SGK1

SGK1, or serum- and glucocorticoid-regulated kinase 1, is a serine/threonine protein kinase in the AGC kinase family. It is encoded by the SGK1 gene in humans and is widely expressed, with relatively high levels in kidney, colon, and other metabolically active tissues. The kinase was first identified for its induction by serum and glucocorticoids, and it functions downstream of signaling pathways that respond to growth factors and insulin.

Activation and regulation: SGK1 activity is driven by the phosphoinositide 3-kinase (PI3K) pathway. It is activated through two phosphorylation steps: phosphorylation of the activation loop by PDK1 at Thr256 and phosphorylation of the hydrophobic motif by mTORC2 at Ser422. These modifications are prompted by growth factors, hormones, and cellular stress that stimulate PI3K signaling. Full activity is modulated by additional cellular context, including phosphatases and subcellular localization.

Functions and substrates: SGK1 regulates a range of cellular processes, including ion transport, metabolism, cell survival, and stress responses. In epithelial cells, it promotes sodium reabsorption by increasing the surface expression of the epithelial sodium channel ENaC, largely through inhibition of the E3 ubiquitin ligase NEDD4-2. SGK1 also phosphorylates substrates such as NDRG1 and members of the FOXO transcription factor family, influencing gene expression, cell cycle control, and apoptosis resistance. Through these targets, SGK1 links hormonal signaling to metabolic and stress-related responses.

Clinical and research relevance: Altered SGK1 signaling has been associated with hypertension, metabolic disorders, and cancer, and SGK1 is studied as a potential therapeutic target to modulate electrolyte balance, insulin signaling, and cell survival. The SGK family includes related kinases SGK2 and SGK3, which share regulatory features and substrates.