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.
Debonneville
C
C
Institute of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland.
Flores
S Y
SY
Kamynina
E
E
Plant
P J
PJ
Tauxe
C
C
Thomas
M A
MA
Münster
C
C
Chraïbi
A
A
Pratt
J H
JH
Horisberger
J D
JD
Pearce
D
D
Loffing
J
J
Staub
O
O
D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002460:Cell Line / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D008025:Ligases / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins; D009865:Oocytes / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D008025:Ligases; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D015222:Sodium Channels; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C000618482:Nedd4 protein, Xenopus; C000618460:nedd4l protein, Xenopus