Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors

Abstract

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase belonging to the protein kinase A, G, and C (AGC) family. Upon initiation of the phosphoinositide 3-kinase (PI3K) signaling pathway, mammalian target of rapamycin complex 2 (mTORC2) and phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylate the hydrophobic motif and kinase domain of SGK1, respectively, inducing SGK1 activation. SGK1 modulates essential cellular processes such as proliferation, survival, and apoptosis. Hence, dysregulated SGK1 expression can result in multiple diseases, including hypertension, cancer, autoimmunity, and neurodegenerative disorders. This review provides a current understanding of SGK1, particularly in sodium transport, cancer progression, and autoimmunity. In addition, we summarize the developmental status of SGK1 inhibitors, their structures, and respective potencies evaluated in pre-clinical experimental settings. Collectively, this review highlights the significance of SGK1 and proposes SGK1 inhibitors as potential drugs for treatment of clinically relevant diseases.

Differential transcriptomic alterations in nasal versus lung tissue of acrolein-exposed rats

“…Overall, acrolein-exposed rats exhibited many gene expression changes modulated by GR and GPCR signaling in the nose that were not observed in the lung. Prominent genes enriched in the nasal GR signaling pathway included Hsp70 encoding genes ( Hspa1a/Hspa1b , Hspa1l , and Hspa8 ) and Sgk1 ( Figure 6A ), which is a glucocorticoid-regulated kinase prompted by cellular stress ( Jang et al, 2022 ). Multiple GPCR signaling network changes were observed in the nose following acrolein exposure, whereas these effects were not seen in the lung ( Figure 6B ).…”

The role of serum-glucocorticoid regulated kinase 1 in reproductive viability: implications from prenatal programming and senescence

“…Since inundated with a diverse array of extracellular stimuli, overwhelming data has landed SGK1 center stage of numerous signaling pathways integrating several cellular processes important to the organism viability, including cell survival and/or apoptosis, cell proliferation and growth, cell migration and differentiation, nutrients and energy conditions with extracellular signals [ 3 , 4 , 116 , 117 ]. Significantly, as a focal point of several signaling outputs, SGK1 is deeply involved in the regulation of prenatal programming, such as gametogenesis, embryonic and fetal development, and reproductive life span as well via osmoregulation and balancing anti- or pro-apoptotic actions [ 31 ].…”

“…Indeed, the increasing expressions and restriction to the nucleus of SGK1 in proliferating granulosa cells synergizes with the markedly down-regulation of FOXO3a [ 3 , 4 ], a specific nuclear substrate of SGK1 inducing G 1 phase cell cycle arrest to maintain ovarian follicles in long-term developmental arrest [ 37 , 40 , 47 ]. Meanwhile, exclusion of SGK1 from the nucleus in luteal cells favors phosphorylation of cytoplasmic targets that sustain a terminally differentiated state of luteal cells or the arrested stage within oocytes [ 37 ].…”

“…Moreover, a considerable number of reports have described the SGK1-activated channels and carriers in Xenopus laevis oocytes, including ENaC, voltage-gated Na + channel Nav1.5 (encoded by the SCN5A gene), voltage-gated potassium channels KCNQ1/KCNE1, Kv 4.3 and Kv1.5, epithelial Ca 2+ channel TRPV5 and TRPV6, Cl − channel ClC-Ka and ClC-2, cystic fibrosis transmembrane conductance regulator Cl − channel CFTR, amino acid transporter SN1, excitatory amino acid transporter (EAAT)1 and EAAT5, electrogenic Na + coupled dicarboxylate transporter NaDC-1, posttranslational modulators PEPT2, Na + -phosphate cotransporter NaPiIIb, and sodium-potassium adenosine triphosphatase (Na + /K + -ATPase) [ 4 , 31 , 50 – 52 ]. All of these ion transporters regulated by SGK1 have been involved in the membrane potential nutrient, transportation and ion homeostasis of oocytes, contributing to normal oogenesis.…”

“…Therefore, to maintain that homeostasis, an appropriate response to dynamic extracellular and intracellular challenges is pivotal to all living organisms. One such key regulatory molecule that coordinately integrates the intracellular signal transduction pathways in this response is serum-glucocorticoid regulated kinase (SGK) 1 [ 3 , 4 ].…”