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| Autor | Florian Lang, Christoph Böhmer, Monica Palmada, Guiscard Seebohm, Natalie Strutz-Seebohm, Volker Vallon |
| Titel | (Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms |
| Zeitschrift | Physiol Rev |
| Herausgeber | American Physiological Society |
| Ausgabe | 86 |
| Jahr | 2006 |
| Seiten | 1151–1178 |
| DOI | 10.1152/physrev.00050.2005 |
| URL | http://physrev.physiology.org/content/physrev/86/4/1151.full.pdf |
Literaturverz. |
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| Fußnoten | yes |
| Fragmente | 10 |
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| SGK kinases are expressed in a wide variety of species including shark and Caenorhabditis elegans. Yeast expresses two orthologs, Ypk1 and Ypk2, which are involved in endocytosis and required for survival. Yeast lacking Ypk1 and Ypk2 can be rescued by mammalian SGK1. SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis.
Little is known about genomic regulation of SGK2 and SGK3, which appear to be less sensitive to hormonal regulation than SGK1. |
SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis.
[page 1152] SGK kinases are expressed in a wide variety of species including shark (348) and Caenorhabditis elegans (142). Yeast express two orthologs, Ypk1 and Ypk2, which are involved in endocytosis (87) and required for survival (60). Yeast lacking Ypk1 and Ypk2 can be rescued by mammalian SGK1 (60). [page 1153] Little is known about genomic regulation of SGK2 and SGK3, which appear to be less sensitive to hormonal regulation than SGK1 (182). 60. Casamayor A, Torrance PD, Kobayashi T, Thorner J, and Alessi DR. Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. Curr Biol 9: 186–197, 1999. 87. DeHart AK, Schnell JD, Allen DA, and Hicke L. The conserved Pkh-Ypk kinase cascade is required for endocytosis in yeast. J Cell Biol 156: 241–248, 2002. 142. Hertweck M, Gobel C, and Baumeister R. C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell 6: 577–588, 2004. 182. Lang F and Cohen P. Regulation and physiological roles of serumand glucocorticoid-induced protein kinase isoforms. Sci STKE 2001: RE17, 2001. 348. Waldegger S, Barth P, Forrest JN Jr, Greger R, and Lang F. Cloning of sgk serine-threonine protein kinase from shark rectal gland: a gene induced by hypertonicity and secretagogues. Pflügers Arch 436: 575–580, 1998 |
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| SGK1 was originally cloned as an immediate early gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells (Firestone G. et al., (2003) Cell Physiol Biochem). The human isoform has been discovered as a cell volume regulated gene upregulated by cell shrinkage.
Transcription of SGK1 is upregulated by both serum and glucocorticoids. Several other hormones and mediators stimulate SGK1 transcription, including mineralocorticoids, gonadotropins (Lang F. et al., (2006) Physiol Rev), 1.25-dihydroxyvitamin D3 [sic] (1.25(OH)2D3), transforming growth factor-α (TGF-α) (Kumar JM. et al., (1999) J Am Soc Nephrol; Lang F. et al., (2000) Proc Natl Acad Sci USA), interleukin-6 (Mc Ewen BS. et al., (1995) Vitam Horm), fibroblast and platelet-derived growth factor (Mizuno H. et al., (2001) Genes Cell), thrombin (Belaiba R. et al., (2006) Circ Res), endothelin (Wolf Sc. et al., (2006) Biochem Pharmacol), as well as other cytokines (Verenivov A. et al., (2001) Physiol Biochem). Moreover, activation of peroxisome proliferator-activated receptor γ (PPAR γ) stimulates SGK1 gene transcription (Hong G. et al., (2003) Faseb J). The human isoform has been identified as a cell volume-regulated gene that is transcriptionally upregulated by cell shrinkage. In renal epithelial (A6) cells, SGK1 expression is stimulated by cell swelling rather than cell shrinkage (Rozansky DJ. et al., (2002) Am J Physiol Renal Physiol). SGK1 transcription is further stimulated by excessive glucose concentrations (Lang F. et al., (2000) Proc Natl Acad Sci USA; Saad S. et al., (2005) Kidney Int), heat shock, ultraviolet (UV) radiation, and oxidative stress. SGK1 transcription is inhibited by heparin (Delmolino LM. et al., (1997) J Cell Physiol) and by mutations in the gene MECP2, which underlies Rett syndrome (RTT), a disorder with severe mental retardation (Nuber UA. et al., (2005) Hum Mol Genet). Intestinal SGK1 transcription is further regulated by dietary iron (Marzullo L. et al., (2004) Gene). Signaling molecules involved in the transcriptional regulation of SGK1 include protein kinase C (Lang F. et al., (2000) Proc Natl Acad Sci USA; Mizuno H and Nishida E., (2001) Genes Cells), the protein kinase Raf (Mizuno H and Nishida E., (2001) Genes Cells), mammalian mitogen-activated protein kinase (BMK1) (Hayashi M. et al., (2001) J Biol Chem), mitogen-activated protein kinase (MKK1) (Davies SP. et al., (2000) Biochem J; Mizuno H and Nishida E., (2001) Genes Cells), stress-activated protein kinase-2 (SAPK2, p38 kinase) (Bell LM. et al., (2000) J Biol Chem; Chen S. et al., (2004) Hypertension; Waldegger S. et al., (2000) Cell Physiol Biochem) and phosphatidylinositol (PI) 3-kinase. Follicle-stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-induced kinase (SGK): evidence for a kinase-independent signaling by FSH in granulosa cells, cAMP (Gonzalez-Robayna IJ. et al., (2000) Mol Endocrinol; Klingel K. et al., (2000) Am J Physiol Gastrointest Liver Physiol) and p53 (Maiyar AC. et al., (1996) J Biol Chem; Maiyar AC. et al., (1997) Mol Endocrinol). |
[page 1152]
The serum- and glucocorticoid-inducible kinase-1 (SGK1) was originally cloned as an immediate early gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells (112, 361, 362). The human isoform has been discovered as a cell volume-regulated gene upregulated by cell shrinkage (349). [...] [...] Transcription of SGK1 is upregulated by both serum and glucocorticoids (49, 78, 96, 112, 162, 167, 221, 232, 289, 361, 362, 388). Several other hormones and mediators stimulate SGK1 transcription, including mineralocorticoids (29, 49, 65, 96, 135, 168, 197, 206, 231, 290), gonad- [page 1153] otropins (68, 129, 263, 264, 278), 1,25-dihydroxyvitamin D [1,25(OH)2D3] (4), transforming growth factor-β (TGF-β) (178, 184, 352), interleukin-6 (216), fibroblast and plateletderived growth factor (222), thrombin (23), endothelin (366), as well as other cytokines (80, 182, 330). Moreover, activation of peroxisome proliferator-activated receptor γ (PPARγ) stimulates SGK1 gene transcription (146). The human isoform has been identified as a cell volume-regulated gene that is transcriptionally upregulated by cell shrinkage (349). In renal epithelial (A6) cells, SGK1 expression is stimulated by cell swelling rather than cell shrinkage (272). SGK1 transcription is further stimulated by excessive glucose concentrations (184, 275), heat shock, ultraviolet (UV) radiation, and oxidative stress (198). SGK1 transcription is inhibited by heparin (90) and by mutations in the gene MECP2, which underlies Rett syndrome (RTT), a disorder with severe mental retardation (237). Intestinal SGK1 transcription is further regulated by dietary iron (212). Signaling molecules involved in the transcriptional regulation of SGK1 include protein kinase C (184, 222), the protein kinase Raf (222), mammalian mitogen-activated protein kinase (BMK1) (137), mitogen-activated protein kinase (MKK1) (85, 222), stress-activated protein kinase-2 (SAPK2, p38 kinase) (24, 64, 351), phosphatidylinositol (PI) 3-kinase (129), cAMP (129, 170), and p53 (207, 209). [...] 