Hormonal control of transepithelial sodium (Na ؉ ) transport utilizes phosphatidylinositide 3 -kinase (PI3K) and Raf-MAPK/ERK kinase (MEK)-ERK-dependent signaling pathways, which impact numerous cell functions. How signals transmitted by these pathways are sorted and appropriately transmitted to alter Na ؉ transport without altering other physiologic processes is not well understood. Here, we report the identification of a signaling complex that selectively modulates the cell surface expression of the epithelial sodium channel (ENaC), an ion channel that is essential for fluid and electrolyte balance in mammals. Raf-1 and the ubiquitin ligase, Nedd4-2, are constitutively-expressed inhibitory components of this ENaC regulatory complex, which interact with, and decrease the expression of, cell surface ENaC. The activities of Nedd4-2 and Raf-1 are inhibited cooperatively by the PI3K-dependent kinase serum-and glucocorticoid-induced kinase 1 (SGK1), and the Raf-1-interacting protein glucocorticoid-induced leucine zipper (GILZ1), which are aldosterone-stimulated components of the complex. Together, SGK1 and GILZ1 synergistically stimulate ENaC cell surface expression. Interestingly, GILZ1 and SGK1 do not have synergistic, and in fact have opposite, effects on an unrelated activity, FKHRL1-driven gene transcription. Together, these data suggest that GILZ1 and SGK1 provide a physical and functional link between the PI3K-and Raf-1-dependent signaling modules and represent a unique mechanism for specifically controlling Na ؉ transport without inappropriately activating other cell functions.glucocorticoid-induced leucine zipper protein ͉ Nedd4-2 ͉ Raf-1 ͉ serum-and glucocorticoid-induced kinase 1

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The kidney plays an important role in the long‐term regulation of sodium (Na+) balance, which is central to the maintenance of appropriate extracellular fluid volume and blood pressure. Renal Na+ reabsorption via the epithelial Na+ channel (ENaC) is dependent on the mineralocorticoid aldosterone. Aldosterone‐mediated Na+ transport includes the function of the PI3K‐dependent kinase SGK1, and a small leucine‐zipper protein called GILZ1, which negatively regulates the Raf‐MEK‐ERK1/2 MAPK pathway. Our studies suggest that GILZ1 and SGK1 demonstrate functional synergy in the modulation of epithelial Na+ transport, and point to a key role for GILZ1 as a scaffolding protein capable of harnessing pleiotropic signaling pathways to control Na+ transport. SGK1 is a short‐lived protein which is predominantly targeted to the ER to undergo rapid proteasome‐mediated degradation. GILZ1 redirects SGK1 away from the ER, and selectively recruits it to an ENaC‐regulatory complex (ERC), which includes Raf‐1 and the ubiquitin ligase Nedd4–2, the constitutively expressed inhibitory components of the ERC. Once in the ERC, GILZ1 and SGK1 (the aldosterone‐stimulated components of the ERC) synergistically stimulate ENaC surface expression and function by disinhibiting the inhibitory activities of Raf‐1 and Nedd4–2. This work is supported by NIH K01‐DK078679 (to RS) and R01‐DK51151 (to DP).