Significance of SGK1 in the regulation of neuronal function

Läng, Florian; Strutz‐Seebohm, Nathalie; Seebohm, Guiscard; Lang, Undine E.

doi:10.1113/jphysiol.2010.190926

Cited by 132 publications

(122 citation statements)

References 53 publications

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“…Demands for the Na + / K + ATPase also change markedly during nerve excitation, renal blood filtration and breathing, and Na + /K + ATPases are highly regulated in context-dependent ways by adrenaline, dopamine, thyroid hormone, aldosterone, catecholamines and insulin (reviewed by Comellas et al, 2010;Ewart and Klip, 1995). Mechanistic details of these regulations are sketchy, though protein kinases including PKA, PKC and SGK have been found to phosphorylate the a and FXYD subunits, triggering trafficking of the Na + /K + ATPase between intercellular membranes and cell surface, as well as changing intrinsic activity of the pump (Fuller et al, 2009;Han et al, 2010;Lang et al, 2010;Poulsen et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase

Hoxhaj

Najafov

Toth

et al. 2012

Journal of Cell Science

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SummaryHere, we describe a phosphorylation-based reverse myristoyl switch for mammalian ZNRF2, and show that this E3 ubiquitin ligase and its sister protein ZNRF1 regulate the Na + /K + pump (Na + /K + ATPase). N-myristoylation localizes ZNRF1 and ZNRF2 to intracellular membranes and enhances their activity. However, when ZNRF2 is phosphorylated in response to agonists including insulin and growth factors, it binds to 14-3-3 and is released into the cytosol. On membranes, ZNRF1 and ZNRF2 interact with the Na + /K + ATPase a1 subunit via their UBZ domains, while their RING domains interact with E2 proteins, predominantly Ubc13 that, together with Uev1a, mediates formation of Lys63-ubiquitin linkages. ZNRF1 and ZNRF2 can ubiquitylate the cytoplasmic loop encompassing the nucleotide-binding and phosphorylation regions of the Na + /K + ATPase a1 subunit. Ouabain, a Na + /K + ATPase inhibitor and therapeutic cardiac glycoside, decreases ZNRF1 protein levels, whereas knockdown of ZNRF2 inhibits the ouabain-induced decrease of cell surface and total Na + /K + ATPase a1 levels. Thus, ZNRF1 and ZNRF2 are new players in regulation of the ubiquitous Na + /K + ATPase that is tuned to changing demands in many physiological contexts.

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Section: Discussionmentioning

confidence: 99%

ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase

Hoxhaj

Najafov

Toth

et al. 2012

Journal of Cell Science

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“…Various studies have shown upregulation of SGK1 as a cell survival response in transgenic models of PD and ALS (1)(2)(3)25). In line with previously published data, in our study we, too, observed an increase in SGK1 expression at both mRNA and protein levels and a corresponding increase in phosphorylated and activated levels of SGK1 in response to neurotoxic stress induced by 6-OHDA in SH-SY5Y cells, which enabled us to utilize this neurotoxin cellular model to study SGK1 biology in neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

“…erum-and glucocorticoid-inducible kinase 1 (SGK1) belongs to the AGC family of kinases and has been shown to have various cellular functions, including the promotion of cell survival (1)(2)(3). SGK1 is activated by insulin and growth factors via phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1), and mammalian target of rapamycin complex 2 (mTORC2) (4,5).…”

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confidence: 99%

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Iqbal

Howard

LoGrasso

2015

Molecular and Cellular Biology

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Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y cells, and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 overexpression in vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3␤ (GSK3␤) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3␤ pathways.S erum-and glucocorticoid-inducible kinase 1 (SGK1) belongs to the AGC family of kinases and has been shown to have various cellular functions, including the promotion of cell survival (1-3). SGK1 is activated by insulin and growth factors via phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1), and mammalian target of rapamycin complex 2 (mTORC2) (4, 5). SGK1 shares its functions and some substrates with another kinase from the AGC family, protein kinase B (PKB/ Akt). Akt, like SGK1, has been shown to mediate cell survival through various signaling cascades and gets activated by a wide range of extracellular stimuli (6). SGK1 lacks the pleckstrin homology (PH) domain that tethers Akt to the plasma membrane, making SGK1 more accessible to cytosolic and nuclear sites and thereby providing it with cellular functions and substrates that do not overlap those of Akt (1, 6). SGK1 plays a protective role in oxidative stress conditions as small interfering RNA (siRNA) knockdown of SGK1 has shown an increase in oxidative stressinduced cell death in HEK293 cells (7). Oxidative stress is a hallmark of neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) (8). In a study published in 2005 by Schoenebeck et al., upregulation of SGK1 was seen in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and in a transgenic model of ALS (SOD1-G93A), and protection from cell death was observed for animals treated with dexamethasone (De...

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“…SGK1 is a serine/threonine kinase implicated in the cellular stress response and neuronal function (7). We and others have previously shown that glucocorticoids increase SGK1 expression in human neural stem cells and in rodent neurons (3,8).…”

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confidence: 99%

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

Anacker

Cattaneo

Musaelyan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

279

215

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Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum-and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.antidepressants | hypothalamus-pituitary-adrenal axis | stem cells | neuroplasticity

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Significance of SGK1 in the regulation of neuronal function

Cited by 132 publications

References 53 publications

ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase

ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

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