129. Gonzalez-Robayna IJ, Falender AE, Ochsner S, Firestone GL, and Richards JS. Follicle-stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced [sic] kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells. Mol Endocrinol 14: 1283–1300, 2000. [...] 170. Klingel K, Warntges S, Bock J, Wagner CA, Sauter M, Waldegger S, Kandolf R, and Lang F. Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am J Physiol Gastrointest Liver Physiol 279: G998–G1002, 2000. [...] 207. Maiyar AC, Huang AJ, Phu PT, Cha HH, and Firestone GL. p53 stimulates promoter activity of the sgk. Serum/glucocorticoid-inducible serine/threonine protein kinase gene in rodent mammary epithelial cells. J Biol Chem 271: 12414–12422, 1996. 209. Maiyar AC, Phu PT, Huang AJ, and Firestone GL. Repression of glucocorticoid receptor transactivation and DNA binding of a glucocorticoid response element within the serum/glucocorticoid-inducible protein kinase (sgk) gene promoter by the p53 tumor suppressor protein. Mol Endocrinol 11: 312–329, 1997 |
The source is mentioned once in the second reference, but without any indication that the entire page is taken from it. For better readability, not all 53 bibliography entries of the source text have been documented. Note also that the title of the publication Gonzalez-Robayna et al. (2000) has made it into the text of the thesis. There is also no entry Gonzales-Robayana et al. (2000) in the thesis bibliography, that author is only listed as second co-author for a different paper published 2000 in a different journal. |
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| Moreover, SGK1 transcription is stimulated by an increased cytosolic Ca2+ concentration (Klingel K. et al., (2000) Am J Physiol Gastrointest Liver Physiol) and by nitric oxide (Turpaev K. et al., (2005) Free Radic Biol Med). SGK1 transcript levels are increased by ischemia of brain (Nishida Y. et al., (2004) Brain Res) and kidney (Feng Y. et al., (2006) Kidney Blood Pressure Res). SGK1 expression is decreased during rejection of transplanted kidneys (Velic A. et al., (2005) Am J Transplant).
Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g.: ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1–5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, α-catenin, nuclear factor kB). Leukocyte SGK1 transcript levels are enhanced by treatment with dialysis (Friedrich B. et al., (2005) Nephrol Dial Transplant). A striking increase of SGK1 expression is observed during wound healing (Iyer V. et al., (1999) Science) and in fibrosing tissue, such as diabetic nephropathy (Kumar J. M et al., (1999) J Am Soc Nephrol), glomerulonephritis (Friedrich B. et al., (2002) Kidney Blood Press Res), liver cirrhosis (Fillon S. et al., (2002) Cell Physiol Biochem), fibrosing pancreatitis (Klingel K. et al., (2000) Am J Physiol Gastrointest Liver Physiol), Crohn’s disease (Waldegger S. et al., (1999) Gastroenterology), lung fibrosis and cardiac fibrosis (Vallon V. et al., (2006) J Mol Med). SGK1 gene transcription is stimulated by DNA damage through p53 and activation of extracellular signalregulated kinase (ERK1/2) (Mizuno H. et al., (2001) Genes Cells; You H. et al., (2004) Proc Natl Acad Sci USA), and is also upregulated after neuronal injury (Imaizumi K. et al., (1994) Brain Res), neuronal excitotoxicity (Hollister R. et al., (1997) Neuroscience), and neuronal challenge by exposure to microgravity (David S. et al., (2005) J Neurosci). The promoter of the rat SGK1 gene carries several putative and confirmed transcription factor binding sites including those for 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), 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) and nuclear factor κB (NFκB), signal transducers and activators of transcription (STAT), the TGF-α-dependent transcription factors SMAD3 and SMAD4, and forkhead activin signal transducer (FAST) (Firestone G. et al., (2003) Cell Physiol Biochem). The regulation of SGK1 transcript levels is fast; appearance and disappearance of SGK1 mRNA require circa 20 min (Waldegger S. et al., (1997) Proc Natl Acad Sci USA). |
[page 1151]
Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1–5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, α-catenin, nuclear factor κB). [page 1153] Moreover, SGK1 transcription is stimulated by an increased cytosolic Ca2+ concentration (170) and by nitric oxide (321). SGK1 transcript levels are increased by ischemia of brain (236) and kidney (108). SGK1 expression is decreased during rejection of transplanted kidneys (329). Leukocyte SGK1 transcript levels are enhanced by treatment with dialysis (116). A striking increase of SGK1 expression is observed during wound healing (164) and in fibrosing tissue, such as diabetic nephropathy (178, 184), glomerulonephritis (118), liver cirrhosis (110), fibrosing pancreatitis (170), Crohn’s disease (352), lung fibrosis (360), and cardiac fibrosis (323). SGK1 gene transcription is stimulated by DNA damage through p53 and activation of extracellular signal-regulated kinase (ERK1/2) (222, 375), and is also upregulated after neuronal injury (159), neuronal excitotoxicity (145), and neuronal challenge by exposure to microgravity (84). The promoter of the rat SGK1 gene carries several putative and confirmed transcription factor binding sites including those for 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), 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) and nuclear factor κB (NFκB), signal transducers and activators of transcription (STAT), the TGF-β-dependent transcription factors SMAD3 and SMAD4, and forkhead activin signal transducer (FAST) (112). The regulation of SGK1 transcript levels is fast; appearance and disappearance of SGK1 mRNA require <20 min (349). 84. David S, Stegenga SL, Hu P, Xiong G, Kerr E, Becker KB, Venkatapathy S, Warrington JA, and Kalb RG. Expression of serum- and glucocorticoid-inducible kinase is regulated in an experience-dependent manner and can cause dendrite growth. J Neurosci 25: 7048–7053, 2005. 108. Feng Y, Wang Y, Xiong J, and Lang F. Expression and significance of serum and glucocorticoid inducible kinase-1 in kidney damage following L-NAME induced hypertension. Kidney Blood Pressure Res. In press. 110. Fillon S, Klingel K, Warntges S, Sauter M, Gabrysch S, Pestel S, Tanneur V, Waldegger S, Zipfel A, Viebahn R, Haussinger D, Broer S, Kandolf R, and Lang F. Expression of the serine/threonine kinase hSGK1 in chronic viral hepatitis. Cell Physiol Biochem 12: 47–54, 2002. 112. Firestone GL, Giampaolo JR, and O’Keeffe BA. Stimulus-dependent regulation of the serum and glucocorticoid inducible protein kinase (Sgk) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 13: 1–12, 2003 116. Friedrich B, Alexander D, Aicher WK, Duszenko M, Schaub TP, Passlick-Deetjen J, Waldegger S, Wolf S, Risler T, and Lang F. Influence of standard haemodialysis treatment on transcription of human serum- and glucocorticoid-inducible kinase SGK1 and taurine transporter TAUT in blood leukocytes. Nephrol Dial Transplant 20: 768–774, 2005. 