Regulation and Physiological Roles of Serum- and Glucocorticoid-Induced Protein Kinase Isoforms

Serum- and glucocorticoid-induced protein kinase 1 (SGK1) was identified in 1993 as an immediate early gene whose mRNA levels increase dramatically within 30 minutes when cells are exposed to serum or glucocorticoids, or both. Subsequently, many other agonists, acting through a variety of signal transduction pathways, have been shown to induce SGK1 gene transcription in cells and tissues. SGK1 is a member of the "AGC" subfamily, which includes protein kinases A, G, and C, and its catalytic domain is most similar to protein kinase B (PKB). Like PKB, SGK1 is activated by phosphorylation in response to signals that stimulate phosphatidylinositol 3-kinase, and this is mediated by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and another protein kinase that has yet to be identified. Thus, SGK1 is remarkable in being activated at both the transcriptional and posttranslational levels by a huge number of extracellular signals. In contrast, little is known about the transcriptional regulation of the two closely related isoforms SGK2 and SGK3, although they can be activated by phosphorylation. The substrate specificity of SGK isoforms superficially resembles that of PKB in that serine and threonine residues lying in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr sequences (where Xaa is a variable amino acid) are phosphorylated. However, although they may have some substrates in common, evidence is emerging that SGK1 and PKB phosphorylate distinct proteins and have different functions in vivo. In particular, SGK1 plays an important role in activating certain potassium, sodium, and chloride channels, suggesting an involvement in the regulation of processes such as cell survival, neuronal excitability, and renal sodium excretion. Moreover, sustained high levels of SGK1 protein and activity may contribute to conditions such as hypertension and diabetic nephropathy. This raises the possibility that specific inhibitors of SGK1 may have therapeutic potential for the treatment of several diseases. The covalent attachment of phosphate to proteins (phosphorylation), catalyzed by enzymes known as protein kinases, and the removal of phosphate from proteins (dephosphorylation), catalyzed by protein phosphatases, regulate most aspects of cell life. Phosphorylation or dephosphorylation alters the conformation of a protein and can change its ability to function in almost every conceivable way. For example, it cannot only switch activity on or off, but alter the rate at which a protein is degraded or its ability to move from one subcellular compartment to another. There are about 500 protein kinases and 150 protein phosphatases encoded by the human genome, and discovering their biological roles is one of the major tasks of the postgenomic era. This article reviews our current knowledge about one of the protein kinase subfamilies, termed serum- and glucocorticoid-induced protein kinases because the first member (SGK1) was identified as a gene that is rapidly transcribed into mRNA when cells are stimulated by serum or glucocorticoid hormones. However, we now know that the SGK1 gene is transcribed in response to a great variety of extracellular signals. Moreover, the SGK1 enzyme is itself activated by phosphorylation in response to different extracellular signals that act via the formation of a lipid mediator called phosphatidylinositol-3,4,5-trisphosphate (PIP3). Evidence is accumulating that SGK1 plays important roles in activating certain potassium, sodium, and chloride channels, suggesting an involvement in the regulation of processes such as cell survival, the functioning of the brain, and the excretion of sodium by the kidney. For the last mentioned reason, sustained high levels of SGK1 protein and activity may contribute to diseases and conditions, such as hypertension and long-term damage to the kidney in type II diabetes. This raises the possibility that drugs that inhibit SGK1 specifically may have therapeutic potential for the treatment of several diseases.