SGK1 (serum/glucocorticoid regulated kinase 1)

2014-09-01   Miranda Menniti , Rodolfo Iuliano , Lucia DAntona , 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)





The SGK1 gene is comprised of 14 coding exons (Ensembl).


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).



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).
Atlas Image
Chain (1-431) serine/threonine-protein kinase Sgk1; domain (98-355) protein kinase; domain (366-431) AGC-kinase C-terminal (UNIPROT).


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).


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).


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 (OKeeffe et al., 2013).
A significant fraction of SGK-1 is membrane-associated and ubiquitilated (Brickley et al., 2002).


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

Entity name
Various cancers
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 name
Colorectal carcinoma
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 name
Kidney cancer
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 name
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 name
Prostate cancer
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 name
Ovarian cancer
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 name
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 name
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 name
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 name
Autoimmune disease
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, Crohns disease, and coeliac disease (Cheng et al., 2010; Lang et al., 2006; Yamahara et al., 2009).


Pubmed IDLast YearTitleAuthors
197564492009Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation.Amato R et al
175712482007IL-2 signals through Sgk1 and inhibits proliferation and apoptosis in kidney cancer cells.Amato R et al
231083932013Sgk1 enhances RANBP1 transcript levels and decreases taxol sensitivity in RKO colon carcinoma cells.Amato R et al
236503972013Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis.Anacker C et al
168178522006A novel N-terminal hydrophobic motif mediates constitutive degradation of serum- and glucocorticoid-induced kinase-1 by the ubiquitin-proteasome pathway.Bogusz AM et al
220318642012The serum- and glucocorticoid-inducible kinase 1 (SGK1) influences platelet calcium signaling and function by regulation of Orai1 expression in megakaryocytes.Borst O et al
122180622002Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1).Brickley DR et al
111542812001Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a).Brunet A et al
100667871999Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signaling pathways.Buse P et al
196173522009Rescue of DeltaF508-CFTR by the SGK1/Nedd4-2 signaling pathway.Caohuy H et al
205682462010Serum and glucocorticoid-inducible kinase 1 (SGK1) is necessary for vascular remodeling during angiogenesis.Catela C et al
206316742010Serum- and glucocorticoid-regulated kinase 1 is upregulated following unilateral ureteral obstruction causing epithelial-mesenchymal transition.Cheng J et al
119945392002FSH-regulated gene expression profiles in ovarian tumours and normal ovaries.Chu S et al
214305562011Genetic variants in serum and glucocortocoid regulated kinase 1, a regulator of the epithelial sodium channel, are associated with ischaemic stroke.Dahlberg J et al
184872072008Wnt signaling inhibits Forkhead box O3a-induced transcription and apoptosis through up-regulation of serum- and glucocorticoid-inducible kinase 1.Dehner M et al
199659292010Serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates adipocyte differentiation via forkhead box O1.Di Pietro N et al
167766522006The N-terminus of the serum- and glucocorticoid-inducible kinase Sgk1 specifies mitochondrial localization and rapid turnover.Engelsberg A et al
221101302012Transcription factor NF-κB regulates expression of pore-forming Ca2+ channel unit, Orai1, and its activator, STIM1, to control Ca2+ entry and affect cellular functions.Eylenstein A et al
214789112011Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells.Fagerli UM et al
118323342002sgk: an essential convergence point for peptide and steroid hormone regulation of ENaC-mediated Na+ transport.Faletti CJ et al
163018232005SGK1-mediated fibronectin formation in diabetic nephropathy.Feng Y et al
126495972003Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity.Firestone GL et al
189258752008mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1).García-Martínez JM et al
185708732008mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation.Hong F et al
175687722007Negative regulation of SEK1 signaling by serum- and glucocorticoid-inducible protein kinase 1.Kim MJ et al
234670952013Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.Kleinewietfeld M et al
101912621999Activation 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.Kobayashi T et al
195847212009The physiological impact of the serum and glucocorticoid-inducible kinase SGK1.Lang F et al
170154872006(Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms.Lang F et al
197648912009Targeting SGK1 in diabetes.Lang F et al