118. Friedrich B, Warntges S, Klingel K, Sauter M, Kandolf R, Risler T, Muller GA, Witzgall R, Kriz W, Grone HJ, and Lang F. Up-regulation of the human serum and glucocorticoid-dependent kinase 1 in glomerulonephritis. Kidney Blood Press Res 25: 303–307, 2002. 145. Hollister RD, Page KJ, and Hyman BT. Distribution of the messenger RNA for the extracellularly regulated kinases 1, 2 and 3 in rat brain: effects of excitotoxic hippocampal lesions. Neuroscience 79: 1111–1119, 1997. 159. Imaizumi K, Tsuda M, Wanaka A, Tohyama M, and Takagi T. Differential expression of sgk mRNA, a member of the Ser/Thr protein kinase gene family, in rat brain after CNS injury. Brain Res 26: 189–196, 1994. 164. Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JC, Trent JM, Staudt LM, Hudson J Jr, Boguski MS, Lashkari D, Shalon D, Botstein D and Brown PO. The transcriptional program in the response of human fibroblasts to serum. Science 283: 83–87, 1999. 170. Klingel K, Warntges S, Bock J, Wagner CA, Sauter M, Waldegger S, Kandolf R, and Lang F. Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am J Physiol Gastrointest Liver Physiol 279: G998–G1002, 2000. 178. Kumar JM, Brooks DP, Olson BA, and Laping NJ. Sgk, a putative serine/threonine kinase, is differentially expressed in the kidney of diabetic mice and humans. J Am Soc Nephrol 10: 2488–2494, 1999. 184. Lang F, Klingel K, Wagner CA, Stegen C, Warntges S, Friedrich B, Lanzendorfer M, Melzig J, Moschen I, Steuer S, Waldegger S, Sauter M, Paulmichl M, Gerke V, Risler T, Gamba G, Capasso G, Kandolf R, Hebert SC, Massry SG, and Broer S. Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc Natl Acad Sci USA 97: 8157–8162, 2000. 222. Mizuno H and Nishida E. The ERK MAP kinase pathway mediates induction of SGK (serum- and glucocorticoid-inducible kinase) by growth factors. Genes Cells 6: 261–268, 2001 236. Nishida Y, Nagata T, Takahashi Y, Sugahara-Kobayashi M, Murata A, and Asai S. Alteration of serum/glucocorticoid regulated kinase-1 (sgk-1) gene expression in rat hippocampus after transient global ischemia. Brain Res 123: 121–125, 2004 321. Turpaev K, Bouton C, Diet A, Glatigny A, and Drapier JC. Analysis of differentially expressed genes in nitric oxide-exposed human monocytic cells. Free Radic Biol Med 38: 1392–1400, 2005 323. Vallon V, Wyatt A, Klingel K, Huang DY, Hussain A, Berchtold S, Friedrich B, Grahammer F, BelAiba RS, Görlach A, Wulff P, Daut J, Dalton ND, Ross J Jr, Flögel U, Schrader J, Osswald H, Kandolf R, Kuhl D, and Lang F. SGK1-dependent cardiac CTGF formation and fibrosis following DOCA treatment. J Mol Med 84; 396–404, 2006. 329. Velic A, Gabriels G, Hirsch JR, Schroter R, Edemir B, Paasche S, and Schlatter E. Acute rejection after rat renal transplantation leads to downregulation of Na+ and water channels in the collecting duct. Am J Transplant 5: 1276–1285, 2005. 349. Waldegger S, Barth P, Raber G, and Lang F. Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. Proc Natl Acad Sci USA 94: 4440–4445, 1997. 352. Waldegger S, Klingel K, Barth P, Sauter M, Rfer ML, Kandolf R, and Lang F. h-Sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116: 1081–1088, 1999. 360. Wärntges S, Klingel K, Weigert C, Fillon S, Buck M, Schleicher E, Rodemann HP, Knabbe C, Kandolf R, and Lang F. Excessive transcription of the human serum and glucocorticoid dependent kinase hSGK1 in lung fibrosis. Cell Physiol Biochem 12: 135–142, 2002. 375. You H, Jang Y, You T, Okada H, Liepa J, Wakeham A, Zaugg K, and Mak TW. p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc Natl Acad Sci USA"" 101: 14057–14062, 2004. |
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Figure nr. 3 - Dual role of SGK1 in the maintenance of salt homeostasis and blood pressure. SGK1 plays a dual role in the regulation of salt balance, i.e., in the stimulation of both renal Na+ reabsorption and salt appetite. SGK1 contributes to aldosterone- and insulin-induced stimulation of renal Na+ reabsorption. The increased extracellular fluid volume (ECV) enhances the cardiac output (C.O.), thus increasing mean arterial blood pressure (MAP). The enhanced blood pressure leads to pressure natriuresis and thus secondarily increases renal salt excretion, eventually counteracting renal salt retention. A II, angiotensin II; R, total peripheral vascular resistance. SGK1 participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na+ retention and K+ elimination of the kidney, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na+/H+ exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. |
SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na+ retention and K+ elimination of the kidney,
[page 1152] mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na+/H+ exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. [page 1163]
FIG. 5. Dual role of SGK1 in the maintenance of salt homeostasis and blood pressure. SGK1 plays a dual role in the regulation of salt balance, i.e., in the stimulation of both renal Na+ reabsorption and salt appetite. SGK1 contributes to aldosterone- and insulin-induced stimulation of renal Na+ reabsorption. The increased extracellular fluid volume (ECV) enhances the cardiac output (C.O.), thus increasing mean arterial blood pressure (MAP). The enhanced blood pressure leads to pressure natriuresis and thus secondarily increases renal salt excretion, eventually counteracting renal salt retention. A II, angiotensin II; R, total peripheral vascular resistance. |
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Figure nr. 4 - Middle: putative role of SGK1 in the regulation of K+ and Ca2+ channels required for stimulation of cell proliferation. Mitogenic factors stimulate the Ca2+ release-activated Ca2+ channel ICRAC. Ca2+ entry through this channel is highly sensitive to cell membrane potential, which is maintained by K+ channels. The stimulation of the voltage-sensitive K+ channel Kv1.3 by SGK1 may serve to maintain the cell membrane polarization and thus sustain oscillating Ca2+ entry through ICRAC. Left: current generated by depolarization of HEK cells overexpressing constitutively active S422DSGK1 (sgk-SD) or the inactive K127NSGK1 mutant (sgk-KN). Right: peak Ca2+ concentration after Ca2+ entry in Ca2+-depleted fibroblasts from wild-type mice (sgk1+/+, open bars) or SGK1 knockout mice (sgk1-/-, solid bars) fibroblasts. Ca2+ entry in sgk1-/- fibroblasts is not sensitive to serum deprivation or to dexamethasone plus IGF-I (Shumilina E. et al, (2005) J Cell Physiol). A common SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, SGK1 cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that is modulated by the SGK and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined. [...] SGK3 is expressed in all tissues tested thus far and is particularly high in the embryo, adult heart and spleen. Expression of SGK2 is most abundant in epithelial tissues including kidney, liver, pancreas, and presumably choroid plexus of the brain. The subcellular distribution may be nuclear and cytoplasmic, as SGK2 and SGK3 contain a similar nuclear localization signal sequence as SGK1. |
A common (~5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.
