Alternative titles; symbols
HGNC Approved Gene Symbol: SGK1
Cytogenetic location: 6q23.2 Genomic coordinates (GRCh38): 6:134,169,256-134,318,112 (from NCBI)
Alterations in hepatocyte cell volume, in response to anisotonicity, concentrative substrate uptake, oxidative stress, and hormonal influence, have a great effect on hepatocellular metabolism and gene expression. Waldegger et al. (1997) performed a differential RNA fingerprinting assay on hepatocytes exposed to isotonic and anisotonic media to identify and characterize genes that are transcriptionally regulated by the cellular hydration state. They isolated a single cDNA, termed SGK, that encodes a putative 431-amino acid protein with a molecular mass of 49 kD. The protein sequence of SGK was found to be 98% identical to that of the rat sgk protein, a novel member of the serine/threonine protein kinase family regulated by serum and glucocorticoids in a rat mammary tumor cell line (Webster et al., 1993).
Using Northern blot analysis, Waldegger et al. (1997) detected a 2.6-kb SGK transcript in hepatoma (HepG2) cells and all human tissues tested, with highest levels in pancreas, liver, and cardiac muscle. A second transcript of 7 kb, which was not found in HepG2 cells, was detected in nearly all human tissues tested, with highest levels in the pancreas.
Arteaga et al. (2008) cloned 2 splice variants of mouse Sgk1, which they called Sgk1.1 and Sgk1.2. Sgk1, Sgk1.1, and Sgk1.2 are driven by distinct promoters. RT-PCR detected Sgk1.1 expression exclusively in brain, whereas Sgk1.2 was expressed at low levels in all tissues examined. In situ hybridization showed that Sgk1.1 localized throughout mouse hippocampus, dentate gyrus, and cerebral cortex. In cerebellum, Sgk1.1 localized to Purkinje cells and granular cell layer. Expression of Sgk1.1 in brain largely overlapped expression of Sgk1. Western blot analysis detected the Sgk1 and Sgk1.1 proteins in brain only. Sgk1 protein showed lower abundance than expected based on its mRNA level, suggesting that it is rapidly degraded. In contrast, Sgk1.1 protein appeared to be more stable and showed high abundance compared with its low mRNA level.
By fluorescence in situ hybridization, Waldegger et al. (1998) mapped the SGK gene to 6q23.
By Northern blot analysis, Waldegger et al. (1997) characterized the levels of a 2.6-kb SGK transcript in HepG2 cells in response to osmotic changes. Transcription levels were rapidly raised with exposure to hypertonicity and decreased with hypotonicity. The transcriptional control mechanism was very sensitive to extracellular molarity, and the induction of SGK RNA was independent of de novo protein synthesis. The SGK mRNA had a short half-life. The authors also determined that it was cell volume rather than osmolarity that modified transcriptional regulation of SGK in HepG2 cells, and showed that comparable changes in transcript levels occurred in MDCK (Madin-Darby-Canine kidney) cells. However, unlike previous observations in rat mammary tumor cells, they did not detect changes in SGK transcript levels after treatment of HepG2 cells with glucocorticoids or fetal calf serum.
Transforming growth factor-beta (TGFB1; 190180) participates in the pathophysiology of diabetic complications. TGF-beta stimulates the expression of SGK. Lang et al. (2000) demonstrated markedly enhanced transcription of SGK in diabetic nephropathy (see 603933), with particularly high expression in mesangial cells, interstitial cells, and cells in the thick ascending limbs of the loop of Henle and distal tubules. The enhanced SGK transcription, which results from excessive extracellular glucose concentrations, stimulates renal tubular Na(+) transport. These observations disclosed an additional element in the pathophysiology of diabetic nephropathy.
