von Dr. Diana Sandulache
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| [1.] Dsa/Fragment 027 04 - Diskussion Zuletzt bearbeitet: 2016-08-03 17:13:23 WiseWoman | Boini 2006, Dsa, Fragment, Gesichtet, KomplettPlagiat, SMWFragment, Schutzlevel sysop |
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Quelle: Boini 2006 Seite(n): 10, 11, 12, Zeilen: 10: 4ff; 11: 1ff; 12: 1ff |
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| The three enzymes differ in the region N-terminal of the C-terminal catalytic domain: SGK2 contains a relatively short N terminus (98 amino acids), with no discernable domain, whereas SGK3 has a longer N terminus (162 amino acids) comprising a phox homology (PX) domain (Xu J. et al., (2001) Cell Biol).
PX domains were originally found as conserved domains in the p40phox and p47phox subunits of the neutrophil NADPH oxidase (phox) superoxide-generating complex (Ponting CP., (1996) Protein Sci). These domains are part of many proteins involved in intracellular protein trafficking, such as the sorting nexins. PX domains are phosphoinositide-binding domains that appear to be important for localization of these proteins to membranes (especially endosomes) enriched in phosphoinositides. In this respect, these domains resemble other domains such as the pleckstrin homology (PH), FYFE, FERM and ENTH domains. PKB/Akt contains a PH domain in its N terminus, which is important for PKB/Akt activation by phosphoinositide-3 kinases (PI-3Ks). This domain enables the colocalization with the 3- phosphoinositide-dependent protein kinase-1 (PDK1), which is known to phosphorylate and activate PKB/Akt. Similarly, SGK3’s PX domain is involved in SGK3 localization and activity: It is necessary for phosphoinositide binding, endosomal localization, and proper kinase activity. Moreover, structural studies indicate that it may play a role in dimerization of the kinase. With respect to their physiological role(s), it has been shown in vitro that both the SGK2 and SGK3 enzymes have the same phosphorylation consensus as SGK1 (and PKB/Akt), namely R-X-R-X-X-(S/T). It is likely, however, that other factors, such as surrounding amino acids, subcellular localization, or cofactors are important for the specificity of and functional differences between the enzymes. For example, in Xenopus A6 cells, only SGK1 and not the coexpressed PKB modulates the activity of the epithelial Na+ channel (ENaC) (Arteaga MF. et al., (2005) Am J Physiol Renal Physiol). The role of SGK2 has mainly been studied in heterologous expression systems such as Xenopus laevis oocytes or HEK293 cells and with respect to numerous transport and channel proteins. These studies revealed that SGK2 can stimulate the activity of K+ channels such as the voltage- gated K+ channel Kv1.3 (Gamper et al., (2002) Pflügers Arc,; Henke et al., (2004) J Cell Physiol), Na+-K+-ATPase (Henke G. et al., (2002) Kidney Blood Press Res), KCNE1 (Embark et al., (2003) Pflügers Arch), ENaC (Friedrich et al., (2003) Pflügers Arch), the glutamate transporter EEAT4 (Böhmer et al., (2004) Biochem Biophys Res Commun), and the glutamate receptors GluR6 (Strutz-Seebohm et al., (2005) J Physiol) and GluR1 (Strutz-Seebohm et al., (2005a) J Physiol). All of these transport proteins are also stimulated in the same cellular systems by SGK1, SGK3, and/or PKB; hence, the physiological relevance of these findings has to be considered with caution. To define more precisely the role of SGK2, it will be necessary to carry out additional studies, using more relevant cell or animal systems and knocking down SGK2 by either RNA interference protocols or by gene inactivation. SGK3/CISK, which is better characterized than SGK2, was identified in a screen for antiapoptotic genes (Liu et al., (2000) Curr Biol) and found to act downstream of the PI-3K pathway and in parallel with PKB/Akt. Moreover, it was demonstrated to phosphorylate and inhibit Bad (a proapoptotic protein) and FKHRL1, a proapoptotic transcription factor. Knockout (ko) mice have been generated; these mice are viable and fertile and have normal Na+ handling and glucose tolerance, as opposed to the KO mice of SGK1 or PKB/Akt2 (McCormick et al., (2004) Mol Biol Cell; Garofalo et al., (2003) J Clin Invest; Wulff et al., (2002) J Clin Invest). However, they display after birth a defect in hair follicle development, a defect preceded by disturbances in the β-catenin/Lef1 gene regulation (McCormick et al., (2004) Mol Biol Cell). |