[...] SGK3 is expressed in all tissues tested thus far (172) and is particularly high in the embryo (152, 193) and adult heart and spleen (172). Expression of SGK2 is most abundant in epithelial tissues including kidney, liver, pancreas, and presumably choroid plexus of the brain (172). The subcellular distribution may be nuclear and cytoplasmic, as SGK2 and SGK3 contain a similar nuclear localization signal sequence as SGK1 (112). [page 1160]
FIG. 3. Middle: putative role of SGK1 in the regulation of K+ and Ca2+ channels required for stimulation of cell proliferation. Mitogenic factors stimulate the Ca2+ release-activated Ca2+ channel ICRAC. Ca2+ entry through this channel is highly sensitive to cell membrane potential, which is maintained by K+ channels. The stimulation of the voltage-sensitive K+ channel Kv1.3 by SGK1 may serve to maintain the cell membrane polarization and thus sustain oscillating Ca2+ entry through ICRAC. Left: current generated by depolarization of HEK cells overexpressing constitutively active S422DSGK1 (sgk-SD) or the inactive K127NSGK1 mutant (sgk-KN). Right: peak Ca2+ concentration after Ca2+ entry in Ca2+-depleted fibroblasts from wild-type mice (sgk1+/+, open bars) or SGK1 knockout mice (sgk1-/-, solid bars) fibroblasts. Ca2+ entry in sgk1-/- fibroblasts is not sensitive to serum deprivation or to dexamethasone + IGF-I. [Data modified from Shumilina et al. (293).] 112. Firestone GL, Giampaolo JR, and O’Keeffe BA. Stimulus-dependent regulation of the serum and glucocorticoid inducible protein kinase (Sgk) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 13: 1–12, 2003. 152. Huber SM, Friedrich B, Klingel K, Lenka N, Hescheler J, and Lang F. Protein and mRNA expression of serum and glucocorticoid-dependent kinase 1 in metanephrogenesis. Dev Dyn 221: 464–469, 2001. 172. Kobayashi T, Deak M, Morrice N, and Cohen P. Characterization of the structure and regulation of two novel isoforms of serumand glucocorticoid-induced protein kinase. Biochem J 344: 189–197, 1999. 193. Lee E, Lein ES, and Firestone GL. Tissue-specific expression of the transcriptionally regulated serum and glucocorticoid-inducible protein kinase (Sgk) during mouse embryogenesis. Mech Dev 103: 177–181, 2001. 293. Shumilina E, Lampert A, Lupescu A, Myssina S, Strutz-Seebohm N, Henke G, Grahammer F, Wulff P, Kuhl D, and Lang F. Deranged Kv channel regulation in fibroblasts from mice lacking the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol 204: 87–98, 2005. |
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| 1.6. Regulation of SGK kinase activity
To become functional, the SGK protein kinases require activation by phosphorylation, which is accomplished through a signaling cascade involving PI 3-kinase, the 3- phosphoinositide (PIP3)-dependent kinase PDK1, and a yet unidentified but also PIP3- dependent kinase that has been referred to as PDK2 or “hydrophobic motif” (H-motif) kinase (Collins BJ. et al., (2003) EMBO J; Frodin M. et al., (2002) EMBO J; Kobayashi T. et al., (1999) Biochem J; Mora A. et al., (2004) Semin Cell Dev Biol; Nilsen T. et al., (2004) J Biol Chem; Park J. et al., (1999) EMBO J). PIP3 is degraded by the phosphatase and tensin homolog PTEN (Lian Z. et al., (2005) Oncogene; Oudit GY. et al., (2004) J Mol Cell Cardiol; Sulis ML. et al., (2003) Trends Cell Biol), which thus disrupts PI 3-kinasedependent activation of the SGKs. Maximal stimulation of SGK1 activity requires the PDK1-dependent phosphorylation at 256Thr within the activation loop (T-loop) and phosphorylation at 422Ser in the hydrophobic motif at its COOH terminus by PDK2/H-motif kinase (Kobayashi T. et al., (1999) Biochem J; Park J. et al., (1999) EMBO J). The PDK1-mediated SGK1 phosphorylation is facilitated when 422Ser is already phosphorylated. Phosphorylation of SGK1 at 422Ser promotes SGK1 binding to the PDK1 interacting fragment (PIF)-binding pocket and phosphorylation at 256Thr by PDK1 (Biondi RM. et al., (2001) EMBO J). An alternate mechanism of SGK1 activation by PDK1 involves the scaffold protein Na+-H+ exchanger regulating factor 2 (NHERF2). NHERF2 mediates the assembly of SGK1 and PDK1 via its PDZ domains and PIF consensus sequence (Chun J. et al., (2003) J Biochem Tokyo). NHERF2 interacts with the PDZ binding motif of SGK1 through its first PDZ domain and with PIF-binding pocket of PDK1 through its PIF tail. The formation of the ternary complex facilitates the phosphorylation of SGK1 on 256Thr in its T-loop by PDK1 (Chun J. et al., (2003) J Biochem Tokyo). Most recent evidence suggests that the activation of SGK1 by PDK1 may indirectly involve the serine/threonine kinase WNK1 (with no lysine kinase 1) (Xu BE. et al., (2005) Proc Natl Acad Sci Usa). It is well established that insulin-like growth factor I (IGF-I) enhances SGK1 activity in a PI3-kinase-dependent manner via PDK1. |
B. Regulation of SGK Kinase Activity
