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Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression.

The epithelial Na(+) channel (ENaC) plays an essential role in the regulation of whole body Na(+) balance and blood pressure. The cell surface expression of this channel, a complex of three subunits (alpha, beta and gamma ENaC), has been shown to be regulated by hormones such as aldosterone and vasopressin and by intracellular signaling, including ubiquitylation and/or phosphorylation. However, the molecular mechanisms involving phosphorylation in the regulation of ENaC are unclear. 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. Such phosphorylation reduces the interaction between Nedd4-2 and ENaC, leading to elevated ENaC cell surface expression. These data show that phosphorylation of an enzyme involved in the ubiquitylation cascade (Nedd4-2) controls cell surface density of ENaC and propose a paradigm for the control of ion channels. Moreover, they suggest a novel and complete signaling cascade for aldosterone-dependent regulation of ENaC.

Pubmed ID: 11742982


  • Debonneville C
  • Flores SY
  • Kamynina E
  • Plant PJ
  • Tauxe C
  • Thomas MA
  • Münster C
  • Chraïbi A
  • Pratt JH
  • Horisberger JD
  • Pearce D
  • Loffing J
  • Staub O


The EMBO journal

Publication Data

December 17, 2001

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Binding Proteins
  • Cell Line
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Immediate-Early Proteins
  • Ligases
  • Nuclear Proteins
  • Oocytes
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Sodium Channels
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Xenopus laevis