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Division of Nephrology, Department of Medicine (V.B., H.L., A.C.P., J.W., D.P.), and Department of Cellular and Molecular Pharmacology (D.P.), University of California, San Francisco, California 94143-0532; Department of Pharmacology and Toxicology, University of Lausanne (D.D., O.S.), CH-1005 Lausanne, Switzerland; Department of Physiology, University of Texas Health Science Center (L.P.L., J.D.S.), San Antonio, Texas 78229-3900; and Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat (A.V.), 75870 Paris, France
Address all correspondence and requests for reprints to: Dr. David Pearce, 600 16th Street, N272 Genentech Hall, Mission Bay, Box 2140, University of California, San Francisco, California 94107-214. E-mail: pearce{at}medicine.ucsf.edu.
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 that of the epithelial sodium channel (ENaC). Recent evidence has established that SGK1 phosphorylates and inhibits Nedd4-2 (neural precursor cell-expressed, developmentally down-regulated protein 4-2), a ubiquitin ligase that decreases cell surface expression of the channel and possibly stimulates its degradation. The mechanistic basis for this SGK1-induced Nedd4-2 inhibition is currently unknown. In this study we show that SGK1-mediated phosphorylation of Nedd4-2 induces its interaction with members of the 14-3-3 family of regulatory proteins. Through functional characterization of Nedd4-2-mutant proteins, we demonstrate that this interaction is required for SGK1-mediated inhibition of Nedd4-2. The concerted action of SGK1 and 14-3-3 appears to disrupt Nedd4-2-mediated ubiquitination of ENaC, thus providing a mechanism by which SGK1 modulates the ENaC-mediated Na+ current. Finally, the expression pattern of 14-3-3 is also consistent with a functional role in distal nephron Na+ transport. These results demonstrate a novel, physiologically significant role for 14-3-3 proteins in modulating ubiquitin ligase-dependent pathways in the control of epithelial ion transport.
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