Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1) with the WW-domains of Nedd4-2 is required for epithelial sodium channel regulation

Dominik Wiemuth; J Shaun Lott; Kevin Ly; Ying Ke; Paul Teesdale-Spittle; Peter M Snyder; Fiona J McDonald

doi:10.1371/journal.pone.0012163

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Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1) with the WW-domains of Nedd4-2 is required for epithelial sodium channel regulation

Journal article

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Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1) with the WW-domains of Nedd4-2 is required for epithelial sodium channel regulation

Dominik Wiemuth, J Shaun Lott, Kevin Ly, Ying Ke, Paul Teesdale-Spittle, Peter M Snyder and Fiona J McDonald

PloS one, Vol.5(8), pp.e12163-e12163

08/13/2010

DOI: 10.1371/journal.pone.0012163

PMCID: PMC2921341

PMID: 20730100

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Abstract

The epithelial sodium channel (ENaC) is an integral component of the pathway for Na(+) absorption in epithelial cells. The ubiquitin ligases Nedd4 and Nedd4-2 bind to ENaC and decrease its activity. Conversely, Serum- and Glucocorticoid regulated Kinase-1 (SGK1), a downstream mediator of aldosterone, increases ENaC activity. This effect is at least partly mediated by direct interaction between SGK and Nedd4-2. SGK binds both Nedd4 and Nedd4-2, but it is only able to phosphorylate Nedd4-2. Phosphorylation of Nedd4-2 reduces its ability to bind to ENaC, due to the interaction of phosphorylated Nedd4-2 with 14-3-3 proteins, and hence increases ENaC activity. WW-domains in Nedd4-like proteins bind PY-motifs (PPXY) present in ENaC subunits, and SGK also has a PY-motif. Here we show that single or tandem WW-domains of Nedd4 and Nedd4-2 mediate binding to SGK and that different WW-domains of Nedd4 and Nedd4-2 are involved. Our data also show that WW-domains 2 and 3 of Nedd4-2 mediate the interaction with SGK in a cooperative manner, that activated SGK has increased affinity for the WW-domains of Nedd4-2 in vitro, and a greater stimulatory effect on ENaC Na(+) transport compared to wildtype SGK. Further, SGK lacking a PY motif failed to stimulate ENaC activity in the presence of Nedd4-2. Binding of Nedd4-2 WW-domains to SGK is necessary for SGK-induced ENaC activity.

Cercopithecus aethiops

Epithelial Sodium Channels - metabolism

Dose-Response Relationship, Drug

Immediate-Early Proteins - metabolism

Immediate-Early Proteins - chemistry

Nedd4 Ubiquitin Protein Ligases

Endosomal Sorting Complexes Required for Transport - chemistry

Protein-Serine-Threonine Kinases - metabolism

Protein Structure, Tertiary

Endosomal Sorting Complexes Required for Transport - pharmacology

Peptide Fragments - metabolism

Endosomal Sorting Complexes Required for Transport - metabolism

Ubiquitin-Protein Ligases - metabolism

Models, Molecular

Tryptophan

Ubiquitin-Protein Ligases - chemistry

Amino Acid Motifs

Ubiquitin-Protein Ligases - pharmacology

Peptide Fragments - chemistry

Animals

Protein Binding

Epithelial Sodium Channel Blockers

Protein-Serine-Threonine Kinases - chemistry

Enzyme Activation

COS Cells

Details

Title: Subtitle: Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1) with the WW-domains of Nedd4-2 is required for epithelial sodium channel regulation
Creators: Dominik Wiemuth - Department of Physiology, University of Otago, Dunedin, New Zealand
J Shaun Lott
Kevin Ly
Ying Ke
Paul Teesdale-Spittle
Peter M Snyder
Fiona J McDonald
Resource Type: Journal article
Publication Details: PloS one, Vol.5(8), pp.e12163-e12163
DOI: 10.1371/journal.pone.0012163
PMID: 20730100
PMCID: PMC2921341
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 HL058812 / NHLBI NIH HHS R01 HL072256 / NHLBI NIH HHS
Language: English
Date published: 08/13/2010
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
Record Identifier: 9984025698702771

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