SGK1 regulation of epithelial sodium transport

Epithelial ion transport is regulated in vertebrates by a variety of hormonal and non-hormonal factors, including mineralocorticoids, insulin, and osmotic shock. SGK1 has been established as an important convergence point for multiple regulators of Na+transport. Unlike most serine-threonine kinases, SGK1 is under dual control: protein levels are controlled through effects on its gene transcription, while its activity is dependent on phosphatidylinositol-3-kinase (PI3K) activity. Aldosterone is the most notable regulator of SGK1 protein level in ion transporting epithelia, while insulin and other activators of the of PI3K are key regulators of its activity. Activated SGK1 regulates a variety of ion transporters, the best characterized of which is the epithelial sodium channel (ENaC). The apical targeting of ENaC is controlled by the ubiquitin ligase, Nedd4-2, and SGK1 acts, at least in part, through phosphorylation-dependent inhibition of Nedd4-2. This effect of SGK1 requires physical associations of Nedd4-2 with both SGK1 and ENaC. Moreover, direct physical association between SGK1 and ENaC may also be implicated in the formation of a tertiary complex. Osmotic shock is likely the most important non-hormonal regulator of SGK1 expression, and surprisingly, SGK1 expression can be induced by hypotonic or hypertonic stress in a cell-type dependent fashion. The SGK family represents an ancient arm of the serine-threonine kinase family, present in all eukaryotes that have been examined, including yeast. SGK1 appears to have been implicated in membrane trafficking and possibly in the control of ion transport and cell volume in early single cell eukaryotes. In metazoan epithelia, it seems likely that SGK1 was adapted to the regulation of ion transport in response to hormonal and osmotic signals.