Kobayashi and Cohen (1999) showed that human PDK1 (PDPK1; 605213) activated human SGK in vitro by phosphorylating thr256. In response to IGF1 (147440) or hydrogen peroxide, transfected SGK was activated in 293 cells via a phosphatidylinositol (PtdIns) 3-kinase (see 171834)-dependent pathway involving phosphorylation of thr256 and ser422. Activation of SGK by PDK1 in vitro was unaffected by PtdIns(3,4,5)P3, abolished by mutation of ser422 to ala, and greatly potentiated by mutation of ser422 to asp, although this mutation did not activate SGK itself. The ser422-to-asp mutant of SGK was activated by phosphorylation, probably at thr256, in unstimulated 293 cells, and this activation was unaffected by PtdIns 3-kinase inhibitors. Kobayashi and Cohen (1999) proposed a model in which activation of SGK by IGF1 or hydrogen peroxide is initiated by PtdIns(3,4,5)P3-dependent activation of PDK2 (602525), which phosphorylates ser422, followed by PtdIns(3,4,5)P3-independent phosphorylation at thr256, which activates SGK and is catalyzed by PDK1.
Independently, Park et al. (1999) identified rat Sgk as a downstream target of PtdIns 3-kinase-stimulated growth factor signaling and found that Pdk1 could phosphorylate thr256 in the activation loop of Sgk, leading to Sgk activation in vivo and in vitro.
Using several breast cancer cell lines, Mikosz et al. (2001) determined that the antiapoptotic effect of glucocorticoid receptor (GCCR; 138040) activation involved SGK1. SGK1 expression was rapidly induced after GCCR activation by serum withdrawal, and ectopic expression of SGK1 inhibited apoptosis in the absence of all growth factors. Expression of a kinase-dead SGK1 mutant (lys127 to met) did not inhibit apoptosis. Mikosz et al. (2001) concluded that SGK1 is a downstream target of GCCR-mediated cell survival and that it is primarily regulated at the level of transcription.
Gamper et al. (2002) found that expression of SGK1, SGK2 (607589), and SGK3 (SGKL; 607591) in human embryonic kidney cells and Xenopus oocytes significantly stimulated voltage-gated K(+) channels. K(+) currents were fully blocked by tetraethylammonium chloride and partially inhibited by a Kv1 (see 176260) channel blocker.
Arteaga et al. (2006) found that mouse Sgk1 is a short-lived protein with a significantly shorter half-life than Sgk2 (607589) or Akt (164730). Sgk1 was ubiquitinated and degraded at the endoplasmic reticulum (ER) membrane by the action of the ER-associated ubiquitin-conjugating enzymes Ubc6 and Ubc7 (see UBE2G1; 601569) and the ligase Hrd1 (SYVN1; 608046). A hydrophobic alpha helix located within the N terminus of Sgk1 serves as the signal for targeting the protein to the ER for ubiquitination and subsequent degradation.
Arteaga et al. (2008) found that depolarization increased the amount of Sgk1.1 mRNA in a mouse neuronal cell line. Immunofluorescence analysis of transfected CHO cells showed that Sgk1.1 localized to the plasma membrane. Activation of phospholipase C (see PLCG1; 172420) caused translocation of Sgk1.1 to the cytosol, indicating that membrane localization of Sgk1.1 was due to its interaction with phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Mutation analysis showed that a cluster of positively charged and hydrophobic residues in the N terminus of Sgk1.1 were required for PtdIns(4,5)P2 binding. Expression of Sgk1.1 in Xenopus oocytes or CHO cells downregulated neuronal Asic1 (ACCN2; 602866) channel activity. Asic1 downregulation was due, at least in part, to decreased expression of Asic1 at the cell surface and required the kinase activity of Sgk1.1, although Asic1 was not phosphorylated.
Using yeast 2-hybrid and pull-down assays, Menniti et al. (2010) found that LYSOLP (ASPG; 618472) and SGK1 interacted. LYSOLP and SGK1 colocalized in cytoplasm of transfected COS-7 cells. SGK1 kinase activity was not necessary for its interaction with LYSOLP, and the interaction had no effect on the lysophospholipase activity of LYSOLP. Moreover, LYSOLP had no effect on SGK1-dependent kinase activity. LYSOLP stimulated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) phosphorylation, whereas SGK1 inhibited it. Expression of SGK1 increased epithelial sodium channel activity in Xenopus oocytes, but coexpression of LYSOLP reversed the effect.
