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Gene Review

Nedd4l  -  neural precursor cell expressed,...

Mus musculus

Synonyms: 1300012C07Rik, E3 ubiquitin-protein ligase NEDD4-like, Kiaa0439, NEDD4.2, Nedd4-2, ...
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High impact information on Nedd4l

  • The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels [1].
  • Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel [2].
  • In Xenopus laevis oocytes, UBE2E3 reduces ENaC activity marginally, consistent with Nedd4-2 being the rate-limiting factor in this process, whereas a catalytically inactive mutant of UBE2E3 (UBE2E3-CS) causes elevated ENaC activity by increasing cell surface expression [2].
  • Previously we showed that these PY motifs serve as binding sites for the E3 enzyme Nedd4-2, implying ubiquitination as a regulatory mechanism of ENaC [2].
  • 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 [3].

Biological context of Nedd4l

  • Incubation of cell extracts with a selective phospho-Nedd4-2 antibody blocked the aldosterone-induced association of 14-3-3beta with Nedd4-2, implicating SGK1 phosphorylation at Ser-328 as the primary site of 14-3-3beta binding [4].
  • These findings indicate that AMPK-dependent ENaC inhibition is mediated through a decrease in the number of active channels at the plasma membrane (N), presumably through enhanced Nedd4-2-dependent ENaC endocytosis [5].
  • Because there are four WW domains in Nedd4-2, we analyzed binding kinetics and affinity between individual WW domains and ENaC subunits [6].

Anatomical context of Nedd4l

  • Nedd4-2, but not Nedd4-1, inhibits ENaC activity when coexpressed in Xenopus oocytes and this property correlates with the ability to bind to ENaC, as only Nedd4-2 coimmunoprecipitates with ENaC [3].
  • Here it is shown, with the use of an anti-phospho-Ser328-mNedd4-2 antibody, that 2 to 6 h of aldosterone treatment induces an increase in Nedd4-2 phosphorylation, both in a mouse cortical collecting duct cell line (mpkCCDcl4) and in kidneys of adrenalectomized rats [7].

Associations of Nedd4l with chemical compounds

  • We evaluated the hypothesis that 14-3-3 proteins participate in the aldosterone-mediated regulation of ENaC by associating with phosphorylated Nedd4-2 [4].

Physical interactions of Nedd4l


Other interactions of Nedd4l


  1. The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels. Dinudom, A., Fotia, A.B., Lefkowitz, R.J., Young, J.A., Kumar, S., Cook, D.I. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel. Debonneville, C., Staub, O. Mol. Cell. Biol. (2004) [Pubmed]
  3. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. Kamynina, E., Debonneville, C., Bens, M., Vandewalle, A., Staub, O. FASEB J. (2001) [Pubmed]
  4. 14-3-3 isoforms are induced by aldosterone and participate in its regulation of epithelial sodium channels. Liang, X., Peters, K.W., Butterworth, M.B., Frizzell, R.A. J. Biol. Chem. (2006) [Pubmed]
  5. Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells. Carattino, M.D., Edinger, R.S., Grieser, H.J., Wise, R., Neumann, D., Schlattner, U., Johnson, J.P., Kleyman, T.R., Hallows, K.R. J. Biol. Chem. (2005) [Pubmed]
  6. The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels. Fotia, A.B., Dinudom, A., Shearwin, K.E., Koch, J.P., Korbmacher, C., Cook, D.I., Kumar, S. FASEB J. (2003) [Pubmed]
  7. Aldosterone-induced serum and glucocorticoid-induced kinase 1 expression is accompanied by Nedd4-2 phosphorylation and increased Na+ transport in cortical collecting duct cells. Flores, S.Y., Loffing-Cueni, D., Kamynina, E., Daidié, D., Gerbex, C., Chabanel, S., Dudler, J., Loffing, J., Staub, O. J. Am. Soc. Nephrol. (2005) [Pubmed]
  8. Stimulation of the epithelial sodium channel (ENaC) by the serum- and glucocorticoid-inducible kinase (Sgk) involves the PY motifs of the channel but is independent of sodium feedback inhibition. Rauh, R., Dinudom, A., Fotia, A.B., Paulides, M., Kumar, S., Korbmacher, C., Cook, D.I. Pflugers Arch. (2006) [Pubmed]
  9. Regulation of epithelial Na+ channel activity by conserved serine/threonine switches within sorting signals. Staruschenko, A., Pochynyuk, O., Stockand, J.D. J. Biol. Chem. (2005) [Pubmed]
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