin ligase as proteins with potentially important roles in androgen action and prostate physiology [1].
  • By targeting the epithelial sodium channel (ENaC) for degradation, NEDD4L is a significant determinant of sodium reabsorption in the distal nephron [2].
  • Glutamate induces a current in Xenopus oocytes expressing EAAT1, but not in water-injected oocytes, which is decreased by co-expression of Nedd4-2, an effect reversed by additional co-expression of S422DSGK1, SGK3 and T308D,S473DPKB, but not K127NSGK1 [14].
  • Using intrinsic tryptophan fluorescence imaging of WW domains, we found that Na(v)1.5 PY motif binds preferentially to the fourth WW domain of Nedd4-2 with a K(d) of approximately 55 muM [15].

Physical interactions of NEDD4L


Enzymatic interactions of NEDD4L


Regulatory relationships of NEDD4L

  • Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination [19].
  • When expressed in HEK-293 cells and studied using whole cell voltage clamping, the neuronal Na(v)1.2 and Na(v)1.3 were also downregulated by Nedd4-2 [15].
  • RESULTS: Expression of ClC-Ka/barttin induced a slightly inwardly rectifying current that was significantly decreased upon coexpression of Nedd4-2, but not the catalytically inactive mutant C938SNedd4-2 [20].

Other interactions of NEDD4L

  • Site-directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4-2 protein (S382A,S468ANedd4-2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1 [14].
  • 5. Interestingly, coexpression of WWP2 competed with the effect of Nedd4-2 [15].
  • Pull-down experiments using fusion proteins bearing the PY motif of Na(v)1.2, Na(v)1.3, and Na(v)1.5 indicated that mouse brain Nedd4-2 binds to the Na(v) PY motif [15].
  • Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases [20].
  • Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2 [21].

