3hdn

Structural highlights

Function

[SGK1_HUMAN] 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.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Serine/threonine protein kinase 3D structures

References

1. ↑ Raikwar NS, Snyder PM, Thomas CP. An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function. Am J Physiol Renal Physiol. 2008 Nov;295(5):F1440-8. doi:, 10.1152/ajprenal.90239.2008. Epub 2008 Aug 27. PMID:18753299 doi:http://dx.doi.org/10.1152/ajprenal.90239.2008
2. ↑ Zhang BH, Tang ED, Zhu T, Greenberg ME, Vojtek AB, Guan KL. Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf. J Biol Chem. 2001 Aug 24;276(34):31620-6. Epub 2001 Jun 15. PMID:11410590 doi:http://dx.doi.org/10.1074/jbc.M102808200
3. ↑ Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol. 2001 Feb;21(3):952-65. PMID:11154281 doi:http://dx.doi.org/10.1128/MCB.21.3.952-965.2001
4. ↑ Snyder PM, Olson DR, Thomas BC. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. J Biol Chem. 2002 Jan 4;277(1):5-8. Epub 2001 Nov 5. PMID:11696533 doi:10.1074/jbc.C100623200
5. ↑ Henke G, Setiawan I, Bohmer C, Lang F. Activation of Na+/K+-ATPase by the serum and glucocorticoid-dependent kinase isoforms. Kidney Blood Press Res. 2002;25(6):370-4. PMID:12590200 doi:http://dx.doi.org/68699
6. ↑ Gamper N, Fillon S, Feng Y, Friedrich B, Lang PA, Henke G, Huber SM, Kobayashi T, Cohen P, Lang F. K+ channel activation by all three isoforms of serum- and glucocorticoid-dependent protein kinase SGK. Pflugers Arch. 2002 Oct;445(1):60-6. Epub 2002 Aug 28. PMID:12397388 doi:http://dx.doi.org/10.1007/s00424-002-0873-2
7. ↑ Palmada M, Embark HM, Yun C, Bohmer C, Lang F. Molecular requirements for the regulation of the renal outer medullary K(+) channel ROMK1 by the serum- and glucocorticoid-inducible kinase SGK1. Biochem Biophys Res Commun. 2003 Nov 21;311(3):629-34. PMID:14623317
8. ↑ Boehmer C, Wilhelm V, Palmada M, Wallisch S, Henke G, Brinkmeier H, Cohen P, Pieske B, Lang F. Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A. Cardiovasc Res. 2003 Mar 15;57(4):1079-84. PMID:12650886
9. ↑ Chun J, Kwon T, Kim DJ, Park I, Chung G, Lee EJ, Hong SK, Chang SI, Kim HY, Kang SS. Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1. J Biochem. 2003 Jan;133(1):103-8. PMID:12761204
10. ↑ Boehmer C, Henke G, Schniepp R, Palmada M, Rothstein JD, Broer S, Lang F. Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. J Neurochem. 2003 Sep;86(5):1181-8. PMID:12911626
11. ↑ Embark HM, Bohmer C, Vallon V, Luft F, Lang F. Regulation of KCNE1-dependent K(+) current by the serum and glucocorticoid-inducible kinase (SGK) isoforms. Pflugers Arch. 2003 Feb;445(5):601-6. Epub 2002 Dec 4. PMID:12634932 doi:http://dx.doi.org/10.1007/s00424-002-0982-y
12. ↑ Palmada M, Dieter M, Speil A, Bohmer C, Mack AF, Wagner HJ, Klingel K, Kandolf R, Murer H, Biber J, Closs EI, Lang F. Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4-2 and by serum- and glucocorticoid-dependent kinase 1. Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G143-50. Epub 2004 Mar, 25. PMID:15044175 doi:http://dx.doi.org/10.1152/ajpgi.00121.2003
