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Nierenfunktion Kinase-defizienter Mäuse

von Dr. Diana Sandulache

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[1.] Dsa/Fragment 029 14 - Diskussion
Zuletzt bearbeitet: 2016-08-09 20:11:02 WiseWoman
Dsa, Fragment, Gesichtet, KomplettPlagiat, Lang et al 2006, SMWFragment, Schutzlevel sysop

Typus
KomplettPlagiat
Bearbeiter
Hindemith
Gesichtet
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Untersuchte Arbeit:
Seite: 29, Zeilen: 14-41
Quelle: Lang et al 2006
Seite(n): 1153, Zeilen: r.col: 13ff
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.

Anmerkungen

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Sichter
(Hindemith), WiseWoman


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