The three enzymes differ in the region N-terminal of the C-terminal catalytic domain: SGK2 contains a relatively short N terminus (98 amino
[page 11] acids), with no discernable domain, whereas SGK3 has a longer N terminus (162 amino acids) comprising a phox homology (PX) domain (Xu et al., 2001). PX domains were originally found as conserved domains in the p40phox and p47phox subunits of the neutrophil NADPH oxidase (phox) superoxide-generating complex (Ponting 1996). These domains are part of many proteins involved in intracellular protein trafficking, such as the sorting nexins (Worby and Dixon 2002). PX domains are phosphoinositide-binding domains that appear to be important for localization of these proteins to membranes (especially endosomes) enriched in phosphoinositides. In this respect, these domains resemble other domains such as the pleckstrin homology (PH), FYFE, FERM and ENTH domains. PKB/Akt contains a PH domain in its N terminus, which is important for PKB/Akt activation by phosphoinositide-3 kinases (PI-3Ks). This domain enables the colocalization with the 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which is known to phosphorylate and activate PKB/Akt. Similarly, SGK3’s PX domain is involved in SGK3 localization and activity: It is necessary for phosphoinositide binding, endosomal localization, and proper kinase activity (Xu et al., 2001; Liu et al., 2000). Moreover, structural studies indicate that it may play a role in dimerization of the kinase (Xing et al., 2004). With respect to their physiological role(s), it has been shown in vitro that both the SGK2 and SGK3 enzymes have the same phosphorylation consensus as SGK1 (and PKB/Akt), namely R-X-R-X-X-(S/T) (Kobayashi et al., 1999). It is likely, however, that other factors, such as surrounding amino acids, subcellular localization, or cofactors are important for the specificity of and functional differences between the enzymes. For example, in Xenopus A6 cells, only SGK1 and not the coexpressed PKB modulates the activity of the epithelial Na+ channel (ENaC) (Artega et al., 2005). The role of SGK2 has mainly been studied in heterologous expression systems such as Xenopus laevis oocytes or HEK293 cells and with respect to numerous transport and channel proteins. These studies revealed that SGK2 can stimulate the activity of K+ channels such as the voltage- gated K+ channel Kv1.3 (Gamper et al., 2002; Henke et al., 2004), Na+,K+-ATPase (Henke et al., 2002), KCNE1 (Embark et al., 2003), ENaC (Friedrich et al., 2003), the glutamate transporter EEAT4 (Bohmer et al., 2004), and the glutamate receptors GluR6 (Strutz-Seebohm et al., 2005) and GluR1 (Strutz-Seebohm et al., 2005a). All of these transport proteins are also stimulated in the same cellular systems by SGK1, SGK3, and/or PKB; hence, the physiological relevance of these findings has to be considered with caution. To define more precisely the role of SGK2, it will be necessary to [page 12] carry out additional studies, using more relevant cell or animal systems and knocking down SGK2 by either RNA interference protocols or by gene inactivation. SGK3/CISK, which is better characterized than SGK2, was identified in a screen for antiapoptotic genes (Liu et al., 2000) and found to act downstream of the PI-3K pathway and in parallel with PKB/Akt. Moreover, it was demonstrated to phosphorylate and inhibit Bad (a proapoptotic protein) and FKHRL1, a proapoptotic transcription factor. Knockout (KO) mice have been generated; these mice are viable and fertile and have normal Na+ handling and glucose tolerance, as opposed to the KO mice of SGK1 or PKB/Akt2 (McCormick et al., 2004; Garofalo et al., 2003; Wulff et al., 2002; Cho et al., 2001). However, they display after birth a defect in hair follicle development, a defect preceded by disturbances in the β-catenein/Lef1 gene regulation (McCormick et al., 2004). |
The source is not given. |
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