13. ↑ Boehmer C, Embark HM, Bauer A, Palmada M, Yun CH, Weinman EJ, Endou H, Cohen P, Lahme S, Bichler KH, Lang F. Stimulation of renal Na+ dicarboxylate cotransporter 1 by Na+/H+ exchanger regulating factor 2, serum and glucocorticoid inducible kinase isoforms, and protein kinase B. Biochem Biophys Res Commun. 2004 Jan 23;313(4):998-1003. PMID:14706641
14. ↑ Embark HM, Setiawan I, Poppendieck S, van de Graaf SF, Boehmer C, Palmada M, Wieder T, Gerstberger R, Cohen P, Yun CC, Bindels RJ, Lang F. Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cell Physiol Biochem. 2004;14(4-6):203-12. PMID:15319523 doi:http://dx.doi.org/10.1159/000080329
15. ↑ Diakov A, Korbmacher C. A novel pathway of epithelial sodium channel activation involves a serum- and glucocorticoid-inducible kinase consensus motif in the C terminus of the channel's alpha-subunit. J Biol Chem. 2004 Sep 10;279(37):38134-42. Epub 2004 Jul 1. PMID:15234985 doi:http://dx.doi.org/10.1074/jbc.M403260200
16. ↑ Henke G, Maier G, Wallisch S, Boehmer C, Lang F. Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol. 2004 May;199(2):194-9. PMID:15040001 doi:10.1002/jcp.10430
17. ↑ Embark HM, Bohmer C, Palmada M, Rajamanickam J, Wyatt AW, Wallisch S, Capasso G, Waldegger P, Seyberth HW, Waldegger S, Lang F. Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases. Kidney Int. 2004 Nov;66(5):1918-25. PMID:15496163 doi:http://dx.doi.org/10.1111/j.1523-1755.2004.00966.x
18. ↑ Wang D, Sun H, Lang F, Yun CC. Activation of NHE3 by dexamethasone requires phosphorylation of NHE3 at Ser663 by SGK1. Am J Physiol Cell Physiol. 2005 Oct;289(4):C802-10. Epub 2005 May 11. PMID:15888551 doi:http://dx.doi.org/10.1152/ajpcell.00597.2004
19. ↑ Palmada M, Speil A, Jeyaraj S, Bohmer C, Lang F. The serine/threonine kinases SGK1, 3 and PKB stimulate the amino acid transporter ASCT2. Biochem Biophys Res Commun. 2005 May 27;331(1):272-7. PMID:15845389 doi:http://dx.doi.org/10.1016/j.bbrc.2005.03.159
20. ↑ Boehmer C, Rajamanickam J, Schniepp R, Kohler K, Wulff P, Kuhl D, Palmada M, Lang F. Regulation of the excitatory amino acid transporter EAAT5 by the serum and glucocorticoid dependent kinases SGK1 and SGK3. Biochem Biophys Res Commun. 2005 Apr 8;329(2):738-42. PMID:15737648 doi:http://dx.doi.org/10.1016/j.bbrc.2005.02.035
21. ↑ Shojaiefard M, Christie DL, Lang F. Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3. Biochem Biophys Res Commun. 2005 Sep 2;334(3):742-6. PMID:16036218 doi:http://dx.doi.org/10.1016/j.bbrc.2005.06.164
22. ↑ David S, Kalb RG. Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB. FEBS Lett. 2005 Feb 28;579(6):1534-8. PMID:15733869 doi:http://dx.doi.org/10.1016/j.febslet.2005.01.040
23. ↑ Palmada M, Boehmer C, Akel A, Rajamanickam J, Jeyaraj S, Keller K, Lang F. SGK1 kinase upregulates GLUT1 activity and plasma membrane expression. Diabetes. 2006 Feb;55(2):421-7. PMID:16443776