To become functional, the SGK protein kinases require activation by phosphorylation, which is accomplished through a signaling cascade involving PI 3-kinase, the 3-phosphoinositide (PIP3)-dependent kinase PDK1, and a yet unidentified but also PIP3-dependent kinase that has been referred to as PDK2 or “hydrophobic motif” (H-motif) kinase (5, 31, 75, 119, 171, 224, 235, 249, 369). PIP3 is degraded by the phosphatase and tensin homolog PTEN (202, 240, 309), which thus disrupts PI 3-kinasedependent activation of the SGKs. Maximal stimulation of SGK1 activity requires the PDK1-dependent phosphorylation at 256Thr within the activation loop (T-loop) and phosphorylation at 422Ser in the hydrophobic motif at its COOH terminus by PDK2/H-motif kinase (171, 172, 249). The PDK1-mediated SGK1 phosphorylation is facilitated when 422Ser is already phosphorylated (Fig. 1). Phosphorylation of SGK1 at 422Ser promotes SGK1 binding to the PDK1 interacting fragment (PIF)-binding pocket and phosphorylation at 256Thr by PDK1 (31). An alternate mechanism of SGK1 activation by PDK1 involves the scaffold protein Na+/H+ exchanger regulating factor 2 (NHERF2). NHERF2 mediates the assembly of SGK1 and PDK1 via its PDZ domains and PIF consensus sequence (70). NHERF2 interacts with the PDZ binding motif of SGK1 through its first PDZ domain and with PIF-binding pocket of PDK1 through its PIF tail. The formation of the ternary complex facilitates the phosphorylation of SGK1 on 256Thr in its T-loop by PDK1 (70). Most recent evidence suggests that the activation of SGK1 by PDK1 may indirectly involve the serine/threonine kinase WNK1 (with no lysine kinase 1) (370). It is well established that insulin-like growth factor I (IGF-I) enhances SGK1 activity in a PI 3-kinase-dependent manner via PDK1. 5. Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A, and Bownes M. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 7: 776–789, 1997. 31. Biondi RM, Kieloch A, Currie RA, Deak M, and Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J 20: 4380–4390, 2001. 70. Chun J, Kwon T, Lee E, Suh PG, Choi EJ, and Sun KS. The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1. Biochem Biophys Res Commun 298: 207–215, 2002. 75. Collins BJ, Deak M, Arthur JS, Armit LJ, and Alessi DR. In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation. EMBO J 22: 4202–4211, 2003. 119. Frodin M, Antal TL, Dummler BA, Jensen CJ, Deak M, Gammeltoft S, and Biondi RM.'#' A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation. EMBO J 21: 5396–5407, 2002. 171. Kobayashi T and Cohen P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphati-dylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 339: 319–328, 1999. 172. Kobayashi T, Deak M, Morrice N, and Cohen P. Characterization of the structure and regulation of two novel isoforms of serumand glucocorticoid-induced protein kinase. Biochem J 344: 189–197, 1999. 202. Lian Z and Di Cristofano A. Class reunion: PTEN joins the nuclear crew. Oncogene 24: 7394–7400, 2005. 224. Mora A, Komander D, van Aalten DM, and Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 15: 161–170, 2004. 235. Nilsen T, Slagsvold T, Skjerpen CS, Brech A, Stenmark H, and Olsnes S. Peroxisomal targeting as a tool for assaying protein-protein interactions in the living cell: cytokine-independent survival kinase (CISK) binds PDK-1 in vivo in a phosphorylationdependent manner. J Biol Chem 279: 4794–4801, 2004. 240. Oudit GY, Sun H, Kerfant BG, Crackower MA, Penninger JM, and Backx PH. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37: 449–471, 2004. 249. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, and Hemmings BA. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J 18: 3024–3033, 1999. 309. Sulis ML and Parsons R. PTEN: from pathology to biology. Trends Cell Biol 13: 478–483, 2003. 369. Xing Y, Liu D, Zhang R, Joachimiak A, Songyang Z, and Xu W. Structural basis of membrane targeting by the Phox homology domain of cytokine-independent survival kinase (CISK-PX). J Biol Chem 279: 30662–30669, 2004. 370. Xu BE, Stippec S, Chu PY, Lazrak A, Li XJ, Lee BH, English JM, Ortega B, Huang CL, and Cobb MH. WNK1 activates SGK1 to regulate the epithelial sodium channel. Proc Natl Acad Sci USA 102: 10315–10320, 2005. |
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| [Recent evidence] suggested a role of WNK1 in the activation of SGK1 by IGF-I (Xu BE. et al., (2005) J Biol Chem). According to this evidence, IGF-I induces SGK1 activity by stimulating WNK1 phosphorylation at 58Thr, a site that is phosphorylated by protein kinase B (PKB/Akt). The PI3-kinase-dependent step in the activation of SGK1 by IGF-I was thus suggested to be the PDK1-dependent activation of PKB/Akt and the subsequent phosphorylation of WNK1 at 58Thr (Xu BE. et al., (2005) J Biol Chem). Neither the catalytic activity nor the kinase domain but the NH2 [sic] -terminal 220 residues of WNK1 are required for activation of SGK1 (Xu BE. et al., (2005) J Biol Chem). WNK1 binds SGK1 directly but does not phosphorylate it, suggesting that WNK1 serves as a scaffold protein to assemble other molecules required for maximal SGK1 activation. Its phosphorylation at 58Thr by PKB-Akt may induce binding of accessory proteins or a conformational change in SGK1 that stimulates the kinase. However, further experimental evidence is needed to elucidate how WNK1 phosphorylation promotes SGK1 activation. SGK2 and SGK3 may similarly be activated by PDK1 and PDK2/H-motif kinase. The equivalent phosphorylation sites for SGK2 and SGK3 are predicted to be at 193Thr-356Ser and 253Thr-419Ser, respectively, but this requires further investigation. The kinases are also regulated by WNK1, although to a lesser extent than SGK1 (Xu BE. et al., (2005) J Biol Chem).
