Written | 2014-09 | Miranda Menniti, Rodolfo Iuliano, Lucia D'Antona, Cristina Talarico, Rosario Amato, Nicola Perrotti |
Dipartimento di Scienze della Salute, Universita degli Studi Magna Graecia di Catanzaro (MM, RA, NP); Dipartimento di Medicina Sperimentale e Clinica, Universita degli Studi Magna Graecia di Catanzaro (RI, LDA,CT) |
Identity |
Alias (NCBI) | SGK |
HGNC (Hugo) | SGK1 |
HGNC Previous name | SGK |
HGNC Previous name | serum/glucocorticoid regulated kinase |
LocusID (NCBI) | 6446 |
Atlas_Id | 42281 |
Location | 6q23.2 [Link to chromosome band 6q23] |
Location_base_pair | Starts at 134169256 and ends at 134174866 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping SGK1.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
CD74 (5q32) / SGK1 (6q23.2) | CDC42BPA (1q42.13) / SGK1 (6q23.2) | FGF13 (Xq26.3) / SGK1 (6q23.2) | |
KIF3C (2p23.3) / SGK1 (6q23.2) | LOC100507412 (-) / SGK1 (6q23.2) | PLP1 (Xq22.2) / SGK1 (6q23.2) | |
SGK1 (6q23.2) / IGFBP4 (17q21.2) | SGK1 (6q23.2) / NUFIP2 (17q11.2) | SGK1 (6q23.2) / SGK1 (6q23.2) | |
SLC2A12 (6q23.2) / SGK1 (6q23.2) |
DNA/RNA |
Description | The SGK1 gene is comprised of 14 coding exons (Ensembl). |
Transcription | Sgk1 contains 28 distinct gt-ag introns, it presents 32 different mRNAs transcription products with 28 alternatively spliced variants and 4 unspliced forms. 8 probable alternative promoters have been identified, 10 non overlapping alternative last exons and 8 validated alternative polyadenylation sites (AceView). The SGK1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and C. elegans (Gene ID: 6446, NCBI). |
Protein |
Note | The serum- and glucocorticoid-inducible kinase 1 (SGK1) was discovered as a gene regulated transcriptionally by serum- and glucocorticoids in rat mammary tumor cells (Firestone et al., 2003). |
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Chain (1-431) serine/threonine-protein kinase Sgk1; domain (98-355) protein kinase; domain (366-431) AGC-kinase C-terminal (UNIPROT). | |
Description | SGK1 is a member of the "AGC" subfamily (García Martínez and Alessi, 2008). SGK1 activation is dependent on phosphorylation. mTOR was found to be the H-motif kinase that phosphorylates Sgk1 at S422 and PDK1 at T256 (Hong et al., 2008; Amato et al., 2007; Kobayashi and Cohen, 1999; Perrotti et al., 2001). Sgk1 is involved in mediating growth factor-, insulin-, IL-2- and steroid-dependent survival signals (Lang et al., 2009a; Mikosz et al., 2001). |
Expression | SGK1 transcription is regulated by the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the progesterone receptor (PR), the vitamin D receptor (VDR), the retinoid X receptor (RXR), the farnesoid X receptor (FXR), the sterol regulatory element binding protein (SREBP), peroxisome proliferator-activated receptor γ (PPARγ), the cAMP response element binding protein (CREB), the p53 tumor suppressor protein, the Sp1 transcription factor, the activating protein 1 (AP1), the activating transcription factor 6 (ATF6), the heat shock factor (HSF), reticuloendotheliosis viral oncogene homolog (c-Rel), nuclear factor κB (NFκB), signal transducers and activators of transcription (STAT), TGFβ dependent transcription factors SMAD3 and SMAD4, and fork-head activin signal transducer (FAST) (Lang et al., 2009a). |
Localisation | SGK presents a stimulus-dependent regulation for the subcellular localization. SGK actively shuttles between the nucleus (in S and G2/M) and the cytoplasm (in G1) in synchrony with the cell cycle (Buse et al., 1999). The nuclear localization signal (NLS) of SGK (located at an external surface of the molecule) binds the importin-alpha nuclear import receptor regulating the nuclear-cytoplasmic shuttling (Firestone et al., 2003). SGK-1 localizes in the mitochondria, under hyperosmotic stress, that permits access to physiologically appropriate mitochondrial interacting proteins and substrates, such as IF-1 and the F1F0-ATPase, as part of the cellular stressed induced program (O'Keeffe et al., 2013). A significant fraction of SGK-1 is membrane-associated and ubiquitilated (Brickley et al., 2002). |
