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Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease
Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD—laforin phosphatase and malin ubiquitin ligase—are believed to be inv...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861076/ https://www.ncbi.nlm.nih.gov/pubmed/24131995 http://dx.doi.org/10.1091/mbc.E13-05-0261 |
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author | Singh, Pankaj Kumar Singh, Sweta Ganesh, Subramaniam |
author_facet | Singh, Pankaj Kumar Singh, Sweta Ganesh, Subramaniam |
author_sort | Singh, Pankaj Kumar |
collection | PubMed |
description | Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD—laforin phosphatase and malin ubiquitin ligase—are believed to be involved in glycogen metabolism. We earlier demonstrated that laforin and malin negatively regulate cellular glucose uptake by preventing plasma membrane targeting of glucose transporters. We show here that loss of laforin results in activation of serum/glucocorticoid-induced kinase 1 (SGK1) in cellular and animals models and that inhibition of SGK1 in laforin-deficient cells reduces the level of plasma membrane-bound glucose transporter, glucose uptake, and the consequent glycogen accumulation. We also provide evidence to suggest that mammalian target of rapamycin (mTOR) activates SGK1 kinase in laforin-deficient cells. The mTOR activation appears to be a glucose-dependent event, and overexpression of dominant-negative SGK1 suppresses mTOR activation, suggesting the existence of a feedforward loop between SGK1 and mTOR. Our findings indicate that inhibition of SGK1 activity could be an effective therapeutic approach to suppress glycogen accumulation, inhibit mTOR activity, and rescue autophagy defects in LD. |
format | Online Article Text |
id | pubmed-3861076 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-38610762014-03-02 Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease Singh, Pankaj Kumar Singh, Sweta Ganesh, Subramaniam Mol Biol Cell Articles Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD—laforin phosphatase and malin ubiquitin ligase—are believed to be involved in glycogen metabolism. We earlier demonstrated that laforin and malin negatively regulate cellular glucose uptake by preventing plasma membrane targeting of glucose transporters. We show here that loss of laforin results in activation of serum/glucocorticoid-induced kinase 1 (SGK1) in cellular and animals models and that inhibition of SGK1 in laforin-deficient cells reduces the level of plasma membrane-bound glucose transporter, glucose uptake, and the consequent glycogen accumulation. We also provide evidence to suggest that mammalian target of rapamycin (mTOR) activates SGK1 kinase in laforin-deficient cells. The mTOR activation appears to be a glucose-dependent event, and overexpression of dominant-negative SGK1 suppresses mTOR activation, suggesting the existence of a feedforward loop between SGK1 and mTOR. Our findings indicate that inhibition of SGK1 activity could be an effective therapeutic approach to suppress glycogen accumulation, inhibit mTOR activity, and rescue autophagy defects in LD. The American Society for Cell Biology 2013-12-15 /pmc/articles/PMC3861076/ /pubmed/24131995 http://dx.doi.org/10.1091/mbc.E13-05-0261 Text en © 2013 Singh et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Singh, Pankaj Kumar Singh, Sweta Ganesh, Subramaniam Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease |
title | Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease |
title_full | Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease |
title_fullStr | Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease |
title_full_unstemmed | Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease |
title_short | Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease |
title_sort | activation of serum/glucocorticoid-induced kinase 1 (sgk1) underlies increased glycogen levels, mtor activation, and autophagy defects in lafora disease |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861076/ https://www.ncbi.nlm.nih.gov/pubmed/24131995 http://dx.doi.org/10.1091/mbc.E13-05-0261 |
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