Replacement of the serine at position 422 by aspartate, in the human SGK, leads to the constitutively active S422DSGK1 (Kobayashi T. et al., (1999) Biochem J), whereas replacement of lysine at position 127, within the ATP-binding region required for enzymatic activity, with asparagine leads to the inactive K127NSGK1 (Kobayashi T. et al., (1999) Biochem J). Analogous mutations in the human SGK2 and SGK3 lead to the constitutively active S356DSGK2 and S419DSGK3 and the constitutively inactive K64NSGK2 and K191NSGK3. In part through the PI3-kinase pathway, SGK1 is activated by insulin (Kobayashi T. et al., (1999) Biochem J), IGF-I (Hayashi M. et al., (2001) J Biol Chem; Kobayashi T. et al., (1999) Biochem J), hepatic growth factor (HGF) (Shelly C. et al., (2002) J Cell Sci) and follicle stimulating hormone (FSH) (Richards JS. et al., (2002) Mol Endocrinol). SGK1 can be activated by bone marrow kinase/extracellular signal-regulated kinase 5 (BK/ERK5) or by p38α. The kinases do not phosphorylate SGK1 at 256Thr but at 78Ser, which is outside the catalytic domain (Hayashi M. et al., (2001) J Biol Chem; Meng F. et al., (2005) Am J Physiol Cell Physiol). How this phosphorylation activates SGK1 is not known. SGK1 can also be activated by an increase of cytosolic Ca2+ activity, an effect presumably mediated by calmodulin - dependent protein kinase kinase (CaMKK) (Imai S. et al., (2003) Life Sci). Moreover, the small G protein Rac1 activates SGK1 via a PI3-kinaseindependent pathway (Shelly C. et al., (2002) J Cell Sci). Additional activators of SGK1 include neuronal depolarization (Kumari S. et al., (2001) Brain Res), cAMP (Kumari S. et al., (2001) Brain Res; Perrotti N. et al., (2001) J Biol Chem; Thomas CP. et al., (2004) Am J Physiol Lung Cell Mol Physiol), lithium (Kumari S. et al., (2001) Brain Res), oxidation (Kobayashi T and Cohen P., (1999) Biochem J; Prasad N. et al., (2000) Biochemistry) and adhesion to fibronectin (Shelly C. et al., (2002) J Cell Sci). Similar to SGK1, SGK2 and SGK3 are activated by oxidation, insulin, and IGF-I through a signaling cascade. |
Recent evidence suggested a role of WNK1 in the activation of SGK1 by IGF-I (371). According to this evidence, IGF-I induces SGK1 activity by stimulating WNK1 phosphorylation at 58Thr, a site that is phosphorylated by protein kinase B (PKB/Akt). The PI 3-kinasedependent step in the activation of SGK1 by IGF-I was
[page 1154] thus suggested to be the PDK1-dependent activation of PKB/Akt and the subsequent phosphorylation of WNK1 at 58Thr (371). Neither the catalytic activity nor the kinase domain but the NH2-terminal 220 residues of WNK1 are required for activation of SGK1 (371). WNK1 binds SGK1 directly but does not phosphorylate it, suggesting that WNK1 serves as a scaffold protein to assemble other molecules required for maximal SGK1 activation. Its phosphorylation at 58Thr by PKB/Akt may induce binding of accessory proteins or a conformational change in SGK1 that stimulates the kinase. However, further experimental evidence is needed to elucidate how WNK1 phosphorylation promotes SGK1 activation. SGK2 and SGK3 may similarly be activated by PDK1 and PDK2/H-motif kinase. The equivalent phosphorylation sites for SGK2 and SGK3 are predicted to be at 193Thr/356Ser and 253Thr/419Ser, respectively, but this requires further investigation. The kinases are also regulated by WNK1, although to a lesser extent than SGK1 (371). Replacement of the serine at position 422 by aspartate in the human SGK1 leads to the constitutively active S422DSGK1 (172), whereas replacement of lysine at position 127, within the ATP-binding region required for enzymatic activity, with asparagine leads to the inactive K127NSGK1 (172). Analogous mutations in the human SGK2 and SGK3 lead to the constitutively active S356DSGK2 and S419DSGK3 and the constitutively inactive K64NSGK2 and K191NSGK3 (41). In part through the PI 3-kinase pathway, SGK1 is activated by insulin (171, 254), IGF-I (137, 171, 179), hepatic growth factor (HGF) (287), and follicle stimulating hormone (FSH) (265). SGK1 can be activated by bone marrow kinase/extracellular signal-regulated kinase 5 (BK/ERK5) or by p38α. The kinases do not phosphorylate SGK1 at 256Thr but at 78Ser, which is outside the catalytic domain (137, 216). How this phosphorylation activates SGK1 is not known. SGK1 can also be activated by an increase of cytosolic Ca2+ activity, an effect presumably mediated by calmodulin-dependent protein kinase kinase (CaMKK) (158). Moreover, the small G protein Rac1 activates SGK1 via a PI 3-kinase-independent pathway (287). Additional activators of SGK1 include neuronal depolarization (179), cAMP (179, 254, 315), lithium (179), oxidation (171, 256), and adhesion to fibronectin (287). Similar to SGK1, SGK2 and SGK3 are activated by oxidation, insulin, and IGF-I through a signaling cascade [page 1155] involving PI 3-kinase as well as PDK1 and PDK2/H-motif kinase (171, 335). 137. Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, and Lee JD. BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoidinducible kinase. J Biol Chem 276: 8631–8634, 2001. 158. Imai S, Okayama N, Shimizu M, and Itoh M. Increased intracellular calcium activates serum and glucocorticoid-inducible kinase 1 (SGK1) through a calmodulin-calcium calmodulin dependent kinase kinase pathway in Chinese hamster ovary cells. Life Sci 72: 2199–2209, 2003. 171. Kobayashi T and Cohen P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphati-dylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 339: 319–328, 1999. 172. Kobayashi T, Deak M, Morrice N, and Cohen P. Characterization of the structure and regulation of two novel isoforms of serum and glucocorticoid-induced protein kinase. Biochem J 344: 189–197, 1999. 179. Kumari S, Liu X, Nguyen T, Zhang X, and D’Mello SR. Distinct phosphorylation patterns underlie Akt activation by different survival factors in neurons. Brain Res 96: 157–162, 2001. 216. Meng F, Yamagiwa Y, Taffetani S, Han J, and Patel T. IL-6 activates serum and glucocorticoid kinase via p38alpha mitogenactivated protein kinase pathway. Am J Physiol Cell Physiol 289: C971–C981, 2005. 254. Perrotti N, He RA, Phillips SA, Haft CR, and Taylor SI. Activation of serum- and glucocorticoid-induced protein kinase (Sgk) by cyclic AMP and insulin. J Biol Chem 276: 9406–9412, 2001. 256. Prasad N, Topping RS, Zhou D, and Decker SJ. Oxidative stress and vanadate induce tyrosine phosphorylation of phosphoinositide-dependent kinase 1 (PDK1). Biochemistry 39: 6929–6935, 2000. 265. Richards JS, Sharma SC, Falender AE, and Lo YH. Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropins. Mol Endocrinol 16: 580–599, 2002. 287. Shelly C and Herrera R. Activation of SGK1 by HGF, Rac1 and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. J Cell Sci 115: 1985–1993, 2002. 315. Thomas CP, Campbell JR, Wright PJ, and Husted RF. cAMPstimulated Na+ transport in H441 distal lung epithelial cells: role of PKA, phosphatidylinositol 3-kinase, and sgk1. Am J Physiol Lung Cell Mol Physiol 287: L843–L851, 2004. 335. Virbasius JV, Song X, Pomerleau DP, Zhan Y, Zhou GW, and Czech MP. Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate. Proc Natl Acad Sci USA 98: 12908–12913, 2001. 371. Xu BE, Stippec S, Lazrak A, Huang CL, and Cobb MH. WNK1 activates SGK1 by a phosphatidylinositol 3-kinase-dependent and non-catalytic mechanism. J Biol Chem 280: 34218–34223, 2005. |
