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This Article Full Text Full Text (PDF) All Versions of this Article: 292/6/F1741    most recent 00027.2007v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Pao, A. C. Articles by Pearce, D. Search for Related Content PubMed PubMed Citation Articles by Pao, A. C. Articles by Pearce, D.

NH₂ terminus of serum and glucocorticoid-regulated kinase 1 binds to phosphoinositides and is essential for isoform-specific physiological functions

¹Department of Medicine, Division of Nephrology, San Francisco General Hospital; and ²Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

Submitted 15 January 2007 ; accepted in final form 9 March 2007

Serum and glucocorticoid regulated kinase 1 (SGK1) has been identified as a key regulatory protein that controls a diverse set of cellular processes including sodium (Na⁺) homeostasis, osmoregulation, cell survival, and cell proliferation. Two other SGK isoforms, SGK2 and SGK3, have been identified, which differ most markedly from SGK1 in their NH₂-terminal domains. We found that SGK1 and SGK3 are potent stimulators of epithelial Na⁺ channel (ENaC)-dependent Na⁺ transport, while SGK2, which has a short NH₂ terminus, is a weak stimulator of ENaC. Further characterization of the role of the SGK1 NH₂ terminus revealed that its deletion does not affect in vitro kinase activity but profoundly limits the ability of SGK1 either to stimulate ENaC-dependent Na⁺ transport or inhibit Forkhead-dependent gene transcription. The NH₂ terminus of SGK1, which shares sequence homology with the phosphoinositide 3-phosphate [PI(3)P] binding domain of SGK3, binds phosphoinositides in protein lipid overlay assays, interacting specifically with PI(3)P, PI(4)P, and PI(5)P, but not with PI(3,4,5)P₃. Moreover, a point mutation that reduces phosphoinositide binding to the NH₂ terminus also reduces SGK1 effects on Na⁺ transport and Forkhead activity. These data suggest that the NH₂ terminus, although not required for PI 3-kinase-dependent modulation of SGK1 catalytic activity, is required for multiple SGK1 functions, including stimulation of ENaC and inhibition of the proapoptotic Forkhead transcription factor. Together, these observations support the idea that the NH₂-terminal domain acts downstream of PI 3-kinase-dependent activation to target the kinase to specific cellular compartments and/or substrates, possibly through its interactions with a subset of phosphoinositides.

epithelial sodium channel; Forkhead; kinase activity