Salker et al. (2011) analyzed expression of SGK1 in midsecretory endometrial samples from women with proven fertility and from women with either unexplained infertility or a history of recurrent pregnancy loss (RPRGL; see 614389) and found that endometrial SGK1 transcript levels were higher in infertile women than fertile controls. In contrast, expression was lower in RPRGL patients, not only when compared to infertile women but also to fertile controls. Immunohistochemistry showed that phosphorylated SGK1 levels, reflecting activated kinase, were higher in the endometrium of infertile women compared to controls or women with RPRGL, especially in the luminal and glandular epithelial compartments, whereas staining of stromal cells underlying the luminal epithelium appeared lower in RPRGL samples. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from women with RPRGL and sensitized those cells to oxidative cell death. Salker et al. (2011) concluded that, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the fetomaternal interface vulnerable to oxidative damage.
Wu et al. (2013) used transcriptional profiling of developing T(H)17 cells to construct a model of their signaling network and nominate major nodes that regulate T(H)17 development. Wu et al. (2013) identified SGK1, a serine/threonine kinase, as an essential node downstream of IL23 (see 605580) signaling. SGK1 is critical for regulating IL23R (607562) expression and stabilizing the T(H)17 cell phenotype by deactivation of mouse Foxo1 (136533), a direct repressor of IL23R expression. SGK1 has been shown to govern sodium transport and salt (NaCl) homeostasis in other cells. Wu et al. (2013) showed that a modest increase in salt concentration induces SGK1 expression, promotes IL23R expression, and enhances T(H)17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated sodium-mediated T(H)17 differentiation in an IL23-dependent manner. Wu et al. (2013) concluded that their data demonstrated that SGK1 has a critical role in the induction of pathogenic T(H)17 cells and provided a molecular insight into a mechanism by which an environmental factor such as a high-salt diet triggers T(H)17 development and promotes tissue inflammation.
Kleinewietfeld et al. (2013) demonstrated that increased salt concentrations found locally under physiologic conditions in vivo markedly boost the induction of murine and human T(H)17 cells. High-salt conditions activated the p38/MAPK (600289) pathway involving nuclear factor of activated T cells-5 (NFAT5; 604708) and SGK1 during cytokine-induced T(H)17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5, or SGK1 abrogated the high-salt-induced T(H)17 cell development. The T(H)17 cells generated under high-salt conditions displayed a highly pathogenic and stable phenotype characterized by the upregulation of the proinflammatory cytokines GMCSF (138960), TNF-alpha (191160), and IL2 (147680). Moreover, mice fed with a high-salt diet developed a more severe form of autoimmune encephalomyelitis (EAE), in line with augmented central nervous system infiltrating and peripherally induced antigen-specific T(H)17 cells. Thus, Kleinewietfeld et al. (2013) suggested that increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic T(H)17 cells.
Using differential display PCR, Tsai et al. (2002) identified 98 cDNA fragments from the rat dorsal hippocampus that were expressed differentially between the fast learners and slow learners in the water maze learning task. One of these cDNA fragments came from the Sgk gene. Northern blot analysis showed that Sgk mRNA levels were approximately 4-fold higher in the hippocampus of fast learners than slow learners. In situ hybridization results indicated that Sgk mRNA levels were increased markedly in the CA1, CA3, and dentate gyrus of the hippocampus of fast learners. Transient transfection of Sgk mutant DNA to the CA1 area of the hippocampus impaired water maze performance in rats, whereas transfection of Sgk wildtype DNA facilitated it.
Salker et al. (2011) expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus, which prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling, and abolished embryo implantation. In contrast, implantation was unhindered in Sgk1 -/- mice, but pregnancy was often complicated by bleeding at the decidual-placental interface, with fetal growth retardation and subsequent demise. Compared to wildtype mice, Sgk1-deficient mice also had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses.
