6q23.2

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).

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).

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).

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).

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).

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).

Hypertension

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).

Diabetes

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).

Thrombosis

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).

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).