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Gene Review

SGK3  -  serum/glucocorticoid regulated kinase...

Homo sapiens

Synonyms: CISK, Cytokine-independent survival kinase, SGK2, SGKL, Serine/threonine-protein kinase Sgk3, ...
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High impact information on SGK3

  • Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro [1].
  • CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4 [1].
  • We demonstrate that CISK prevents CXCR4 degradation by inhibiting sorting of the receptor from early endosomes to lysosomes [1].
  • Furthermore, early endosome association of expressed epitope-tagged CISK in COS cells directed by binding of its PX domain to PI(3)P is required for activation of the CISK protein kinase by both insulin-like growth factor-1 and epidermal growth factor [2].
  • Both a functional PX domain and PI3K activation are necessary for phosphorylation of SGK3 at two regulatory sites (Thr-320 and Ser-486) and subsequent induction of kinase activity [3].

Biological context of SGK3

  • SGK3 has been implicated in the control of cell survival and regulation of ion channel activity in cultured cells [4].
  • Transfection with SGK1, SGK2 or SGK3 increased the voltage-gated K(+) current to 1056+/-152 pA ( n=17), 555+/-47 pA ( n=17), and 775+/-98 pA ( n=16), respectively [5].
  • In contrast, little is known about the transcriptional regulation of the two closely related isoforms SGK2 and SGK3, although they can be activated by phosphorylation [6].
  • Coexpression of SGK3 but not of SGK1 in Xenopus oocytes resulted in an increase of steady state current (I(HERG)) and enhanced cell membrane protein abundance without affecting gating kinetics of the channel [7].
  • In conclusion, SGK3 participates in the regulation of HERG by increasing HERG protein abundance in the plasma membrane and may thus modify the duration of the cardiac action potential [7].

Anatomical context of SGK3

  • These data establish a role for SGK3 in normal postnatal hair follicle development, possibly involving effects on beta-catenin/Lef-1-mediated gene transcription [4].
  • Furthermore, in cultured keratinocytes, heterologous expression of SGK3 potently modulates activation of beta-catenin/Lef-1-mediated gene transcription [4].
  • CONCLUSION: ClC-Ka/barttin channels are regulated by SGK1 and SGK3, which may thus participate in the regulation of transport in kidney and inner ear [8].
  • Like SGK1, the mRNA encoding SGK3 is expressed in all tissues examined, but SGK2 mRNA is only present at significant levels in liver, kidney and pancreas and, at lower levels, in the brain [9].
  • 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 [9].

Associations of SGK3 with chemical compounds

  • In this study, we determined that the two recently described isoforms, SGK2 and SGK3 are also expressed in renal cortical collecting duct (CCD) cells; however, their expression is not induced by aldosterone or glucocorticoids [10].
  • The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel alpha,beta,gamma-ENaC [11].
  • RESULTS: The outward-directed current was fully abolished by incubation with 1 mM ouabain and was significantly larger in oocytes expressing (S422D)SGK1, SGK1, SGK2 or SGK3, as compared to those injected with water [12].
  • However, in addition to PH domains, a second class of 3' phosphorylated inositol phospholipid-binding domains exists that is termed Phox homology (PX) domain: this domain is found in one of the SGKs (SGK3) [13].
  • In conclusion, SGK3 and stargazin regulate GluR1 independently, and thus, their effects on glutamate-induced currents are additive [14].

Physical interactions of SGK3


Enzymatic interactions of SGK3


Regulatory relationships of SGK3

  • Replacement of serine by alanine at the two SGK consensus sites decreased I(HERG) but neither mutation abolished the stimulating effect of SGK3 [7].

Other interactions of SGK3

  • Regulation of the excitatory amino acid transporter EAAT5 by the serum and glucocorticoid dependent kinases SGK1 and SGK3 [18].
  • Moreover, coexpression of SGK3 significantly altered SCN5A gating, i.e. it hyperpolarized the activation threshold and depolarized the prepotential required for 50% availability of the channel [19].
  • The present study has been performed to explore whether SGK1 and SGK3 participate in the regulation of HERG channel activity [7].
  • Coexpression of Nedd4-2 downregulated SN1-mediated transport, an effect reversed by coexpression of S422DSGK1, SGK3, and T308D,S473DPKB [20].
  • In conclusion, the kinases SGK1 and SGK3 increase SLC6A8 activity by increasing the maximal transport rate of the carrier [21].