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| 1.7. Degradation of SGKs
SGK1 is rapidly degraded, with a half-life of 30 min (Brickley DR. et al., (2002) J Biol Chem). Ubiquitination of SGK1 labels the kinase for degradation by the proteasome (Brickley DR. et al., (2002) J Biol Chem). SGK1 degradation may be mediated by the ubiquitin ligase Nedd4–2 (neuronal precursor cells expressed developmentally downregulated) (Zhou R.et al., (2005) Biol Chem). Nedd4–2 contains a series of tryptophan-rich sequences (WW motifs) that interact with a proline-tyrosine PY motif present in its target proteins. SGK1 bears such a PY motif. Overexpression of Nedd4–2 decreases steady state levels of SGK1 in a dose-dependent manner by increasing SGK1 ubiquitination (presumably within the first 60 NH2-terminal amino acids) and subsequent degradation in the 26S proteasome. Conversely, silencing of Nedd4–2 by RNA interference, or loss of the NH2-terminal amino acids, abrogates the ubiquitination and thus increases the half-life of SGK1. The effect of Nedd4–2 apparently requires phosphorylation of the ubiquitin ligase by SGK1, as SGK1 degradation is reduced by a phosphorylation site-deficient Nedd4–2 mutant (Nedd4–2S/T-A) or by SGK1 inhibition. Accordingly, active SGK1 favors its own degradation, thus contributing to the limitation of its action (Zhou R. et al., (2005) J Biol Chem). 1.8. Influence of SGK on renal function SGKs activate ion channels (e.g. ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g. NHE3, GLUT1, SGLT1, EAAT1–5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g. glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g. forkhead transcription factor FKHRL1). The functional significance of SGK1, SGK2, and SGK3 is still far from understood. Notably, all three kinases are potent regulators of ion channel activity, transport, and transcription (Bhargava A. and Pearce D., (2004) Trends Endocrinol Metab; Fillon S. et al., (2001) Comp Biochemi Physiol Mol Integr Physiol). Functional analysis of gene-targeted mice lacking SGK1 (Wulff P. et al., (2002) J Clin Invest) and SGK3 (McCormick JA. et al., (2004) Moll Biol Cell) provided insight into the functional significance of SGK1- and SGK3-dependent regulation of physiological functions. Interestingly, neither knockout of SGK1 or SGK3, nor knockout of both SGK1 and SGK3 leads to a severe phenotype, suggesting that neither SGK1 nor SGK3 is required for survival. Closer inspection of the renal physiology of those mice discloses, however, multiple physiological deficits pointing to the broad functional role of these kinases. |
SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1–5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, β-catenin, nuclear factor κB).
The functional significance of SGK1, SGK2, and SGK3 is still far from understood. Notably, all three kinases are potent regulators of ion channel activity, transport, and transcription (30, 111, 183, 186, 250, 305, 331, 378). Functional analysis of gene-targeted mice lacking SGK1 (368) and SGK3 (214) provided insight into the functional significance of SGK1- and SGK3-dependent regulation of physiological functions. Interestingly, neither knockout of SGK1 (368) or SGK3 (214), nor knockout of both SGK1 and SGK3 (133) leads to a severe phenotype, suggesting that neither SGK1 nor SGK3 is required for survival. Closer inspection of the physiology of those mice discloses, however, multiple physiological deficits pointing to the broad functional role of these kinases. [page 1155] C. Degradation of SGKs SGK1 is rapidly degraded, with a half-life of 30 min (50). Ubiquitination of SGK1 labels the kinase for degradation by the proteasome (50). SGK1 degradation may be mediated by the ubiquitin ligase Nedd4–2 (neuronal precursor cells expressed developmentally downregulated) (386). Nedd4–2 contains a series of tryptophan-rich sequences (WW motifs) that interact with a proline-tyrosine PY motif present in its target proteins. SGK1 bears such a PY motif. Overexpression of Nedd4–2 decreases steady-state levels of SGK1 in a dose-dependent manner by increasing SGK1 ubiquitination (presumably within the first 60 NH2-terminal amino acids) and subsequent degradation in the 26S proteasome. Conversely, silencing of Nedd4–2 by RNA interference, or loss of the NH2-terminal amino acids, abrogates the ubiquitination and thus increases the half-life of SGK1. The effect of Nedd4–2 apparently requires phosphorylation of the ubiquitin ligase by SGK1, as SGK1 degradation is reduced by a phosphorylation site-deficient Nedd4–2 mutant (Nedd4–2S/T-A) or by SGK1 inhibition (Fig. 1). Accordingly, active SGK1 favors its own degradation, thus contributing to the limitation of its action (386). 30. Bhargava A and Pearce D. Mechanisms of mineralocorticoid action: determinants of receptor specificity and actions of regulated gene products. Trends Endocrinol Metab 15: 147–153, 2004. 50. Brickley DR, Mikosz CA, Hagan CR, and Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1). J Biol Chem 277: 43064–43070, 2002. 111. Fillon S, Warntges S, Matskevitch J, Moschen I, Setiawan I, Gamper N, Feng YX, Stegen C, Friedrich B, Waldegger S, Broer S, Wagner CA, Huber SM, Klingel K, Vereninov A, and Lang F. Serum- and glucocorticoid-dependent kinase, cell volume, and the regulation of epithelial transport. Comp Biochem Physiol A Mol Integr Physiol 130: 367–376, 2001. 133. Grahammer F, Henke G, Sandu C, Rexhepaj R, Hussain A, Friedrich B, Risler T, Just L, Skutella T, Wulff P, Kuhl D, and Lang F. Intestinal function of gene targeted mice lacking the serum and glucocorticoid inducible kinase SGK1. Am J Physiol Gastrointest Liver Physiol 290: G1114–G1123, 2006. 183. Lang F, Henke G, Embark HM, Waldegger S, Palmada M, Bohmer C, and Vallon V. Regulation of channels by the serum and glucocorticoid-inducible kinase: implications for transport, excitability and cell proliferation. Cell Physiol Biochem 13: 41–50, 2003. 186. Lang F, Vallon V, Grahammer F, Palmada M, and Bohmer C. Transport regulation by the serum- and glucocorticoid-inducible kinase SGK1. Biochem Soc Trans 33: 213–215, 2005. 214. McCormick JA, Feng Y, Dawson K, Behne MJ, Yu B, Wang J, Wyatt AW, Henke G, Grahammer F, Mauro TM, Lang F, and Pearce D. Targeted disruption of the protein kinase SGK3/CISK impairs postnatal hair follicle development. Mol Biol Cell 15: 4278– 4288, 2004. 250. Pearce D. SGK1 regulation of epithelial sodium transport. Cell Physiol Biochem 13: 13–20, 2003. 305. Stockand JD. New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol 282: F559–F576, 2002. 331. Verrey F, Loffing J, Zecevic M, Heitzmann D, and Staub O. SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. Cell Physiol Biochem 13: 21–28, 2003. 368. Wulff P, Vallon V, Huang DY, Volkl H, Yu F, Richter K, Jansen M, Schlunz M, Klingel K, Loffing J, Kauselmann G, Bosl MR, Lang F, and Kuhl D. Impaired renal Na+ retention in the sgk1-knockout mouse. J Clin Invest 110: 1263–1268, 2002. 378. Yun CC. Concerted roles of SGK1 and the Na+/H+ exchanger regulatory factor 2 (NHERF2) in regulation of NHE3. Cell Physiol Biochem 13: 029–040, 2003. 386. Zhou R and Snyder PM. Nedd4–2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. J Biol Chem 280: 4518–4523, 2005. |
