Disease relevance of SGK

• SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia [1].
• A common ( approximately 5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight [1].
• Up-regulation of tubular SGK-1 mRNA in diabetes mellitus was confirmed in vivo [2].
• DISCUSSION: Overactivity of SGK1 may lead not only to excessive ENaC activity and hypertension but also to enhanced SGLT1 activity and obesity [3].
• In retinal amacrine and ganglion cells, EAAT5 is colocalized with the serum and glucocorticoid inducible kinase SGK1, a serine/threonine kinase known to regulate transport [4].

High impact information on SGK

• Absorption of NaCl is a rather steady process that is controlled by steroid hormones regulating the expression of epithelial Na(+) channels (ENaC), the Na(+)-K(+)-ATPase, and additional modulating factors such as the serum- and glucocorticoid-regulated kinase SGK [5].
• Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro [6].
• Thus, the hydrophobic motif phosphorylation of S6K and SGK converts them into substrates that can be activated by PDK1 [7].
• PKB/Akt and serum and glucocorticoid-regulated kinase (SGK) family kinases are important downstream targets of phosphatidylinositol 3 (PI-3) kinase and have been shown to mediate a variety of cellular processes, including cell growth and survival [8].
• Although regulation of Akt can be achieved through several mechanisms, including its phosphoinositide-binding Pleckstrin homology (PH) domain, how SGK kinases are targeted and regulated remains to be elucidated [8].

Chemical compound and disease context of SGK

• SGK-1 expression was then assessed in vivo in a model of streptozotocin-induced diabetes mellitus type 2 [2].
• The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin [9].
• Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases [10].
• Despite similar cardiac GSK3beta phosphorylation cardiac fibrosis following DOCA/high salt treatment was significantly blunted in SGK1 knockout mice [11].
• Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress [12].

Biological context of SGK

• These findings indicate that SGK acts in concert with Akt to propagate the effects of PI3K activation within the nucleus and to mediate the biological outputs of PI3K signaling, including cell survival and cell cycle progression [13].
• Consistent with these findings, the Ser422Asp mutant of SGK is activated by phosphorylation (probably at Thr256) in unstimulated 293 cells, and activation is unaffected by inhibitors of PtdIns 3-kinase [14].
• Opposite shifts of gating properties were elicited by mutation of serine to alanine (S483ASCN5A and S663ASCN5A) in the SGK consensus sequences of SCN5A [15].
• The in vivo physiological significance of SGK dependent regulation of the other channels remains to be shown even though circumstantial evidence points to involvement in the regulation of epithelial transport, cell volume, cell proliferation, cardiac action potential and neuroexcitability [16].
• The substrate specificity of SGK isoforms superficially resembles that of PKB in that serine and threonine residues lying in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr sequences (where Xaa is a variable amino acid) are phosphorylated [17].

Anatomical context of SGK

• In conclusion, all three SGK isoforms and PKB increase EAAT2 activity and plasma membrane expression and thus, may participate in the regulation of neuroexcitability [18].
• In dual electrode voltage-clamp experiments SGK isoforms up-regulated Kv1 voltage-gated K(+)channels expressed in Xenopus laevis oocytes [19].
• The levels of SGK2 mRNA in H4IIE cells and SGK3 mRNA in Rat2 fibroblasts are not increased by stimulation with serum or dexamethasone, whereas the level of SGK1 mRNA is increased greatly [20].
• Serum and glucocorticoid-inducible kinase 1 (SGK1) is highly expressed in enterocytes [21].
• Immunohistochemistry in human small intestine revealed SGK1 colocalization with Nedd4-2 in villus enterocytes [21].

