SGK1 (serum/glucocorticoid regulated kinase 1)

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).
	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.

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