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| [9.] Dsa/Fragment 033 00 - Diskussion Zuletzt bearbeitet: 2016-08-09 20:57:11 WiseWoman | Dsa, Fragment, Gesichtet, KomplettPlagiat, Lang et al 2006, SMWFragment, Schutzlevel sysop |
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| Untersuchte Arbeit: Seite: 33, Zeilen: figure+caption |
Quelle: Lang et al 2006 Seite(n): 1154, Zeilen: figure |
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Figure nr. 6 - Left: model for the Serum- and Glucocorticoid-inducible Kinase-1 (SGK1)-dependent regulation of Na+ reabsorption and K+ secretion in the aldosterone-sensitive distal nephron. Aldosterone binds to mineralocorticoid receptors (MR) and stimulates the expression of SGK1, α-epithelial Na+ channel (αENaC), renal outer medullary K+ channel (ROMK), and the Na+-K+-ATPase. αENaC associates with constitutive β- and γ-subunits to form fully active ENaC. SGK1 can be phosphorylated on 422Ser by insulin or insulin-like growth factor I (IGF-I) through a signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and an unknown kinase (PDK2?/hydrophobic motif kinase). Phosphorylated 422Ser allows binding of PDK1 and/or NHERF2 with subsequent phosphorylation of SGK1 at 256Thr. PDK1 might activate SGK1 indirectly through phosphorylation of WNK1 kinase. The mechanism of SGK1 activation by WNK1 is yet unknown but does not require SGK1 phosphorylation. Activated SGK1 increases Na+ reabsorption in part by phosphorylation of the ubiquitin ligase Nedd4–2, allowing binding of the chaperone 14–3-3 to phosphorylated 444Ser. This interaction prevents Nedd4–2-mediated ubiquitination of the ENaC-PY motif and thus internalization and degradation of ENaC. SGK1 further stimulates ENaC by upregulation of transcription, by direct phosphorylation of the channel protein and by inhibition of the inducible nitric oxide synthase (iNOS). In addition to its effect on ENaC, SGK1 stimulates the Na+-K+-ATPase and K+ channels including ROMK. Right: arithmetic means ± SE of ENaC-induced currents in Xenopus oocytes coexpression experiments showing that coexpression of wild-type SGK1 but not of the inactive mutant K127NSGK1 leads to stimulation of an ENaC mutant lacking the SGK1 phosphorylation consensus sequence (S622AENaC). |
FIG. 1. Left: model for the Serum- and Glucocorticoid-inducible Kinase-1 (SGK1)-dependent regulation of Na+ reabsorption and K+ secretion in the aldosterone-sensitive distal nephron. Aldosterone binds to mineralocorticoid receptors (MR) and stimulates the expression of SGK1, α-epithelial Na+ channel (αENaC), renal outer medullary K+ channel (ROMK), and the Na+-K+-ATPase. αENaC associates with constitutive β- and γ-subunits to form fully active ENaC. SGK1 can be phosphorylated on 422Ser by insulin or insulin-like growth factor I (IGF-I) through a signaling cascade involving phosphatidylinositol 3-kinase (PI 3K) and an unknown kinase (PDK2?/hydrophobic motif kinase). Phosphorylated 422Ser allows binding of PDK1 and/or NHERF2 with subsequent phosphorylation of SGK1 at 256Thr. PDK1 might activate SGK1 indirectly through phosphorylation of WNK1 kinase. Phosphorylated 422Ser allows binding of PDK1 and/or NHERF2 with subsequent phosphorylation of SGK1 at 256Thr. PDK1 might activate SGK1 indirectly through phosphorylation of WNK1 kinase. The mechanism of SGK1 activation by WNK1 is yet unknown but does not require SGK1 phosphorylation. Activated SGK1 increases Na+ reabsorption in part by phosphorylation of the ubiquitin ligase Nedd4–2, allowing binding of the chaperone 14–3-3 to phosphorylated 444Ser. This interaction prevents Nedd4–2-mediated ubiquitination of the ENaC-PY motif and thus internalization and degradation of ENaC. SGK1 further stimulates ENaC by upregulation of transcription, by direct phosphorylation of the channel protein, and by inhibition of the inducible nitric oxide synthase (iNOS). In addition to its effect on ENaC, SGK1 stimulates the Na+-K+-ATPase and K+ channels including ROMK. Right: arithmetic means ± SE of ENaC-induced currents in Xenopus oocyte coexpression experiments showing that coexpression of wild-type SGK1 but not of the inactive mutant K127NSGK1 leads to stimulation of an ENaC mutant lacking the SGK1 phosphorylation consensus sequence (S622AENaC). |
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| [10.] Dsa/Fragment 045 06 - Diskussion Zuletzt bearbeitet: 2016-08-09 21:02:38 WiseWoman | Dsa, Fragment, Gesichtet, KomplettPlagiat, Lang et al 2006, SMWFragment, Schutzlevel sysop |
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| Untersuchte Arbeit: Seite: 45, Zeilen: 6-12 |
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| As shown in Xenopus oocytes, SGK1 and SGK3 activate the renal epithelial Ca2+ channel TRPV5 by enhancing channel abundance in the plasma membrane, an effect again requiring cooperation with NHERF2 (Embark HM. et al., (2004) Cell Physiol Biochem; Palmada M. et al., (2005) Cell Physiol Biochem). The TRPV5 C-tail interacts in a Ca2+- independent manner with NHERF2. Deletion of the second, but not the first, PDZ domain in NHERF2 abrogates the stimulating effect of SGK1 on TRPV5 protein abundance (Palmada M. et al., (2005) Cell Physiol Biochem). | As shown in Xenopus oocytes, SGK1 and SGK3 activate the renal epithelial Ca2+ channel TRPV5 by enhancing channel abundance in the plasma membrane, an effect again requiring cooperation with NHERF2 (101, 246). The TRPV5 C-tail interacts in a Ca2+-independent manner with NHERF2. Deletion of the second, but not the first, PDZ domain in NHERF2 abrogates the stimulating effect of SGK1 on TRPV5 protein abundance (246).
101. Embark HM, Setiawan I, Poppendieck S, van de Graaf SF, Boehmer C, Palmada M, Wieder T, Gerstberger R, Cohen P, Yun CC, Bindels RJ, and 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 14: 203–212, 2004. 246. Palmada M, Poppendieck S, Embark HM, van de Graaf SF, Boehmer C, Bindels RJ, and Lang F. Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1. Cell Physiol Biochem 15: 175–182, 2005. |
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