24. ↑ Yang YC, Lin CH, Lee EH. Serum- and glucocorticoid-inducible kinase 1 (SGK1) increases neurite formation through microtubule depolymerization by SGK1 and by SGK1 phosphorylation of tau. Mol Cell Biol. 2006 Nov;26(22):8357-70. Epub 2006 Sep 18. PMID:16982696 doi:http://dx.doi.org/10.1128/MCB.01017-06
25. ↑ Jeyaraj S, Boehmer C, Lang F, Palmada M. Role of SGK1 kinase in regulating glucose transport via glucose transporter GLUT4. Biochem Biophys Res Commun. 2007 May 11;356(3):629-35. Epub 2007 Mar 12. PMID:17382906 doi:http://dx.doi.org/10.1016/j.bbrc.2007.03.029
26. ↑ Bohmer C, Palmada M, Kenngott C, Lindner R, Klaus F, Laufer J, Lang F. Regulation of the epithelial calcium channel TRPV6 by the serum and glucocorticoid-inducible kinase isoforms SGK1 and SGK3. FEBS Lett. 2007 Dec 11;581(29):5586-90. Epub 2007 Nov 20. PMID:18005662 doi:http://dx.doi.org/10.1016/j.febslet.2007.11.006
27. ↑ Lee EJ, Chun J, Hyun S, Ahn HR, Jeong JM, Hong SK, Hong JT, Chang IK, Jeon HY, Han YS, Auh CK, Park JI, Kang SS. Regulation Fe65 localization to the nucleus by SGK1 phosphorylation of its Ser566 residue. BMB Rep. 2008 Jan 31;41(1):41-7. PMID:18304449
28. ↑ Won M, Park KA, Byun HS, Kim YR, Choi BL, Hong JH, Park J, Seok JH, Lee YH, Cho CH, Song IS, Kim YK, Shen HM, Hur GM. Protein 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. J Hepatol. 2009 Jul;51(1):67-76. doi: 10.1016/j.jhep.2009.02.027. Epub 2009 Apr, 16. PMID:19447520 doi:http://dx.doi.org/10.1016/j.jhep.2009.02.027
29. ↑ Amato R, D'Antona L, Porciatti G, Agosti V, Menniti M, Rinaldo C, Costa N, Bellacchio E, Mattarocci S, Fuiano G, Soddu S, Paggi MG, Lang F, Perrotti N. Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation. J Mol Med (Berl). 2009 Dec;87(12):1221-39. doi: 10.1007/s00109-009-0525-5. Epub, 2009 Sep 11. PMID:19756449 doi:http://dx.doi.org/10.1007/s00109-009-0525-5
30. ↑ Bohmer C, Sopjani M, Klaus F, Lindner R, Laufer J, Jeyaraj S, Lang F, Palmada M. The serum and glucocorticoid inducible kinases SGK1-3 stimulate the neutral amino acid transporter SLC6A19. Cell Physiol Biochem. 2010;25(6):723-32. doi: 10.1159/000315092. Epub 2010 May, 18. PMID:20511718 doi:http://dx.doi.org/10.1159/000315092
31. ↑ Wiemuth D, Lott JS, Ly K, Ke Y, Teesdale-Spittle P, Snyder PM, McDonald FJ. Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1) with the WW-domains of Nedd4-2 is required for epithelial sodium channel regulation. PLoS One. 2010 Aug 13;5(8):e12163. doi: 10.1371/journal.pone.0012163. PMID:20730100 doi:http://dx.doi.org/10.1371/journal.pone.0012163
32. ↑ He P, Lee SJ, Lin S, Seidler U, Lang F, Fejes-Toth G, Naray-Fejes-Toth A, Yun CC. Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids. Mol Biol Cell. 2011 Oct;22(20):3812-25. doi: 10.1091/mbc.E11-04-0328. Epub 2011, Aug 24. PMID:21865597 doi:http://dx.doi.org/10.1091/mbc.E11-04-0328
33. ↑ Hammond M, Washburn DG, Hoang HT, Manns S, Frazee JS, Nakamura H, Patterson JR, Trizna W, Wu C, Azzarano LM, Nagilla R, Nord M, Trejo R, Head MS, Zhao B, Smallwood AM, Hightower K, Laping NJ, Schnackenberg CG, Thompson SK. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4441-5. Epub 2009 May 18. PMID:19497745 doi:10.1016/j.bmcl.2009.05.051