ID:SGK1_HUMAN DESCRIPTION: RecName: Full=Serine/threonine-protein kinase Sgk1; EC=2.7.11.1; AltName: Full=Serum/glucocorticoid-regulated kinase 1; FUNCTION: Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis. Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis. Sustained high levels and activity may contribute to conditions such as hypertension and diabetic nephropathy. Isoform 2 exhibited a greater effect on cell plasma membrane expression of SCNN1A/ENAC and Na(+) transport than isoform 1. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Two specific sites, one in the kinase domain (Thr-256) and the other in the C-terminal regulatory region (Ser- 422), need to be phosphorylated for its full activation. Phosphorylation at Ser-397 and Ser-401 are also essential for its activity. Activated by WNK1, WNK2, WNK3 and WNK4. SUBUNIT: Homodimer; disulfide-linked. Forms a trimeric complex with FBXW7 and NOTCH1. Interacts with MAPK3/ERK1, MAPK1/ERK2, MAP2K1/MEK1, MAP2K2/MEK2, NEDD4, NEDD4L, MAPT/TAU, MAPK7, CREB1, SLC9A3R2/NHERF2 and KCNJ1/ROMK1. Associates with the mammalian target of rapamycin complex 2 (mTORC2) via an interaction with MAPKAP1/SIN1. SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Endoplasmic reticulum membrane. Cell membrane. Mitochondrion. Note=The subcellular localization is controlled by the cell cycle, as well as by exposure to specific hormones and environmental stress stimuli. In proliferating cells, it shuttles between the nucleus and cytoplasm in synchrony with the cell cycle, and in serum/growth factor- stimulated cells it resides in the nucleus. In contrast, after exposure to environmental stress or treatment with glucocorticoids, it is detected in the cytoplasm and with certain stress conditions is associated with the mitochondria. In osmoregulation through the epithelial sodium channel, it can be localized to the cytoplasmic surface of the cell membrane. Nuclear, upon phosphorylation. SUBCELLULAR LOCATION: Isoform 2: Cell membrane. TISSUE SPECIFICITY: Expressed in most tissues with highest levels in the pancreas, followed by placenta, kidney and lung. Isoform 2 is strongly expressed in brain and pancreas, weaker in heart, placenta, lung, liver and skeletal muscle. INDUCTION: Induced by a very large spectrum of stimuli distinct from glucocorticoids and serum. These include aldosterone, cell shrinkage, cell swelling, TGF-beta, ischemic injury of the brain, neuronal excitotoxicity memory consolidation, chronic viral hepatitis, DNA-damaging agents, vitamin D3 psychophysiological stress, iron, glucose, EDN1, CSF2, fibroblast growth factor, platelet-derived growth factor, phorbolesters, follicle- stimulating hormone, sorbitol, heat shock, oxidative stress, UV irradiation, and p53/TP53. Many of these stimuli are highly cell- specific, as is the case, for example for aldosterone, which has been found to stimulate its expression only in cells derived from aldosterone-responsive epithelia. Isoform 2 is not induced by glucocorticoids but by excessive extracellular glucose and by TGFB1, in cultured cells. DOMAIN: Isoform 2 subcellular localization at the cell membrane and resistance to proteasomal degradation is mediated by the sequences within the first 120 amino acids. PTM: Regulated by phosphorylation. Activated by phosphorylation on Ser-422 by mTORC2, transforming it into a substrate for PDPK1 which phosphorylates it on Thr-256. Phosphorylation on Ser-397 and Ser-401 are also essential for its activity. Phosphorylation on Ser-78 by MAPK7 is required for growth factor-induced cell cycle progression. PTM: Ubiquitinated by NEDD4L; which promotes proteasomal degradation. Ubiquitinated by SYVN1 at the endoplasmic reticulum; which promotes rapid proteasomal degradation and maintains a high turnover rate in resting cells. Isoform 2 shows enhanced stability. SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. SIMILARITY: Contains 1 AGC-kinase C-terminal domain. SIMILARITY: Contains 1 protein kinase domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF00433 - Protein kinase C terminal domain PF07714 - Protein tyrosine and serine/threonine kinase PF14531 - Kinase-like
ModBase Predicted Comparative 3D Structure on O00141
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001558 regulation of cell growth GO:0006468 protein phosphorylation GO:0006814 sodium ion transport GO:0006915 apoptotic process GO:0006974 cellular response to DNA damage stimulus GO:0007616 long-term memory GO:0008217 regulation of blood pressure GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0030334 regulation of cell migration GO:0032411 positive regulation of transporter activity GO:0034220 ion transmembrane transport GO:0035556 intracellular signal transduction GO:0042127 regulation of cell proliferation GO:0042981 regulation of apoptotic process GO:0048812 neuron projection morphogenesis GO:0050790 regulation of catalytic activity GO:0051090 regulation of sequence-specific DNA binding transcription factor activity GO:0060453 regulation of gastric acid secretion GO:0070294 renal sodium ion absorption
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