Arteaga, M. F., Coric, T., Straub, C., Canessa, C. M. A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons. Proc. Nat. Acad. Sci. 105: 4459-4464, 2008. [PubMed: 18334630] [Full Text: https://doi.org/10.1073/pnas.0800958105]
Arteaga, M. F., Wang, L., Ravid, T., Hochstrasser, M., Canessa, C. M. An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery. Proc. Nat. Acad. Sci. 103: 11178-11183, 2006. [PubMed: 16847254] [Full Text: https://doi.org/10.1073/pnas.0604816103]
Gamper, N., Fillon, S., Feng, Y., Friedrich, B., Lang, P. A., Henke, G., Huber, S. M., Kobayashi, T., Cohen, P., Lang, F. K+ channel activation by all three isoforms of serum- and glucocorticoid-dependent protein kinase SGK. Pflugers Arch. 445: 60-66, 2002. [PubMed: 12397388] [Full Text: https://doi.org/10.1007/s00424-002-0873-2]
Kleinewietfeld, M., Manzel, A., Titze, J., Kvakan, H., Yosef, N., Linker, R. A., Muller, D. N., Hafler, D. A. Sodium chloride drives autoimmune disease by the induction of pathogenic T(H)17 cells. Nature 496: 518-522, 2013. [PubMed: 23467095] [Full Text: https://doi.org/10.1038/nature11868]
Kobayashi, T., Cohen, P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem. J. 339: 319-328, 1999. [PubMed: 10191262]
Lang, F., Klingel, K., Wagner, C. A., Stegen, C., Warntges, S., Friedrich, B., Lanzendorfer, M., Melzig, J., Moschen, I., Steuer, S., Waldegger, S., Sauter, M., and 9 others. Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc. Nat. Acad. Sci. 97: 8157-8162, 2000. [PubMed: 10884438] [Full Text: https://doi.org/10.1073/pnas.97.14.8157]
Menniti, M., Iuliano, R., Foller, M., Sopjani, M., Alesutan, I., Mariggio, S., Nofziger, C., Perri, A. M., Amato, R., Blazer-Yost, B., Corda, D., Lang, F., Perrotti, N. 60 kDa lysophospholipase, a new Sgk1 molecular partner involved in the regulation of ENaC. Cell. Physiol. Biochem. 26: 587-596, 2010. [PubMed: 21063096] [Full Text: https://doi.org/10.1159/000322326]
Mikosz, C. A., Brickley, D. R., Sharkey, M. S., Moran, T. W., Conzen, S. D. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J. Biol. Chem. 276: 16649-16654, 2001. [PubMed: 11278764] [Full Text: https://doi.org/10.1074/jbc.M010842200]
Park, J., Leong, M. L. L., Buse, P., Maiyar, A. C., Firestone, G. L., Hemmings, B. A. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J. 18: 3024-3033, 1999. [PubMed: 10357815] [Full Text: https://doi.org/10.1093/emboj/18.11.3024]
Salker, M. S., Christian, M., Steel, J. H., Nautiyal, J., Lavery, S., Trew, G., Webster, Z., Al-Sabbagh, M., Puchchakayala, G., Foller, M., Landles, C., Sharkey, A. M., Quenby, S., Aplin, J. D., Regan, L., Lang, F., Brosens, J. J. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nature Med. 17: 1509-1513, 2011. [PubMed: 22001908] [Full Text: https://doi.org/10.1038/nm.2498]
Tsai, K. J., Chen, S. K., Ma, Y. L., Hsu, W. L., Lee, E. H. Y. sgk, a primary glucocorticoid-induced gene, facilitates memory consolidation of spatial learning in rats. Proc. Nat. Acad. Sci. 99: 3990-3995, 2002. [PubMed: 11891330] [Full Text: https://doi.org/10.1073/pnas.062405399]
Waldegger, S., Barth, P., Raber, G., Lang, F. Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. Proc. Nat. Acad. Sci. 94: 4440-4445, 1997. [PubMed: 9114008] [Full Text: https://doi.org/10.1073/pnas.94.9.4440]
Waldegger, S., Erdel, M., Nagl, U. O., Barth, P., Raber, G., Steuer, S., Utermann, G., Paulmichl, M., Lang, F. Genomic organization and chromosomal localization of the human SGK protein kinase gene. Genomics 51: 299-302, 1998. [PubMed: 9722955] [Full Text: https://doi.org/10.1006/geno.1998.5258]
Webster, M. K., Goya, L., Ge, Y., Maiyar, A. C., Firestone, G. L. Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Molec. Cell. Biol. 13: 2031-2040, 1993. [PubMed: 8455596] [Full Text: https://doi.org/10.1128/mcb.13.4.2031-2040.1993]
Wu, C., Yosef, N., Thalhamer, T., Zhu, C., Xiao, S., Kishi, Y., Regev, A., Kuchroo, V. K. Induction of pathogenic T(H)17 cells by inducible salt-sensing kinase SGK1. Nature 496: 513-517, 2013. [PubMed: 23467085] [Full Text: https://doi.org/10.1038/nature11984]