Analytical, diagnostic and therapeutic context of SGK3


  1. CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4. Slagsvold, T., Marchese, A., Brech, A., Stenmark, H. EMBO J. (2006) [Pubmed]
  2. Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate. Virbasius, J.V., Song, X., Pomerleau, D.P., Zhan, Y., Zhou, G.W., Czech, M.P. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Role of the Phox homology domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3. Tessier, M., Woodgett, J.R. J. Biol. Chem. (2006) [Pubmed]
  4. Targeted disruption of the protein kinase SGK3/CISK impairs postnatal hair follicle development. McCormick, J.A., Feng, Y., Dawson, K., Behne, M.J., Yu, B., Wang, J., Wyatt, A.W., Henke, G., Grahammer, F., Mauro, T.M., Lang, F., Pearce, D. Mol. Biol. Cell (2004) [Pubmed]
  5. K+ channel activation by all three isoforms of serum- and glucocorticoid-dependent protein kinase SGK. Gamper, N., Fillon, S., Feng, Y., Friedrich, B., Lang, P.A., Henke, G., Huber, S.M., Kobayashi, T., Cohen, P., Lang, F. Pflugers Arch. (2002) [Pubmed]
  6. Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Lang, F., Cohen, P. Sci. STKE (2001) [Pubmed]
  7. Upregulation of HERG Channels by the Serum and Glucocorticoid Inducible Kinase Isoform SGK3. Maier, G., Palmada, M., Rajamanickam, J., Shumilina, E., Bohmer, C., Lang, F. Cell. Physiol. Biochem. (2006) [Pubmed]
  8. Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases. Embark, H.M., Böhmer, C., Palmada, M., Rajamanickam, J., Wyatt, A.W., Wallisch, S., Capasso, G., Waldegger, P., Seyberth, H.W., Waldegger, S., Lang, F. Kidney Int. (2004) [Pubmed]
  9. Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Kobayashi, T., Deak, M., Morrice, N., Cohen, P. Biochem. J. (1999) [Pubmed]
  10. Regulation of sodium transport in mammalian collecting duct cells by aldosterone-induced kinase, SGK1: structure/function studies. Náray-Fejes-Tóth, A., Helms, M.N., Stokes, J.B., Fejes-Tóth, G. Mol. Cell. Endocrinol. (2004) [Pubmed]
  11. The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel alpha,beta,gamma-ENaC. Friedrich, B., Feng, Y., Cohen, P., Risler, T., Vandewalle, A., Bröer, S., Wang, J., Pearce, D., Lang, F. Pflugers Arch. (2003) [Pubmed]
  12. Activation of Na+/K+-ATPase by the serum and glucocorticoid-dependent kinase isoforms. Henke, G., Setiawan, I., Böhmer, C., Lang, F. Kidney Blood Press. Res. (2002) [Pubmed]
  13. Serum and glucocorticoid-regulated protein kinases: variations on a theme. Tessier, M., Woodgett, J.R. J. Cell. Biochem. (2006) [Pubmed]
  14. Additive regulation of GluR1 by stargazin and serum- and glucocorticoid-inducible kinase isoform SGK3. Strutz-Seebohm, N., Seebohm, G., Korniychuk, G., Baltaev, R., Ureche, O., Striegel, M., Lang, F. Pflugers Arch. (2006) [Pubmed]
  15. Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction. Dai, F., Yu, L., He, H., Chen, Y., Yu, J., Yang, Y., Xu, Y., Ling, W., Zhao, S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  16. Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4-2 and by serum- and glucocorticoid-dependent kinase 1. Palmada, M., Dieter, M., Speil, A., Böhmer, C., Mack, A.F., Wagner, H.J., Klingel, K., Kandolf, R., Murer, H., Biber, J., Closs, E.I., Lang, F. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  17. Peroxisomal targeting as a tool for assaying potein-protein interactions in the living cell: cytokine-independent survival kinase (CISK) binds PDK-1 in vivo in a phosphorylation-dependent manner. Nilsen, T., Slagsvold, T., Skjerpen, C.S., Brech, A., Stenmark, H., Olsnes, S. J. Biol. Chem. (2004) [Pubmed]
  18. Regulation of the excitatory amino acid transporter EAAT5 by the serum and glucocorticoid dependent kinases SGK1 and SGK3. Boehmer, C., Rajamanickam, J., Schniepp, R., Kohler, K., Wulff, P., Kuhl, D., Palmada, M., Lang, F. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  19. Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A. Boehmer, C., Wilhelm, V., Palmada, M., Wallisch, S., Henke, G., Brinkmeier, H., Cohen, P., Pieske, B., Lang, F. Cardiovasc. Res. (2003) [Pubmed]
  20. Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB. Boehmer, C., Okur, F., Setiawan, I., Bröer, S., Lang, F. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  21. Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3. Shojaiefard, M., Christie, D.L., Lang, F. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  22. Cloning and mapping of a novel human serum/glucocorticoid regulated kinase-like gene, SGKL, to chromosome 8q12.3-q13.1. Dai, F., Yu, L., He, H., Zhao, Y., Yang, J., Zhang, X., Zhao, S. Genomics (1999) [Pubmed]
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