Serum- and glucocorticoid-inducible kinase 1 and the response to cell stress

Expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) is up-regulated by several types of cell stress, such as ischemia, radiation and hyperosmotic shock. The SGK1 protein is activated by a signaling cascade involving phosphatidylinositide-3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1) and mammalian target of rapamycin (mTOR). SGK1 up-regulates Na+/K+-ATPase, a variety of carriers including Na+-,K+-,2Cl−- cotransporter (NKCC), NaCl cotransporter (NCC), Na+/H+ exchangers, diverse amino acid transporters and several glucose carriers such as Na+-coupled glucose transporter SGLT1. SGK1 further up-regulates a large number of ion channels including epithelial Na+ channel ENaC, voltagegated Na+ channel SCN5A, Ca2+ release-activated Ca2+ channel (ORAI1) with its stimulator STIM1, epithelial Ca2+ channels TRPV5 and TRPV6 and diverse K+ channels. Furthermore, SGK1 influences transcription factors such as nuclear factor kappa-B (NF-κB), p53 tumor suppressor protein, cAMP responsive element-binding protein (CREB), activator protein-1 (AP-1) and forkhead box O3 protein (FOXO3a). Thus, SGK1 supports cellular glucose uptake and glycolysis, angiogenesis, cell survival, cell migration, and wound healing. Presumably as last line of defense against tissue injury, SGK1 fosters tissue fibrosis and tissue calcification replacing energy consuming cells.

The present review discusses the role of SGK1 in the orchestration of cellular response to stress such as energy depletion. The case is made that SGK1 supports cellular energy supply by stimulation of glucose uptake and glycolysis, as well as by stimulation of angiogenesis. SGK1 supports cell survival and cell migration, a prerequisite of tissue repair. As last line of defense, SGK1 replaces energy consuming cells with extracellular matrix by stimulation of tissue fibrosis and tissue calcification. In order to limit the number of citations some of the earlier original papers have been replaced by reviews.

GLUCOSE UPTAKE AND GLYCOLYSIS
SGK1 stimulates cellular glucose uptake and thus enhances the availability of glucose for glycolysis [3]. SGK1 further stimulates the Na + /H + ion exchanger [36] which generates an alkaline cytosolic pH, a prerequisite for an increase of glycolytic flux [1]. The up-regulation of SGK1 in ischemia thus supports energy supply by glycolysis [2,3,10,45].

CELL MIGRATION
SGK1 is part of the machinery stimulating cell migration [47,57,58,63,64]. As shown in vascular smooth muscle cells (VSMCs) [64], the stimulation of migration by plateletderived growth factor PDGF is paralleled by up-regulation of both, SGK1 expression and SGK1 activity [65,66]. Genetic knockout of SGK1 decreases migration [64]. SGK1 is effective, at least in part, by up-regulation of the store-operated Ca 2+ entry (SOCE), which is accomplished by the Ca 2+ channel ORAI1 and its regulator STIM1. Expression of ORAI1 and STIM1 is stimulated by NF-κB, a transcription factor up-regulated by SGK1 [1,64]. In VSMCs, SGK1 triggers nuclear translocation of transcription factor NF-κB [64].

THE ROLE OF SGK1 IN DISEASE -CLINICAL IMPLICATIONS
A wide variety of observations point to a role of SGK1 in human pathophysiology [12]. Excessive expression and activity of SGK1 participates in the pathophysiology of di verse disorders, such as hypertension, obesity, diabetes, thrombosis, stroke, fibrosing disease, vascular calcification, infertility, autoimmune disease, and tumor growth [12,71,84]. A SGK1 gene variant (prevalence approx. 3-5% in Caucasians and approx. 10% in Africans) is associated with hypertension, stroke, obesity and type 2 diabetes [12]. Little is known about the clinical impact of SGK1 deficiency. In a SV129 genetic background, the phenotype of SGK1 knockout mice is mild and SGK1-dependent functions are apparently in large part maintained by other kinases [12]. In view of the putative role of SGK1 in neuronal survival [51], however, the possibility must be kept in mind that lack of SGK1 may accelerate the clinical course of neurodegeneration. Clearly, additional experimental and observational effort is required to define the pathophysiological impact of deranged SGK1 activity in human disease.

CONCLUSIONS
Expression of the serum-and glucocorticoid-inducible kinase SGK1 is steeply up-regulated following cell stress, such as ischemia, radiation and hyperosmotic shock. The SGK1 protein is activated by a signaling cascade involving phosphatidylinositide-3-kinase (PI3K), 3-phosphoinositidedependent kinase 1 (PDK1) and mTOR. SGK1 is a powerful stimulator of transport across the cell membrane, such as Na + /K + -ATPase, Na + /H + exchangers, cellular glucose uptake and ORAI1/STIM1-dependent store-operated Ca 2+ entry (SOCE). SGK1 is further a powerful stimulator of transcription factors including nuclear factor κB (NF-κB; Figure 1). Upon cell stress such as energy depletion, SGK1 supports cellular glucose uptake and glycolysis, angiogenesis, cell survival, cell migration, and wound healing. If those functions fail to remove the cell stress, SGK1 initiates replacement of energy consuming cells by fibrotic and/or calcified tissue.