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Autor     Jeyaganesh Rajamanickam
Titel    The Serum and Glucocorticoid inducible Kinase in the regulation of sodium coupled amino acid transporters
Jahr    2007
Anmerkung    Universität Tübingen, Fakultät für Biologie, Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften, Tag der mündlichen Prüfung : 07.03.2007
URL    https://publikationen.uni-tuebingen.de/xmlui/bitstream/handle/10900/49020/pdf/jeyaganesh_rajamanickam_ph_d_ger.pdf?sequence=1

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Fragmente    4


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1.4 The Serum and Glucocorticoid inducible Kinase SGK1

The Serum and Glucocorticoid inducible protein Kinase 1 (SGK1) was originally cloned in 1993 as an immediate early gene transcriptionally stimulated by serum or glucocorticoids in rat and mammary tumor cells (81;82). Transcription of SGK1 was also shown to occur rapidly in response to many agonists like mineralocorticoids(83) , follicle stimulating hormone (FSH) (84), transforming growth factor (TGF- β) (85;86), thrombin (87), hypertonicity (88-90), high glucose (85;88) and neuronal injury or excitotoxicity (88;91;92)

SGK1 belongs to the ‘AGC’ subfamily of serine/threonine protein kinases, which include protein kinase A (PKA) or adenosine 3’, 5’ monophophate (cAMP)-dependent protein kinase, protein kinase G (PKG) or guanosine 3’, 5’ monophosphate (cGMP)-dependent protein kinase and isoforms of protein kinase C (PKC). SGK1 is present in the genomes of all eukaryotic organisms examined so far, including Caenorhabditis elegans, Drosphila, fish and mammals. Structure of SGK1 has been highly conserved through evolution like many other protein kinases (90;93;94).

Two other isoforms of SGK1 that have been identified in mammals and are named as SGK2 and SGK3. The catalytic domains of SGK2 and SGK3 isoforms share 80% amino acid sequence identity with one another and with SGK1 (89). The human gene encoding SGK1 was found in chromosome 6q23 (94) whereas the gene encoding SGK2 was identified in chromosome 20q12. SGK-like gene which encodes a protein having predicted amino acid sequence identical to that of human SGK3 (95) was found in chromosome 8q12.2.

SGK1 is expressed in humans that have been studied including the pancreas, liver, heart, lung, skeletal muscle, placenta, kidney and brain (90) but SGK1 is not expressed in all cell types within those tissues. For example, SGK1 transcript levels are found high in acinar cells in the pancreas (96). High transcript levels of SGK1 are also found in the distal tubule and collecting duct of the kidney and in thick ascending limb epithethial cells (85). The expression of SGK2 mRNA is restricted in human tissues. It expresses most abundantly in liver, kidney and pancreas (89). As like SGK1, SGK3 mRNA is present in all human and murine tissues examined but expression is particularly high in the mouse, heart and spleen and in the embryo (89;97).


81. Lang,F, Cohen,P: Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Sci.STKE<. 2001:RE17, 2001

82. Webster,MK, Goya,L, Ge,Y, Maiyar,AC, Firestone,GL: Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol.Cell Biol. 13:2031-2040, 1993

83. Brennan,FE, Fuller,PJ: Rapid upregulation of serum and glucocorticoid-regulated kinase (sgk) gene expression by corticosteroids in vivo. Mol.Cell Endocrinol. 166:129- 136, 2000

84. Alliston,TN, Maiyar,AC, Buse,P, Firestone,GL, Richards,JS: Follicle stimulating hormone-regulated expression of serum/glucocorticoid-inducible kinase in rat ovarian granulosa cells: a functional role for the Sp1 family in promoter activity. Mol.Endocrinol. 11:1934-1949, 1997

85. 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, Broer,S: Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc.Natl.Acad.Sci.U.S.A 97:8157-8162, 2000

86. Waldegger,S, Klingel,K, Barth,P, Sauter,M, Rfer,ML, Kandolf,R, Lang,F: h-sgk serinethreonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116:1081-1088, 1999

87. Kumar,S, Harvey,KF, Kinoshita,M, Copeland,NG, Noda,M, Jenkins,NA: cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Genomics 40:435-443, 1997

88. Bell,LM, Leong,ML, Kim,B, Wang,E, Park,J, Hemmings,BA, Firestone,GL: Hyperosmotic stress stimulates promoter activity and regulates cellular utilization of the serum- and glucocorticoid-inducible protein kinase (Sgk) by a p38 MAPKdependent pathway. J.Biol.Chem. 275:25262-25272, 2000

89. Kobayashi,T, Deak,M, Morrice,N, Cohen,P: Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem.J. 344 Pt 1:189-197, 1999

90. Waldegger,S, Barth,P, Raber,G, 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.U.S.A 94:4440-4445, 1997

91. Hollister,RD, Page,KJ, 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

92. Imaizumi,K, Tsuda,M, Wanaka,A, Tohyama,M, 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.Mol.Brain Res. 26:189-196, 1994

93. Gonzalez-Robayna,IJ, Falender,AE, Ochsner,S, Firestone,GL, Richards,JS: Follicle- Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells. Mol.Endocrinol. 14:1283- 1300, 2000

94. Waldegger,S, Erdel,M, Nagl,UO, Barth,P, Raber,G, Steuer,S, Utermann,G, Paulmichl,M, Lang,F: Genomic organization and chromosomal localization of the human SGK protein kinase gene. Genomics 51:299-302, 1998

95. Dai,F, Yu,L, He,H, Zhao,Y, Yang,J, Zhang,X, Zhao,S: Cloning and mapping of a novel human serum/glucocorticoid regulated kinase-like gene, SGKL, to chromosome 8q12.3-q13.1. Genomics 62:95-97, 1999

96. Klingel,K, Warntges,S, Bock,J, Wagner,CA, Sauter,M, Waldegger,S, Kandolf,R, Lang,F: Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am.J.Physiol Gastrointest.Liver Physiol 279:G998-G1002, 2000

97. Liu,D, Yang,X, Songyang,Z: Identification of CISK, a new member of the SGK kinase family that promotes IL-3-dependent survival. Curr.Biol. 10:1233-1236, 2000

3.1 The Serum and Glucocorticoid inducible Kinase SGK1

The Serum and Glucocorticoid inducible protein Kinase 1 (SGK1) was identified in 1993 as an immediate early gene whose mRNA level increases noticeably within 30 minutes when mammary tumour or fibroblast cells are stimulated with serum or glucocorticoids1-3. SGK1 gene transcription was also shown to occur rapidly in response to many agonists like mineralocorticoids4-6, follicle stimulating hormone (FSH)7,8, transforming growth factor (TGF- β)9,10, thrombin11, hypertonicity12-14, high glucose9,11 and neuronal injury or excitotoxicity15,16.

SGK1 is a member of the ‘AGC’ subfamily of serine/threonine protein kinases, which include protein kinase A (PKA) or adenosine 3’, 5’ monophophate (cAMP)-dependent protein kinase, protein kinase G (PKG) or guanosine 3’, 5’ monophosphate (cGMP)-dependent protein kinase and isoforms of protein kinase C (PKC). SGK1 is present in the genomes of all eukaryotic organisms examined so far, including Caenorhabditis elegans, Drosphila, fish and mammals. Structure of SGK1 has been highly conserved through evolution like many other protein kinases8,13,17.

There are two other isoforms of SGK1 that have been identified in mammals and are named as SGK2 and SGK3. The catalytic domains of SGK2 and SGK3 isoforms share 80% amino acid sequence identity with one another and with SGK114. The human gene encoding SGK1 was found in chromosome 6q2317. The gene encoding SGK2 was identified in chromosome 20q12 and SGK-like gene which encodes a protein having predicted amino acid sequence identical to that of human SGK318 was found in chromosome 8q12.2.

SGK1 is expressed in all human tissues that have been studied including the pancreas, liver, heart, lung, skeletal muscle, placenta, kidney and brain13 but SGK1 is not expressed in all cell types within those tissues. For example, SGK1 transcript levels are found high in acinar cells in the pancreas19. High transcript levels of SGK1 are also found in the distal tubule and collecting duct of the kidney and in

[page 10]

thick ascending limb epithethial cells9. The expression of SGK2 mRNA is restricted in human tissues. It express most abundantly in liver, kidney and pancreas20. As like SGK1, SGK3 mRNA is present in all human and murine tissues examined but expression is particularly high in the mouse heart and spleen and in the embryo20,21.


1. Lang,F. & Cohen,P. Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Sci. STKE. 2001, RE17 (2001).

2. Webster,M.K., Goya,L. & Firestone,G.L. Immediate-early transcriptional regulation and rapid mRNA turnover of a putative serine/threonine protein kinase. J. Biol. Chem. 268, 11482-11485 (1993).

3. Webster,M.K., Goya,L., Ge,Y., Maiyar,A.C. & Firestone,G.L. Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol. Cell Biol. 13, 2031-2040 (1993).

4. Brennan,F.E. & Fuller,P.J. Rapid upregulation of serum and glucocorticoidregulated kinase (sgk) gene expression by corticosteroids in vivo. Mol. Cell Endocrinol. 166, 129-136 (2000).

5. Chen,S.Y. et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc. Natl. Acad. Sci. U. S. A 96, 2514-2519 (1999).

6. Shigaev,A., Asher,C., Latter,H., Garty,H. & Reuveny,E. Regulation of sgk by aldosterone and its effects on the epithelial Na(+) channel. Am. J. Physiol Renal Physiol 278, F613-F619 (2000).

7. Alliston,T.N., Maiyar,A.C., Buse,P., Firestone,G.L. & Richards,J.S. Follicle stimulating hormone-regulated expression of serum/glucocorticoid-inducible kinase in rat ovarian granulosa cells: a functional role for the Sp1 family in promoter activity. Mol. Endocrinol. 11, 1934-1949 (1997).

8. Gonzalez-Robayna,I.J., Falender,A.E., Ochsner,S., Firestone,G.L. & Richards,J.S. Follicle-Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells. Mol. Endocrinol. 14, 1283-1300 (2000).

9. Lang,F. et al. Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc. Natl. Acad. Sci. U. S. A 97, 8157- 8162 (2000).

10. Waldegger,S. et al. h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116, 1081-1088 (1999).

11. Kumar,J.M., Brooks,D.P., Olson,B.A. & Laping,N.J. 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).

12. Bell,L.M. et al. Hyperosmotic stress stimulates promoter activity and regulates cellular utilization of the serum- and glucocorticoid-inducible protein kinase (Sgk) by a p38 MAPK-dependent pathway. J. Biol. Chem. 275, 25262-25272 (2000).

13. Waldegger,S., Barth,P., Raber,G. & 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. U. S. A 94, 4440-4445 (1997).

14. Kobayashi,T., Deak,M., Morrice,N. & Cohen,P. Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoidinduced protein kinase. Biochem. J. 344 Pt 1, 189-197 (1999).

15. Hollister,R.D., Page,K.J. & Hyman,B.T. 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).

16. Imaizumi,K., Tsuda,M., Wanaka,A., Tohyama,M. & 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. Mol. Brain Res. 26, 189-196 (1994).

17. Waldegger,S. et al. Genomic organization and chromosomal localization of the human SGK protein kinase gene. Genomics 51, 299-302 (1998).

18. Dai,F. et al. Cloning and mapping of a novel human serum/glucocorticoid regulated kinase-like gene, SGKL, to chromosome 8q12.3-q13.1. Genomics 62, 95-97 (1999).

19. Klingel,K. et al. Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am. J. Physiol Gastrointest. Liver Physiol 279, G998-G1002 (2000).

20. Kobayashi,T. & Cohen,P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem. J. 339 ( Pt 2), 319-328 (1999).

21. Liu,D., Yang,X. & Songyang,Z. Identification of CISK, a new member of the SGK kinase family that promotes IL-3-dependent survival. Curr. Biol. 10, 1233-1236 (2000).

Anmerkungen

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SGK1 has been observed as cytosolic in differentiated cells such as luteal cells (84;93) or in tumour cells arrested in the G1 phase of the cell division cycle by glucocorticoids (84;98). It has also been observed as nuclear in proliferating glomerulosa cells (84;93;98) or mammary tumour cells during the S and G2-M phases of the cell cycle{Gonzalez-Robayna, 1999 514 /id}. However, the localization of SGK1 in any given cell is regulated by extracellular signals. Thus, in serum-stimulated mammary epithelial cells, the endogenously expressed SGK1 is nuclear, but becomes cytosolic after the inhibition of phophatidylinositol (PI) 3- kinase. Translocation from the cytosol to the nucleus also occurs in response to serum stimulation of HEK293 or COS cells transfected with SGK1(99).

To become functional, SGK1 is activated by phosphorylation through a signaling cascade including phosphatidylinositol (PI) 3-kinase and phosphoinositide dependent kinase PDK1 and PDK2/H-motif kinase. While PDK1 phosphorylates SGK1 at 256Thr, PDK2/H-motif kinase phosphorylates the kinase at 422Ser. SGK2 and SGK3 may similarly be activated by PDK1 and PDK2/H-motif kinase. The equivalent phosphorylation sites for SGK2 and SGK3 are found at 193Thr/356Ser and 253Thr/419Ser, respectively (89)

Replacement of the serine at position 422 by aspartate in the human SGK1 leads to the constitutively active S422DSGK1 whereas replacement of lysine at position 127 with asparagine, within the ATP binding region required for the enzymatic activity, leads to the constitutively inactive K127NSGK1. Analogous mutations in SGK2 and SGK3 lead to the constitutively active S356DSGK2 and S419DSGK3, and the constitutively inactive K64NSGK2 and K191NSGK3 (89).

SGK isoforms resemble PKB in the substrate specificity, recognizing a serine or threonine residue lying in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr sequence (where Xaa is a variable amino acid) and thereby phosphorylating it (89). SGK1 has a considerable physiological role through the regulation of transporters and ion channels. Sodium channel conductance stimulated by SGK1 may result in cell volume regulation (88;90;100). SGK1 mediated activation of sodium channels leads to Na+ entry which in turn depolarizes the cell membrane. The depolarized cell membrane allows the entry of chloride ions and the accumulation of NaCl that further increases the intracellular osmolarity. The osmotic gradient makes water to enter the cell by which the volume of cell increases (94). SGK1 was found to stimulate Na+, K+ and 2Cl- cotransporter activity in the thick ascending limb of the [kidney, a key nephron segment in urinary concentration, which is of importance in renal Na+ reabsorption (85).]


84. Alliston,TN, Maiyar,AC, Buse,P, Firestone,GL, Richards,JS: Follicle stimulating hormone-regulated expression of serum/glucocorticoid-inducible kinase in rat ovarian granulosa cells: a functional role for the Sp1 family in promoter activity. Mol.Endocrinol. 11:1934-1949, 1997

85. 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, Broer,S: Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc.Natl.Acad.Sci.U.S.A 97:8157-8162, 2000

88. Bell,LM, Leong,ML, Kim,B, Wang,E, Park,J, Hemmings,BA, Firestone,GL: Hyperosmotic stress stimulates promoter activity and regulates cellular utilization of the serum- and glucocorticoid-inducible protein kinase (Sgk) by a p38 MAPKdependent pathway. J.Biol.Chem. 275:25262-25272, 2000

89. Kobayashi,T, Deak,M, Morrice,N, Cohen,P: Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem.J. 344 Pt 1:189-197, 1999

90. Waldegger,S, Barth,P, Raber,G, 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.U.S.A 94:4440-4445, 1997

93. Gonzalez-Robayna,IJ, Falender,AE, Ochsner,S, Firestone,GL, Richards,JS: Follicle- Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells. Mol.Endocrinol. 14:1283- 1300, 2000

94. Waldegger,S, Erdel,M, Nagl,UO, Barth,P, Raber,G, Steuer,S, Utermann,G, Paulmichl,M, Lang,F: Genomic organization and chromosomal localization of the human SGK protein kinase gene. Genomics 51:299-302, 1998

98. Buse,P, Tran,SH, Luther,E, Phu,PT, Aponte,GW, Firestone,GL: Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signaling pathways. J.Biol.Chem. 274:7253-7263, 1999

99. Park,J, Leong,ML, Buse,P, Maiyar,AC, Firestone,GL, 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

100. Bohmer,C, Wagner,CA, Beck,S, Moschen,I, Melzig,J, Werner,A, Lin,JT, Lang,F, Wehner,F: The shrinkage-activated Na(+) conductance of rat hepatocytes and its possible correlation to rENaC. Cell Physiol Biochem. 10:187-194, 2000

SGK1 has been observed as cytosolic in differentiated cells such as luteal

cells22,23 or in tumour cells arrested in the G1 phase of the cell division cycle by glucocorticoids24. It has also been observed as nuclear in proliferating glomerulosa cells22,23 or mammary tumour cells during the S and G2-M phases of the cell cycle23. However, the localization of SGK1 in any given cell is regulated by extracellular signals. Thus, in serum-stimulated mammary epithelial cells, the endogenously expressed SGK1 is nuclear, but becomes cytosolic after the inhibition of phophatidylinositol (PI) 3-kinase. Translocation from the cytosol to the nucleus also occurs in response to serum stimulation of HEK293 or COS cells transfected with SGK125.

SGK1 is activated by phosphorylation through a signaling cascade including phosphatidylinositol (PI) 3-kinase and phosphoinositide dependent kinase PDK1 and PDK2/H-motif kinase. While PDK1 phosphorylates SGK1 at 256Thr, PDK2/Hmotif kinase phosphorylates the kinase at 422Ser. SGK2 and SGK3 may similarly be activated by PDK1 and PDK2/H-motif kinase. The equivalent phosphorylation sites for SGK2 and SGK3 are found at 193Thr/356Ser and 253Thr/419Ser, respectively14,20,25.

Replacement of the serine at position 422 by aspartate in the human SGK1 leads to the constitutively active S422DSGK1 whereas replacement of lysine at position 127 with asparagine leads to the constitutively inactive K127NSGK1. Analogous mutations in SGK2 and SGK3 lead to the constitutively active S356DSGK2 and S419DSGK3, and the constitutively inactive K64NSGK2 and K191NSGK314.

SGK isoforms resemble PKB in the substrate specificity, recognizing a serine or threonine residue lying in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr sequence (where Xaa is a variable amino acid) and thereby phosphorylating it14,20,25.

SGK1 has a considerable physiological role through the regulation of transporters and ion channels. Sodium channel conductance stimulated by SGK1

[page 11]

may result in cell volume regulation12,13,26. SGK1 mediated activation of sodium channels leads to Na+ entry which in turn depolarizes the cell membrane. The depolarized cell membrane allows the entry of chloride ions and the accumulation of NaCl that further increases the intracellular osmolarity. The osmotic gradient makes water to enter the cell by which the volume of cell increases27,28. SGK1 was found to stimulate Na+, K+ and 2Cl- cotransporter activity in the thick ascending limb of the kidney, a key nephron segment in urinary concentration, which is of importance in renal Na+ reabsorption9.


9. Lang,F. et al. Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc. Natl. Acad. Sci. U. S. A 97, 8157- 8162 (2000).

12. Bell,L.M. et al. Hyperosmotic stress stimulates promoter activity and regulates cellular utilization of the serum- and glucocorticoid-inducible protein kinase (Sgk) by a p38 MAPK-dependent pathway. J. Biol. Chem. 275, 25262-25272 (2000).

13. Waldegger,S., Barth,P., Raber,G. & 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. U. S. A 94, 4440-4445 (1997).

14. Kobayashi,T., Deak,M., Morrice,N. & Cohen,P. Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoidinduced protein kinase. Biochem. J. 344 Pt 1, 189-197 (1999).

20. Kobayashi,T. & Cohen,P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem. J. 339 ( Pt 2), 319-328 (1999).

22. Alliston,T.N., Gonzalez-Robayna,I.J., Buse,P., Firestone,G.L. & Richards,J.S. Expression and localization of serum/glucocorticoid-induced kinase in the rat ovary: relation to follicular growth and differentiation. Endocrinology 141, 385- 395 (2000).

23. Gonzalez-Robayna,I.J., Alliston,T.N., Buse,P., Firestone,G.L. & Richards,J.S. Functional and subcellular changes in the A-kinase-signaling pathway: relation to aromatase and Sgk expression during the transition of granulosa cells to luteal cells. Mol. Endocrinol. 13, 1318-1337 (1999).

24. Buse,P. et al. Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signaling pathways. J. Biol. Chem. 274, 7253-7263 (1999).

25. Park,J. et al. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J. 18, 3024-3033 (1999).

26. Bohmer,C. et al. The shrinkage-activated Na(+) conductance of rat hepatocytes and its possible correlation to rENaC. Cell Physiol Biochem. 10, 187-194 (2000).

27. Lang,F. et al. Functional significance of cell volume regulatory mechanisms. Physiol Rev. 78, 247-306 (1998).

28. Lang,F., Busch,G.L. & Volkl,H. The diversity of volume regulatory mechanisms. Cell Physiol Biochem. 8, 1-45 (1998).

Anmerkungen

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[SGK1 was found to stimulate Na+, K+ and 2Cl- cotransporter activity in the thick ascending limb of the] kidney, a key nephron segment in urinary concentration, which is of importance in renal Na+ reabsorption (85). Abundant SGK1 gene transcription has been observed in diabetic nephropathy (85-87), fibrosing pancreatitis (90) and inflammatory bowel disease (96) but SGK1 involvement in the formation of abnormal fibrosis tissues remains to be established.

Moreover SGK1 and its isoforms are well proved in stimulating the activity and the cell membrane abundance of several transporters and ion channels. For instance, SGK isoforms regulate the epithelial Na+ channel, ENaC (101) , the voltage-gated Na+ channel, SCN5A (101;102), the K+ channels ROMK1 (103), KCNE1/KCNQ1 (104) and Kv1.3 (105), the Na+/H+ exchanger NHE3 (103), the dicarboxylate transporter NaDCT (103), the glutamate transporters EAAT1 (106), EAAT3 (107), EAAT4 (108) and EAAT5 (109) and the Na+/K+- ATPase. The regulatory activity of SGK1 plays a diverse role in essential cell functions such as epithelial transport, excitability, cell proliferation and apoptosis.

[...]

To date, two modes of SGK1 action in regulating transporters and ion channels have been identified. It either regulates transporters by phosphorylating them at the putative consensus site (Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr) or by inhibiting the downregulating effect of protein ubiquitin ligase Nedd4-2. These two modes of regulation of SGK1 were observed in epithelial Na+ channel, ENaC (110) (Figure 5).


85. 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, Broer,S: Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc.Natl.Acad.Sci.U.S.A 97:8157-8162, 2000

86. Waldegger,S, Klingel,K, Barth,P, Sauter,M, Rfer,ML, Kandolf,R, Lang,F: h-sgk serinethreonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116:1081-1088, 1999

87. Kumar,S, Harvey,KF, Kinoshita,M, Copeland,NG, Noda,M, Jenkins,NA: cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Genomics 40:435-443, 1997

90. Waldegger,S, Barth,P, Raber,G, 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.U.S.A 94:4440-4445, 1997

96. Klingel,K, Warntges,S, Bock,J, Wagner,CA, Sauter,M, Waldegger,S, Kandolf,R, Lang,F: Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am.J.Physiol Gastrointest.Liver Physiol 279:G998-G1002, 2000

101. Chen,SY, Bhargava,A, Mastroberardino,L, Meijer,OC, Wang,J, Buse,P, Firestone,GL, Verrey,F, Pearce,D: Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc.Natl.Acad.Sci.U.S.A 96:2514-2519, 1999

102. 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. 57:1079-1084, 2003

103. Yun,CC, Palmada,M, Embark,HM, Fedorenko,O, Feng,Y, Henke,G, Setiawan,I, Boehmer,C, Weinman,EJ, Sandrasagra,S, Korbmacher,C, Cohen,P, Pearce,D, Lang,F: The serum and glucocorticoid-inducible kinase SGK1 and the Na+/H+ exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K+ channel ROMK1. J.Am.Soc.Nephrol. 13:2823-2830, 2002

104. 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. 445:601-606, 2003

105. Gamper,N, Fillon,S, Huber,SM, Feng,Y, Kobayashi,T, Cohen,P, Lang,F: IGF-1 upregulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Arch. 443:625-634, 2002

106. 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. 86:1181-1188, 2003

107. Schniepp,R, Kohler,K, Ladewig,T, Guenther,E, Henke,G, Palmada,M, Boehmer,C, Rothstein,JD, Broer,S, Lang,F: Retinal colocalization and in vitro interaction of the glutamate transporter EAAT3 and the serum- and glucocorticoid-inducible kinase SGK1 [correction]. Invest Ophthalmol.Vis.Sci. 45:1442-1449, 2004

108. Rajamanickam,J, Palmada,M, Lang,F, Boehmer,C: EAAT4 phosphorylation at the SGK1 consensus site is required for transport modulation by the kinase. J.Neurochem. 102:858-866, 2007

109. 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. 329:738-742, 2005

110. Debonneville,C, Flores,SY, Kamynina,E, Plant,PJ, Tauxe,C, Thomas,MA, Munster,C, Chraibi,A, Pratt,JH, Horisberger,JD, Pearce,D, Loffing,J, Staub,O: Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J. 20:7052-7059, 2001

SGK1 was found to stimulate Na+, K+ and 2Cl- cotransporter activity in the thick ascending limb of the kidney, a key nephron segment in urinary concentration, which is of importance in renal Na+ reabsorption9. Abundant SGK1 gene transcription has been observed in diabetic nephropathy10,11,29, fibrosing pancreatitis13 and inflammatory bowel disease19 but SGK1 involvement in the formation of abnormal fibrosis tissues remains to be established.

Moreover SGK1 and its isoforms are well proved in stimulating the activity and the cell membrane abundance of several transporters and ion channels. For instance, SGK isoforms regulate the epithelial Na+ channel, ENaC5, the voltage-gated Na+ channel, SCN5A30, the K+ channels ROMK131, KCNE1/KCNQ132 and Kv1.333-35, the Na+/H+ exchanger NHE336, the dicarboxylate transporter NaDCT37, the glutamate transporters EAAT138, EAAT339, EAAT440 and EAAT541 and the Na+/K+-ATPase42. The regulatory activity of SGK1 plays a diverse role in essential cell functions such as epithelial transport, excitability, cell proliferation and apoptosis.

[page 12]

To date, two modes of SGK1 action in regulating transporters and ion channels have been identified. It either regulates transporters by phosphorylating them at the putative consensus site (Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr) or by inhibiting the downregulating effect of protein ubiquitin ligase Nedd4-2. These two modes of regulation of SGK1 were observed in epithelial Na+ channel, ENaC60,61 (Figure 1).


9. Lang,F. et al. Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc. Natl. Acad. Sci. U. S. A 97, 8157-8162 (2000).

10. Waldegger,S. et al. h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116, 1081-1088 (1999).

11. Kumar,J.M., Brooks,D.P., Olson,B.A. & Laping,N.J. 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).

13. Waldegger,S., Barth,P., Raber,G. & 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. U. S. A 94, 4440-4445 (1997).