Function | SGK1 regulates different ion channels, transporters, transcription factors and enzyme: ion channels like ENaC (Faletti et al., 2002), TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6; carriers like NHE3, GLUT1, SGLT1, EAAT1, EAAT2, EAAT3, EAAT4, EAAT5, Na+-K+-ATPase. SGK1 regulates the activity of enzymes like glycogen synthase kinase-3, ubiquitin ligase Nedd4-2, phosphomannomutase-2 and transcription factors like forkhead transcription factor FKHRL1, beta-catenin, nuclear factor kappaB. Moreover, SGK1 contributes to the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis (Lang et al., 2006). Sgk1 can phosphorylate and activate MDM2, driving p53 to degradation, protecting cells from stress dependent apoptosis (Amato et al., 2009). Sgk1 was demonstrated to interact with phosphomannomutase 2 (PMM2), inhibiting its activity, with and without insulin stimulus (Menniti et al., 2005). Moreover, it was demonstrated that the 60 kDa Lysophospholipase (LysoLP) interacts with SGK1, and that the expression of LysoLP in Xenopus oocytes decreases membrane expression of ENaC, inhibiting basal and Sgk1-dependent activation of the channel (Menniti et al., 2010). Sgk1 can regulates RANBP1 at the gene transcription level with functional consequences on microtubule stability and cell sensitivity to taxol (Amato et al., 2013). Alternative initiation of transcription at -2981, -850 upstream of the transcription initiation site (+1) of the reference mRNA of SGK1 was studied. Transcription of three distinct splice variants are all markedly upregulated in tumor tissues but differentially up-regulated under differentiation or hypoxia. |
Implicated in |
Note | |
Entity | Various cancers |
Note | Increased expression of SGK1 have been observed in colon cancer, myeloma, medulloblastoma, prostate cancer, ovarian tumors and non-small cell lung cancer (Lang et al., 2013). SGK1-sensitive implication in tumour growth include activation of K(+) channels and Ca(2+) channels, Na(+)/H(+) exchanger, amino acid transporters, glucose transporters, upregulation of the nuclear factor NFkappaB and beta-catenin and downregulation of the transcription factors Foxo3a/FKHRL1 and p53 (Lang et al., 2010). SGK1 phosphorylates MDM2 with consequent p53 ubiquitylation, and influences cell proliferation, survival, and differentiation (Amato et al., 2009). In cancer cells, SGK1 up-regulates RanBP1, a major effector of the GTPase RAN, which in turn influences mitotic microtubule activity and decreases taxol sensitivity (Amato et al., 2013). SGK1 expression mediated the phosphorylation of ERK2, then the MEK/ERK complexes formation during liver regeneration (Won et al., 2009). SGK1 negatively regulates stress-activated signaling through inhibition of SEK1 function (Kim et al., 2007). SGK1 interferes with the binding of SEK1 to JNK1 and MEKK1 (Lang et al., 2010), down-regulates vinculin phosphorylation, which in turn may enhance migration via actin cytoskeleton redistribution (Schmidt et al., 2012). SGK1 influences the activity of channels and transporters, such as Ca2+ release-activated channels (ICRAC) Orai1/STIM (Eylenstein et al., 2012) and the K+ channel Kv1.3, influencing cell proliferation and cell death (Schmidt et al., 2012). SGK1 is a direct beta-catenin target gene and in colon cancer cells its up-regulation determines a decrease of apoptosis through the down-regulation of Foxo3a activity (Dehner et al., 2008). SGK-1 has significant homology with the serine-threonine Akt which is considered a relevant player in carcinogenesis, since its activation occurred in the majority of human tumors. Interestingly, some cancer cell lines that are resistant to Akt inhibition showed significant up-regulation of SGK1 expression (Sommer et al., 2013). |
Entity | Colorectal carcinoma |
Note | A recent study confirms the sensitivity of colon carcinoma to the expression of SGK1. Following deficiency of APC (adenoma polyposis coli) or chemical cancerogenesis, SGK1 knockout mice develop less intestinal tumours than their wild-type littermates and pharmacological SGK1 inhibition counteracts growth of cancer cells (Lang et al., 2010). SGK1 up-regulates RanBP1, a major effector of the GTPase RAN, which in turn influences mitotic microtubule activity and decreases taxol sensitivity in RKO colon carcinoma cells (Amato et al., 2013). |