Analytical, diagnostic and therapeutic context of NEDD4L


  1. Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells. Qi, H., Grenier, J., Fournier, A., Labrie, C. Mol. Cell. Endocrinol. (2003) [Pubmed]
  2. Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. Dunn, D.M., Ishigami, T., Pankow, J., von Niederhausern, A., Alder, J., Hunt, S.C., Leppert, M.F., Lalouel, J.M., Weiss, R.B. J. Hum. Genet. (2002) [Pubmed]
  3. Association of NEDD4L ubiquitin ligase with essential hypertension. Russo, C.J., Melista, E., Cui, J., DeStefano, A.L., Bakris, G.L., Manolis, A.J., Gavras, H., Baldwin, C.T. Hypertension (2005) [Pubmed]
  4. (Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms. Lang, F., B??hmer, C., Palmada, M., Seebohm, G., Strutz-Seebohm, N., Vallon, V. Physiol. Rev. (2006) [Pubmed]
  5. Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination. Arévalo, J.C., Waite, J., Rajagopal, R., Beyna, M., Chen, Z.Y., Lee, F.S., Chao, M.V. Neuron (2006) [Pubmed]
  6. Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. Debonneville, C., Flores, S.Y., Kamynina, E., Plant, P.J., Tauxe, C., Thomas, M.A., Münster, C., Chraïbi, A., Pratt, J.H., Horisberger, J.D., Pearce, D., Loffing, J., Staub, O. EMBO J. (2001) [Pubmed]
  7. Liddle's syndrome mutations increase Na+ transport through dual effects on epithelial Na+ channel surface expression and proteolytic cleavage. Knight, K.K., Olson, D.R., Zhou, R., Snyder, P.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. 14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase. Ichimura, T., Yamamura, H., Sasamoto, K., Tominaga, Y., Taoka, M., Kakiuchi, K., Shinkawa, T., Takahashi, N., Shimada, S., Isobe, T. J. Biol. Chem. (2005) [Pubmed]
  9. Alternate promoters and variable splicing lead to hNedd4-2 isoforms with a C2 domain and varying number of WW domains. Itani, O.A., Campbell, J.R., Herrero, J., Snyder, P.M., Thomas, C.P. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  10. Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4-2 and by serum- and glucocorticoid-dependent kinase 1. Palmada, M., Dieter, M., Speil, A., Böhmer, C., Mack, A.F., Wagner, H.J., Klingel, K., Kandolf, R., Murer, H., Biber, J., Closs, E.I., Lang, F. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  11. AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2. Bhalla, V., Oyster, N.M., Fitch, A.C., Wijngaarden, M.A., Neumann, D., Schlattner, U., Pearce, D., Hallows, K.R. J. Biol. Chem. (2006) [Pubmed]
  12. Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. Itani, O.A., Stokes, J.B., Thomas, C.P. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  13. NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene. Chen, H., Ross, C.A., Wang, N., Huo, Y., MacKinnon, D.F., Potash, J.B., Simpson, S.G., McMahon, F.J., DePaulo Jr, J.R., McInnis, M.G. Eur. J. Hum. Genet. (2001) [Pubmed]
  14. Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. Boehmer, C., Henke, G., Schniepp, R., Palmada, M., Rothstein, J.D., Bröer, S., Lang, F. J. Neurochem. (2003) [Pubmed]
  15. Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins. Rougier, J.S., van Bemmelen, M.X., Bruce, M.C., Jespersen, T., Gavillet, B., Apothéloz, F., Cordonier, S., Staub, O., Rotin, D., Abriel, H. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  16. Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. Zhou, R., Snyder, P.M. J. Biol. Chem. (2005) [Pubmed]
  17. Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. Hryciw, D.H., Ekberg, J., Lee, A., Lensink, I.L., Kumar, S., Guggino, W.B., Cook, D.I., Pollock, C.A., Poronnik, P. J. Biol. Chem. (2004) [Pubmed]
  18. The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels. He, Y., Hryciw, D.H., Carroll, M.L., Myers, S.A., Whitbread, A.K., Kumar, S., Poronnik, P., Hooper, J.D. J. Biol. Chem. (2008) [Pubmed]
  19. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. van Bemmelen, M.X., Rougier, J.S., Gavillet, B., Apothéloz, F., Daidié, D., Tateyama, M., Rivolta, I., Thomas, M.A., Kass, R.S., Staub, O., Abriel, H. Circ. Res. (2004) [Pubmed]
  20. Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases. Embark, H.M., Böhmer, C., Palmada, M., Rajamanickam, J., Wyatt, A.W., Wallisch, S., Capasso, G., Waldegger, P., Seyberth, H.W., Waldegger, S., Lang, F. Kidney Int. (2004) [Pubmed]
  21. WNK1 activates SGK1 to regulate the epithelial sodium channel. Xu, B.E., Stippec, S., Chu, P.Y., Lazrak, A., Li, X.J., Lee, B.H., English, J.M., Ortega, B., Huang, C.L., Cobb, M.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  22. 14-3-3 Mediates phosphorylation-dependent inhibition of the interaction between the ubiquitin E3 ligase Nedd4-2 and epithelial Na+ channels. Nagaki, K., Yamamura, H., Shimada, S., Saito, T., Hisanaga, S., Taoka, M., Isobe, T., Ichimura, T. Biochemistry (2006) [Pubmed]
  23. A naturally occurring human Nedd4-2 variant displays impaired ENaC regulation in Xenopus laevis oocytes. Fouladkou, F., Alikhani-Koopaei, R., Vogt, B., Flores, S.Y., Malbert-Colas, L., Lecomte, M.C., Loffing, J., Frey, F.J., Frey, B.M., Staub, O. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  24. Transcriptional diversity and expression of NEDD4L gene in distal nephron. Umemura, M., Ishigami, T., Tamura, K., Sakai, M., Miyagi, Y., Nagahama, K., Aoki, I., Uchino, K., Rohrwasser, A., Lalouel, J.M., Umemura, S. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  25. Long-term effects of vasopressin on the subcellular localization of ENaC in the renal collecting system. Sauter, D., Fernandes, S., Goncalves-Mendes, N., Boulkroun, S., Bankir, L., Loffing, J., Bouby, N. Kidney Int. (2006) [Pubmed]
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