The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner

The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/G...

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Detalles Bibliográficos
Autores: Sanz-Castillo, Belén, Hurtado, Begoña, Vara-Ciruelos, Diana, El Bakkali, Aicha, Hermida, Dario, Salvador-Barbero, Beatriz, Martínez-Alonso, Diego, González-Martínez, José, Santiveri, Clara, Campos-Olivas, Ramón, Ximénez de Embún, Pilar, Redondo-Muñoz, Javier, Álvarez-Fernández, Mónica, Malumbres, Marcos
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/412982
Acceso en línea:http://hdl.handle.net/10261/412982
https://api.elsevier.com/content/abstract/scopus_id/85142003940
Access Level:acceso abierto
Palabra clave:AKT
Cell cycle
Glucose homeostasis
MASTL
mTOR
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spelling The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent mannerSanz-Castillo, BelénHurtado, BegoñaVara-Ciruelos, DianaEl Bakkali, AichaHermida, DarioSalvador-Barbero, BeatrizMartínez-Alonso, DiegoGonzález-Martínez, JoséSantiveri, ClaraCampos-Olivas, RamónXiménez de Embún, PilarRedondo-Muñoz, JavierÁlvarez-Fernández, MónicaMalumbres, MarcosAKTCell cycleGlucose homeostasisMASTLmTORThe AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by the expression of phosphomimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.BS‐C was supported by Foundation la Caixa, and AEB was funded by Comunidad de Madrid. MÁ‐F was supported by a young investigator grant from the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2014‐60442‐JIN; co‐financed by FEDER funds). The Cell Division and Cancer lab of the CNIO is supported by grants from the MICIU (RTI2018‐095582‐B‐I00), Red de Excelencia iDIFFER (RED2018‐102723‐T), Comunidad de Madrid (B2017/BMD‐3884), and Worldwide Cancer Research (WCR‐20‐0155).Peer reviewedEMBO PressSpringerFundación la CaixaComunidad de MadridMinisterio de Economía y Competitividad (España)European CommissionMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Worldwide Cancer ResearchConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/412982https://api.elsevier.com/content/abstract/scopus_id/85142003940reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//SAF2014‐60442‐JINinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095582-B-I00info:eu-repo/grantAgreement/AEI//RED2018‐102723‐TB2017/BMD‐3884The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.15252/embj.2022110833https://doi.org/10.15252/embj.2022110833Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4129822026-05-22T06:33:51Z
dc.title.none.fl_str_mv The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
title The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
spellingShingle The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
Sanz-Castillo, Belén
AKT
Cell cycle
Glucose homeostasis
MASTL
mTOR
title_short The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
title_full The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
title_fullStr The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
title_full_unstemmed The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
title_sort The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner
dc.creator.none.fl_str_mv Sanz-Castillo, Belén
Hurtado, Begoña
Vara-Ciruelos, Diana
El Bakkali, Aicha
Hermida, Dario
Salvador-Barbero, Beatriz
Martínez-Alonso, Diego
González-Martínez, José
Santiveri, Clara
Campos-Olivas, Ramón
Ximénez de Embún, Pilar
Redondo-Muñoz, Javier
Álvarez-Fernández, Mónica
Malumbres, Marcos
author Sanz-Castillo, Belén
author_facet Sanz-Castillo, Belén
Hurtado, Begoña
Vara-Ciruelos, Diana
El Bakkali, Aicha
Hermida, Dario
Salvador-Barbero, Beatriz
Martínez-Alonso, Diego
González-Martínez, José
Santiveri, Clara
Campos-Olivas, Ramón
Ximénez de Embún, Pilar
Redondo-Muñoz, Javier
Álvarez-Fernández, Mónica
Malumbres, Marcos
author_role author
author2 Hurtado, Begoña
Vara-Ciruelos, Diana
El Bakkali, Aicha
Hermida, Dario
Salvador-Barbero, Beatriz
Martínez-Alonso, Diego
González-Martínez, José
Santiveri, Clara
Campos-Olivas, Ramón
Ximénez de Embún, Pilar
Redondo-Muñoz, Javier
Álvarez-Fernández, Mónica
Malumbres, Marcos
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación la Caixa
Comunidad de Madrid
Ministerio de Economía y Competitividad (España)
European Commission
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Worldwide Cancer Research
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv AKT
Cell cycle
Glucose homeostasis
MASTL
mTOR
topic AKT
Cell cycle
Glucose homeostasis
MASTL
mTOR
description The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by the expression of phosphomimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.
publishDate 2023
dc.date.none.fl_str_mv 2023
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/412982
https://api.elsevier.com/content/abstract/scopus_id/85142003940
url http://hdl.handle.net/10261/412982
https://api.elsevier.com/content/abstract/scopus_id/85142003940
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//SAF2014‐60442‐JIN
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095582-B-I00
info:eu-repo/grantAgreement/AEI//RED2018‐102723‐T
B2017/BMD‐3884
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.15252/embj.2022110833
https://doi.org/10.15252/embj.2022110833
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv EMBO Press
Springer
publisher.none.fl_str_mv EMBO Press
Springer
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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