Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation

Ruifeng Zhou; Peter M Snyder

doi:10.1074/jbc.M411053200

Back

Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation

Journal article

Open access

Peer reviewed

Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation

Ruifeng Zhou and Peter M Snyder

The Journal of biological chemistry, Vol.280(6), pp.4518-4523

02/11/2005

DOI: 10.1074/jbc.M411053200

PMID: 15576372

Files and links (1)

url

https://doi.org/10.1074/jbc.M411053200View

Published (Version of record) Open Access

Abstract

Serum and glucocorticoid-regulated kinase (SGK) plays a key role in the regulation of epithelial Na+ transport. SGK phosphorylates Nedd4-2, an E3 ubiquitin-protein ligase that targets the epithelial Na+ channel (ENaC) for degradation. Phosphorylation increases Na+ transport by reducing Nedd4-2 binding to ENaC, which increases ENaC expression at the cell surface. Thus, SGK expression must be tightly controlled to maintain Na+ homeostasis. This occurs in part by regulation of SGK transcription; a variety of signals including steroid hormones (aldosterone and glucocorticoids) increase SGK levels by inducing transcription of SGK. However, SGK has a short half-life, suggesting that SGK levels might also be controlled by regulation of SGK degradation. Here we found that SGK degradation is mediated in part by Nedd4-2. Consistent with this model, overexpression of Nedd4-2 decreased steady-state levels of SGK in a dose-dependent manner by increasing SGK ubiquitination and degradation in the 26S proteasome. Conversely, silencing of Nedd4-2 by RNA interference stabilized SGK. Nedd4-2 phosphorylation potentiates SGK degradation; degradation was reduced by Nedd4-2 and SGK mutations that disrupt phosphorylation or by inhibition of SGK kinase activity. Together with previous work, the data support a model in which SGK and Nedd4-2 regulate one another in a reciprocal manner. SGK phosphorylates Nedd4-2, which reduces Nedd4-2 binding and inhibition of ENaC. Conversely, phosphorylation increases Nedd4-2-mediated degradation of SGK. Thus, by phosphorylating Nedd4-2, SGK induces its own degradation. This feedback inhibition may fine-tune the regulation of epithelial Na+ absorption.

Phosphorylation

Sodium - chemistry

Humans

Ubiquitin - metabolism

Electrophysiology

Sodium - metabolism

Dose-Response Relationship, Drug

Immediate-Early Proteins

Transfection

Time Factors

Nedd4 Ubiquitin Protein Ligases

Cell Membrane - metabolism

Protein-Serine-Threonine Kinases - metabolism

Green Fluorescent Proteins - metabolism

Epithelium - metabolism

Signal Transduction

Endosomal Sorting Complexes Required for Transport

Gene Expression Regulation

Ubiquitin-Protein Ligases - metabolism

Nuclear Proteins - metabolism

Blotting, Western

Animals

Models, Biological

Protein Binding

Models, Genetic

Mutation

Proteasome Endopeptidase Complex - metabolism

COS Cells

DNA, Complementary - metabolism

RNA, Small Interfering - metabolism

Details

Title: Subtitle: Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation
Creators: Ruifeng Zhou - Department of Internal Medicine and Physiology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA
Peter M Snyder
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.280(6), pp.4518-4523
DOI: 10.1074/jbc.M411053200
PMID: 15576372
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: HL58812 / NHLBI NIH HHS HL72256 / NHLBI NIH HHS DK52617 / NIDDK NIH HHS HL55006 / NHLBI NIH HHS
Language: English
Date published: 02/11/2005
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
Record Identifier: 9984025600002771

Metrics

7 Record Views

83 Times Cited - Web of Science