Entity | Kidney cancer |
Note | In A-498 kidney cancer cells, IL-2 binding to its own receptor triggers a signal transduction pathway leading to the inhibition of proliferation and apoptosis. Inhibition of proliferation is associated with Erk1/2 dephosphorylation, whereas the survival signals appear to be mediated by Sgk1 activation (Amato et al., 2007). |
Entity | Myeloma |
Note | SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their malignant growth. Fagerli et al. recently have demonstrated a rapid, strong and sustained induction of SGK1 in primary myeloma cells. Inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway abolished STAT3 phosphorylation and SGK1 induction. Downregulation of SGK1 by shRNAs resulted in decreased proliferation of myeloma cell lines, with induction of cell cycle inhibitory genes, like CDKNA1/p21, and downregulation of CDK6 and RBL2/p130 (Fagerli et al., 2011). |
Entity | Prostate cancer |
Note | Rauhala et al. showed the downregulation of mRNA and protein expressions of SGK, in prostate cancer. The expression of SGK was decreased in about half of the prostate carcinomas, whereas the expression was high in all non-malignant prostate epithelial cells (Rauhala et al., 2005). Low espression of SGK1 is associated with higher tumor grade and increased cancer recurrence, and is a potential indicator of aberrant androgen receptor signaling. Glucocorticoid receptor expression increased with androgen deprivation, potentially providing a mechanism forthe maintenance of androgen pathway signaling in these tumors (Szmulewitz et al., 2012). Inhibition of SGK1 expression or activity antagonizes androgen-induced growth of the prostate cancer cell line LNCaP, suggesting that SGK1 might be a viable target for the treatment of prostate cancer (Sherk et al., 2008). |
Entity | Ovarian cancer |
Note | Sgk was identified like a critical FSH-regulated gene important for the proliferation and maturation of granulosa cells in the normal ovary (Richards, 1994). Specific and reproducible gene expression changes occur in human ovarian tumors over time, following systemic administration of glucocorticoids. Induction of SGK1 gene expression in epithelial tumor cell lines inhibits chemotherapy-induced tumor cell apoptosis (Melhem et al., 2009). Sgk expression is lower in epithelial tumours, serous and mucinous cystadenocarcinomas, and also in normal pre-menopausal ovaries (Chu et al., 2002). |
Entity | Hypertension |
Note | There are different SGK1 gene variants that can influence blood pressure (Rao et al., 2013), including the combination of polymorphisms in intron 6 [I6CC] and exon 8 [E8CC/CT] (Lang et al., 2006; Lang et al., 2009a). The insulin probably stimulates renal tubular salt reabsorption through the activation of SGK1 with consequent renal salt retention and hypertension in type II diabetes (Lang et al., 2006; Lang et al., 2009a). |
Entity | Diabetes |
Note | SGK1 regulates the Na+ coupled glucose transporter SGLT1 (Lang et al., 2006), the adipocyte differentiation and the adipogenesis (Di Pietro et al., 2010). The I6CC/E8CC/CT SGK1 gene variant determines enhancement in body weight and prevalence of type 2 diabetes (Lang et al., 2009b). |
Entity | Thrombosis |
Note | SGK1 stimulates coagulation, through tissue factor expression (Lang et al., 2009a) and regulation of blood platelets by up-regulation of NFκB, and consequent expression of the platelet Ca2+ channel Orai1/STIM1, that predisposing to stroke (Dahlberg et al., 2011) and thrombosis (Borst et al., 2012). |
Entity | Autoimmune disease |
Note | SGK1 is involved in autoimmune disease, through up-regulation of the pathogenic IL-23-dependent interleukin (IL) 17-producing CD4+ helper T cells (TH17 cells) (Kleinewietfeld et al., 2013). In affected tissues of inflammatory and fibrosing diseases was demonstrated an excessive expression of SGK1, like in lung fibrosis, diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, liver scirrhosis, fibrosing pancreatitis, peritoneal fibrosis, Crohn's disease, and coeliac disease (Cheng et al., 2010; Lang et al., 2006; Yamahara et al., 2009). |
Bibliography |