205410342010Colorectal carcinoma cells--regulation of survival and growth by SGK1.Lang F et al
239336862013Serum and glucocorticoid inducible kinase, metabolic syndrome, inflammation, and tumor growth.Lang F et al
126317362003Importin-alpha mediates the regulated nuclear targeting of serum- and glucocorticoid-inducible protein kinase (Sgk) by recognition of a nuclear localization signal in the kinase central domain.Maiyar AC et al
217081342011Phosphorylation of NDRG1 is temporally and spatially controlled during the cell cycle.McCaig C et al
193838272009Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues.Melhem A et al
21063096201060kDa lysophospholipase, a new Sgk1 molecular partner involved in the regulation of ENaC.Menniti M et al
112787642001Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1.Mikosz CA et al
234029122013The serum- and glucocorticoid-induced protein kinase-1 (Sgk-1) mitochondria connection: identification of the IF-1 inhibitor of the F(1)F(0)-ATPase as a mitochondria-specific binding target and the stress-induced mitochondrial localization of endogenous Sgk-1.O'Keeffe BA et al
110960812001Activation of serum- and glucocorticoid-induced protein kinase (Sgk) by cyclic AMP and insulin.Perrotti N et al
242697412014Rapid aldosterone actions on epithelial sodium channel trafficking and cell proliferation.Quinn S et al
226482672013Polymorphisms in the serum- and glucocorticoid-inducible kinase 1 gene are associated with blood pressure and renin response to dietary salt intake.Rao AD et al
159812062005Dual-specificity phosphatase 1 and serum/glucocorticoid-regulated kinase are downregulated in prostate cancer.Rauhala HE et al
126576042003Serum- and glucocorticoid-regulated kinase isoform-1 and epithelial sodium channel subunits in human ocular ciliary epithelium.Rauz S et al
77052791994Hormonal control of gene expression in the ovary.Richards JS et al
230155482013Serum- and glucocorticoid-inducible kinase SGK1 regulates reorganization of actin cytoskeleton in mast cells upon degranulation.Schmid E et al
223093062012Serum- and glucocorticoid-dependent kinase-1-induced cell migration is dependent on vinculin and regulated by the membrane androgen receptor.Schmidt EM et al
187941352008Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.Sherk AB et al
179822542007Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription.Simon P et al
235812962013Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors.Sommer EM et al
173825772007The interdependence of EGF-R and SGK-1 in fibronectin expression in primary kidney cortical fibroblast cells.Stevens VA et al
215631932012Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers.Szmulewitz RZ et al
190880762009SGK1 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 et al
235692152013Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology.Thomanetz V et al
186140422008mTOR and Akt signaling in cancer: SGK cycles in.Toker A et al
157932482005Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates glucocorticoid-induced inhibition of insulin secretion.Ullrich S et al
186155842008Induction of serum- and glucocorticoid-induced kinase-1 (SGK1) by cAMP regulates increases in alpha-ENaC.Vasquez MM et al
194475202009Protein 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 et al
195211082009Direct aldosterone action as a profibrotic factor via ROS-mediated SGK1 in peritoneal fibroblasts.Yamahara H et al
153836582004p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1.You H et al
114105902001Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf.Zhang BH et al

Other Information

Locus ID:

NCBI: 6446
MIM: 602958
HGNC: 10810
Ensembl: ENSG00000118515


dbSNP: 6446
ClinVar: 6446
TCGA: ENSG00000118515


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
mTOR signaling pathwayKEGGko04150
mTOR signaling pathwayKEGGhsa04150
Aldosterone-regulated sodium reabsorptionKEGGko04960
Aldosterone-regulated sodium reabsorptionKEGGhsa04960
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
FoxO signaling pathwayKEGGhsa04068
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Ion channel transportREACTOMER-HSA-983712
Stimuli-sensing channelsREACTOMER-HSA-2672351
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
154615892004Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3.135
185708732008mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation.109
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
236503972013Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis.81
153283452004cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2.72
235812962013Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors.64
173604712007An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis.58
274519072016PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition.58
126845162003Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A.52
195847212009The physiological impact of the serum and glucocorticoid-inducible kinase SGK1.50


Miranda Menniti ; Rodolfo Iuliano ; Lucia DAntona ; Cristina Talarico ; Rosario Amato ; Nicola Perrotti

SGK1 (serum/glucocorticoid regulated kinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: