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Untersuchte Arbeit:
Seite: 18, Zeilen: 1ff (entire page)
Quelle: Rajamanickam 2007
Seite(n): 10, 11, Zeilen: 10: 5ff; 11: 1ff
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).

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