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PMID 22309306 |
Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic. |
Sherk AB, Frigo DE, Schnackenberg CG, Bray JD, Laping NJ, Trizna W, Hammond M, Patterson JR, Thompson SK, Kazmin D, Norris JD, McDonnell DP. |
Cancer Res. 2008 Sep 15;68(18):7475-83. doi: 10.1158/0008-5472.CAN-08-1047. |
PMID 18794135 |
Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription. |
Simon P, Schneck M, Hochstetter T, Koutsouki E, Mittelbronn M, Merseburger A, Weigert C, Niess A, Lang F. |
Cell Physiol Biochem. 2007;20(6):715-28. |
PMID 17982254 |
Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. |
Sommer EM, Dry H, Cross D, Guichard S, Davies BR, Alessi DR. |
Biochem J. 2013 Jun 15;452(3):499-508. doi: 10.1042/BJ20130342. |
PMID 23581296 |
The interdependence of EGF-R and SGK-1 in fibronectin expression in primary kidney cortical fibroblast cells. |
Stevens VA, Saad S, Chen XM, Pollock CA. |
Int J Biochem Cell Biol. 2007;39(5):1047-54. Epub 2007 Feb 23. |
PMID 17382577 |
Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers. |
Szmulewitz RZ, Chung E, Al-Ahmadie H, Daniel S, Kocherginsky M, Razmaria A, Zagaja GP, Brendler CB, Stadler WM, Conzen SD. |
Prostate. 2012 Feb 1;72(2):157-64. doi: 10.1002/pros.21416. Epub 2011 May 11. |
PMID 21563193 |
SGK1 phosphorylation of IkappaB Kinase alpha and p300 Up-regulates NF-kappaB activity and increases N-Methyl-D-aspartate receptor NR2A and NR2B expression. |
Tai DJ, Su CC, Ma YL, Lee EH. |
J Biol Chem. 2009 Feb 13;284(7):4073-89. doi: 10.1074/jbc.M805055200. Epub 2008 Dec 16. |
PMID 19088076 |
Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. |
Thomanetz V, Angliker N, Cloetta D, Lustenberger RM, Schweighauser M, Oliveri F, Suzuki N, Ruegg MA. |
J Cell Biol. 2013 Apr 15;201(2):293-308. doi: 10.1083/jcb.201205030. Epub 2013 Apr 8. |
PMID 23569215 |
mTOR and Akt signaling in cancer: SGK cycles in. |
Toker A. |
Mol Cell. 2008 Jul 11;31(1):6-8. doi: 10.1016/j.molcel.2008.06.007. |
PMID 18614042 |
Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates glucocorticoid-induced inhibition of insulin secretion. |
Ullrich S, Berchtold S, Ranta F, Seebohm G, Henke G, Lupescu A, Mack AF, Chao CM, Su J, Nitschke R, Alexander D, Friedrich B, Wulff P, Kuhl D, Lang F. |
Diabetes. 2005 Apr;54(4):1090-9. |
PMID 15793248 |
Induction of serum- and glucocorticoid-induced kinase-1 (SGK1) by cAMP regulates increases in alpha-ENaC. |
Vasquez MM, Castro R, Seidner SR, Henson BM, Ashton DJ, Mustafa SB. |
J Cell Physiol. 2008 Dec;217(3):632-42. doi: 10.1002/jcp.21534. |
PMID 18615584 |
Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration. |
Won M, Park KA, Byun HS, Kim YR, Choi BL, Hong JH, Park J, Seok JH, Lee YH, Cho CH, Song IS, Kim YK, Shen HM, Hur GM. |
J Hepatol. 2009 Jul;51(1):67-76. doi: 10.1016/j.jhep.2009.02.027. Epub 2009 Apr 16. |
PMID 19447520 |
Direct aldosterone action as a profibrotic factor via ROS-mediated SGK1 in peritoneal fibroblasts. |
Yamahara H, Kishimoto N, Nakata M, Okazaki A, Kimura T, Sonomura K, Matsuoka E, Shiotsu Y, Adachi T, Matsubara H, Iwasaka T, Mori Y. |
Kidney Blood Press Res. 2009;32(3):185-93. doi: 10.1159/000225379. Epub 2009 Jun 12. |
PMID 19521108 |
p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. |
You H, Jang Y, You-Ten AI, Okada H, Liepa J, Wakeham A, Zaugg K, Mak TW. |
Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14057-62. Epub 2004 Sep 21. |
PMID 15383658 |
Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf. |
Zhang BH, Tang ED, Zhu T, Greenberg ME, Vojtek AB, Guan KL. |
J Biol Chem. 2001 Aug 24;276(34):31620-6. Epub 2001 Jun 15. |
PMID 11410590 |
Citation |
This paper should be referenced as such : |
Miranda Menniti, Rodolfo Iuliano, Lucia D'Antona, Cristina Talarico, Rosario Amato |
SGK1 (serum/glucocorticoid regulated kinase 1) |
Atlas Genet Cytogenet Oncol Haematol. 2015;19(8):535-540. |
Free journal version : [ pdf ] [ DOI ] |
Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ] |
t(X;6)(q27;q23) FGF13/SGK1
|
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ] |
SLC2A12/SGK1 (6q23)
t(X;6)(q22;q23) PLP1/SGK1 |
External links |
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