Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis

Abstract Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decrease...

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Autores principales:	Rituraj Pal, Vitaliy V. Bondar, Carolyn J. Adamski, George G. Rodney, Marco Sardiello
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a4d9a93f97c34c3c8f582aba8a8ebcdd
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spelling	oai:doaj.org-article:a4d9a93f97c34c3c8f582aba8a8ebcdd2021-12-02T16:06:23ZInhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis10.1038/s41598-017-04528-52045-2322https://doaj.org/article/a4d9a93f97c34c3c8f582aba8a8ebcdd2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04528-5https://doaj.org/toc/2045-2322Abstract Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3β (GSK3β) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal–regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3β, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2 −/− cells—a model of TS—rescues GSK3β activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS.Rituraj PalVitaliy V. BondarCarolyn J. AdamskiGeorge G. RodneyMarco SardielloNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rituraj Pal Vitaliy V. Bondar Carolyn J. Adamski George G. Rodney Marco Sardiello Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis
description	Abstract Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3β (GSK3β) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal–regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3β, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2 −/− cells—a model of TS—rescues GSK3β activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS.
format	article
author	Rituraj Pal Vitaliy V. Bondar Carolyn J. Adamski George G. Rodney Marco Sardiello
author_facet	Rituraj Pal Vitaliy V. Bondar Carolyn J. Adamski George G. Rodney Marco Sardiello
author_sort	Rituraj Pal
title	Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis
title_short	Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis
title_full	Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis
title_fullStr	Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis
title_full_unstemmed	Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis
title_sort	inhibition of erk1/2 restores gsk3β activity and protein synthesis levels in a model of tuberous sclerosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a4d9a93f97c34c3c8f582aba8a8ebcdd
work_keys_str_mv	AT riturajpal inhibitionoferk12restoresgsk3bactivityandproteinsynthesislevelsinamodeloftuberoussclerosis AT vitaliyvbondar inhibitionoferk12restoresgsk3bactivityandproteinsynthesislevelsinamodeloftuberoussclerosis AT carolynjadamski inhibitionoferk12restoresgsk3bactivityandproteinsynthesislevelsinamodeloftuberoussclerosis AT georgegrodney inhibitionoferk12restoresgsk3bactivityandproteinsynthesislevelsinamodeloftuberoussclerosis AT marcosardiello inhibitionoferk12restoresgsk3bactivityandproteinsynthesislevelsinamodeloftuberoussclerosis
_version_	1718385043721682944

Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis

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