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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/F1440    most recent 90239.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Raikwar, N. S. Articles by Thomas, C. P. Search for Related Content PubMed PubMed Citation Articles by Raikwar, N. S. Articles by Thomas, C. P.

An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function

Department of ¹Internal Medicine and ²Molecular Physiology and Biophysics, ³Graduate Program in Molecular Biology, University of Iowa College of Medicine, and the ⁴Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 7 April 2008 ; accepted in final form 25 August 2008

Sgk1 is an aldosterone-induced kinase that regulates epithelial sodium channel (ENaC)-mediated Na⁺ transport in the collecting duct and connecting tubule of the kidney. The NH₂ terminus of Sgk1 contains instability motifs that direct the ubiquitination of Sgk1 resulting in a rapidly degraded protein. By bioinformatic analysis, we identified a 5' variant alternate transcript of human Sgk1 (Sgk1_v2) that is widely expressed, is conserved from rodent to humans, and is predicted to encode an Sgk1 isoform, Sgk1_i2, with a different NH₂ terminus. When expressed in HEK293 cells, Sgk1_i2 was more abundant than Sgk1 because of an increased protein half-life and this correlated with reduced ubiquitination of Sgk1_i2 and enhanced surface expression of ENaC. Immunocytochemical studies demonstrated that in contrast to Sgk1, Sgk1_i2 is preferentially targeted to the plasma membrane. When coexpressed with ENaC subunits in FRT epithelia, Sgk1_i2 had a significantly greater effect on amiloride-sensitive Na⁺ transport compared with Sgk1. Together, the data demonstrate that a conserved NH₂-terminal variant of Sgk1 shows improved stability, enhanced membrane association, and greater stimulation of epithelial Na⁺ transport in a heterologous expression system.

phosphorylation