Serum- and Glucocorticoid-Regulated Kinase 1 Regulates Ubiquitin Ligase Neural Precursor Cell-Expressed, Developmentally Down-Regulated Protein 4-2 by Inducing Interaction with 14-3-3

• DOI: 10.1210/me.2005-0193
• Publication Date: 2005-08-12T01:43:20Z
• Authors: Vivek Bhalla; Dorothée Daidié; Hongyan Li; Alan C. Pao; Lila P. LaGrange; Jian Wang; Alain Vandewalle; James D. Stockand; Olivier Staub; David Pearce
• Keywords: NEDD4; SGK1; Epithelial sodium channel; HEK 293 cells

Serum- and glucocorticoid-regulated kinase 1 (SGK1) is an aldosterone-regulated early response gene product that regulates the activity of several ion transport proteins, most notably epithelial sodium channel (ENaC). Recent evidence has established SGK1 phosphorylates inhibits Nedd4-2 (neural precursor cell-expressed, developmentally down-regulated protein 4-2), a ubiquitin ligase decreases cell surface expression possibly stimulates its degradation. The mechanistic basis for this SGK1-induced inhibition currently unknown. In study we show SGK1-mediated phosphorylation induces interaction with members 14-3-3 family regulatory proteins. Through functional characterization Nedd4-2-mutant demonstrate required Nedd4-2. concerted action appears to disrupt Nedd4-2-mediated ubiquitination ENaC, thus providing mechanism by which modulates ENaC-mediated Na(+) current. Finally, pattern also consistent role in distal nephron transport. These results novel, physiologically significant proteins modulating ligase-dependent pathways control