Associations of SGK with chemical compounds

• Similar to glutamate-induced currents, [3H] glutamate uptake and cell surface abundance of the transporter were increased by the SGK isoforms and down-regulated by the ubiquitin ligase Nedd4-2 [18].
• The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp (although this mutation does not activate SGK itself) [14].
• This study determined the expression and functional role of SGK-1 in PTCs in high glucose conditions [2].
• SGK-1 overexpression increased PTC growth (P < 0.0001), progression through the cell cycle (P < 0.001), and increased NHE3 mRNA (P < 0.01), which were all reversed with PKI166 [2].
• Regulation of sodium transport in mammalian collecting duct cells by aldosterone-induced kinase, SGK1: structure/function studies [22].
• An endogenous stimulus of SGK1, insulin, increased IKKalpha and NF-kappaB phosphorylation as well as NF-kappaB acetylation and NF-kappaB activity, but SGK1 small interfering RNA transfection blocked these effects of insulin [23].

Physical interactions of SGK

• Pull down assays reveal that SGK1 interacts with NHERF2 through the second PDZ domain of NHERF2 [24].
• Consistent with this model, we found that SGK bound to hNedd4-2 and hNedd4 [25].
• Here, we report the identification of serum and glucocorticoid-inducible kinase (SGK) as a cellular protein that physically interacts with BMK1 [26].

Enzymatic interactions of SGK

• Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a) [13].
• SGK1 phosphorylated NDRG2 at Thr330, Ser332 and Thr348 in vitro [27].
• We show that SGK phosphorylates huntingtin at serine 421 and that phosphorylation can protect striatal neurons against polyQ-huntingtin-induced toxicity [9].
• We were then able to demonstrate that Sgk1 phosphorylated PMM2 in an in vitro assay [28].
• SGK phosphorylates Nedd4-2, which reduces Nedd4-2 binding and inhibition of ENaC [29].

Regulatory relationships of SGK

• SGK1 kinase upregulates GLUT1 activity and plasma membrane expression [30].
• SCN5A currents were activated by coexpression of either wild-type SGK1 or SGK3 or the constitutively active S422DSGK1 [15].
• Replacement of serine by alanine at the two SGK consensus sites decreased I(HERG) but neither mutation abolished the stimulating effect of SGK3 [31].
• The present study aims to explore whether TRPV5 is regulated by the serum and glucocorticoid inducible kinase SGK1, a kinase transcriptionally upregulated by 1,25(OH) 2D3 [32].
• HERG was expressed in Xenopus oocytes with or without additional expression of SGK1 or SGK3 [31].
• Infection of primary hepatocytes with an adenoviral vector encoding SGK1 enhanced the ERK phosphorylation under serum-starved conditions and this was blocked by the expression of kinase-dead SGK1 [33].

Other interactions of SGK

• GLUT1 contains a consensus site ((95)Ser) for phosphorylation by SGK1 [30].
• Its mutation to either Ile or Val severely reduced the efficacy with which NEK6-phosphorylated peptide substrates, and moreover, mutation of the equivalent Leu residue in S6K1 or SGK1 prevented phosphorylation of their hydrophobic motifs by NEK6 in vitro [34].
• The serum and glucocorticoid inducible kinase SGK1 and its isoform SGK3 are both expressed in cardiac tissue [15].
• No EGF protein was detectable in PTCs, suggestive of phosphorylation of the EGFR by high glucose and downstream induction of SGK-1 [2].
• Site-directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4-2 protein (S382A,S468ANedd4-2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1 [35].

Analytical, diagnostic and therapeutic context of SGK

• 3. A variant of the SGK1 gene associates with increased blood pressure and body mass index [36].
• Fluorescence confocal microscopy revealed that the intracellular localization of full-length and PDZ binding mutated SGK1 was identical: they both localize to intracellular vesicular structures [22].
• Here, we show that transcription of sgk1 is increased in several animal models of PD and a transgenic model of amyotrophic lateral sclerosis (ALS) [10].
• Electrophoretic mobility shift assays suggest that these effects are caused by binding of PPARgamma to a specific response element in the SGK1 promoter [37].
• Using this P1 clone as a probe for fluorescence in situ hybridization, a single chromosomal locus for SGK was assigned to band 6q23, a region frequently affected by deletion in various human neoplasms [38].

References