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

EMBO J. 2001 Dec 17;20(24):7052-9. doi: 10.1093/emboj/20.24.7052.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Binding Proteins / metabolism*
  • Cell Line / metabolism
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Immediate-Early Proteins
  • Ligases / metabolism*
  • Nedd4 Ubiquitin Protein Ligases
  • Nuclear Proteins*
  • Oocytes / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sodium Channels / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases*
  • Xenopus Proteins
  • Xenopus laevis

Substances

  • Calcium-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Immediate-Early Proteins
  • Nuclear Proteins
  • Sodium Channels
  • Ubiquitin
  • Xenopus Proteins
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, Xenopus
  • nedd4l protein, Xenopus
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Ligases