19. Klingel,K. et al. Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am. J. Physiol Gastrointest. Liver Physiol 279, G998-G1002 (2000).

29. Hoffman,B.B., Sharma,K., Zhu,Y. & Ziyadeh,F.N. Transcriptional activation of transforming growth factor-beta1 in mesangial cell culture by high glucose concentration. Kidney Int. 54, 1107-1116 (1998).

30. Boehmer,C. et al. Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A. Cardiovasc. Res. 57, 1079-1084 (2003).

31. Yun,C.C. et al. The serum and glucocorticoid-inducible kinase SGK1 and the Na+/H+ exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K+ channel ROMK1. J. Am. Soc. Nephrol. 13, 2823-2830 (2002).

32. Embark,H.M., 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. 445, 601-606 (2003).

33. Gamper,N. et al. IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Arch. 443, 625-634 (2002).

34. Gamper,N. et al. K+ channel activation by all three isoforms of serum- and glucocorticoid-dependent protein kinase SGK. Pflugers Arch. 445, 60-66 (2002).

35. Warntges,S. et al. Cerebral localization and regulation of the cell volumesensitive serum- and glucocorticoid-dependent kinase SGK1. Pflugers Arch. 443, 617-624 (2002).

36. Yun,C.C., Chen,Y. & Lang,F. Glucocorticoid activation of Na(+)/H(+) exchanger isoform 3 revisited. The roles of SGK1 and NHERF2. J. Biol. Chem. 277, 7676-7683 (2002).

37. Boehmer,C. et al. 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. 313, 998-1003 (2004).

38. Boehmer,C. et al. 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. 86, 1181-1188 (2003).

39. Schniepp,R. et al. Retinal colocalization and in vitro interaction of the glutamate transporter EAAT3 and the serum- and glucocorticoid-inducible kinase SGK1 [correction]. Invest Ophthalmol. Vis. Sci. 45, 1442-1449 (2004).

40. Bohmer,C. et al. Stimulation of the EAAT4 glutamate transporter by SGK protein kinase isoforms and PKB. Biochem. Biophys. Res. Commun. 324, 1242-1248 (2004).

41. Boehmer,C. et al. Regulation of the excitatory amino acid transporter EAAT5 by the serum and glucocorticoid dependent kinases SGK1 and SGK3. Biochem. Biophys. Res. Commun. 329, 738-742 (2005).

60. Debonneville,C. et al. Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J. 20, 7052-7059 (2001).

61. Friedrich,B. et al. The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel alpha,beta,gamma-ENaC. Pflugers Arch. 445, 693-696 (2003).

Anmerkungen

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(Hindemith), LieschenMueller, (Graf Isolan)

[4.] Sj/Fragment 020 01 - Diskussion
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Figure 5. Schematic model showing molecular mechanisms of ENaC regulation by SGK1. Aldosterone binding to the mineralocorticoid receptor (MR) can stimulates the transcription of SGK1 as well as ENaC. Insulin or Insulin-like growth factor (IGF-1) phosphorylates SGK1 at Ser422 through PI3 kinase and PDK2/H-motify kinase signaling cascade. Activated (phosphorylated) SGK1 enhances ENaC plasma membrane abundance either directly by phosphorylating the channel or indirectly by inhibiting the downregulating effect of the ubiquitin ligase Nedd4-2.

Sj 20 a source.png

Figure 1 Schematic model showing molecular mechanisms of ENaC regulation by SGK1. Aldosterone binding to the mineralocorticoid receptor (MR) can stimulates the transcription of SGK1 as well as ENaC. Insulin or Insulin-like growth factor (IGF-1) phosphorylates SGK1 at Ser422 through PI3 kinase and PDK2/H-motify kinase signaling cascade. Activated (phosphorylated) SGK1 enhances ENaC plasma membrane abundance either directly by phosphorylating the channel or indirectly by inhibiting the downregulating effect of the ubiquitin ligase Nedd4-2.

Anmerkungen

No source is given.

Sichter
(Hindemith), LieschenMueller

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