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The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation

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dc.contributor.authorGomez-Salinero, Jesus M.
dc.contributor.authorLopez-Olaneta, Marina
dc.contributor.authorOrtiz-Sanchez, Paula
dc.contributor.authorLarrasa-Alonso, Javier
dc.contributor.authorGatto, Alberto
dc.contributor.authorFelkin, Leanne E
dc.contributor.authorBarton, Paul J R
dc.contributor.authorNavarro-Lerida, Inmaculada
dc.contributor.authordel Pozo, Miguel Angel
dc.contributor.authorGarcía-Pavía, Pablo
dc.contributor.authorSundararaman, Balaji
dc.contributor.authorGiovinazzo, Giovanna
dc.contributor.authorYeo, Gene W
dc.contributor.authorLara-Pezzi, Enrique
dc.contributor.funderUnión Europea. Comisión Europea
dc.contributor.funderMinisterio de Ciencia e Innovación (España)
dc.contributor.funderComunidad de Madrid (España)
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderFundación ProCNIC
dc.date.accessioned2019-07-29T06:41:49Z
dc.date.available2019-07-29T06:41:49Z
dc.date.issued2016-11-17
dc.description.abstractEmbryonic stem cells (ESC) have the potential to generate all the cell lineages that form the body. However, the molecular mechanisms underlying ESC differentiation and especially the role of alternative splicing in this process remain poorly understood. Here, we show that the alternative splicing regulator MBNL1 promotes generation of the atypical calcineurin Aβ variant CnAβ1 in mouse ESCs (mESC). CnAβ1 has a unique C-terminal domain that drives its localization mainly to the Golgi apparatus by interacting with Cog8. CnAβ1 regulates the intracellular localization and activation of the mTORC2 complex. CnAβ1 knockdown results in delocalization of mTORC2 from the membrane to the cytoplasm, inactivation of the AKT/GSK3β/β-catenin signaling pathway, and defective mesoderm specification. In summary, here we unveil the structural basis for the mechanism of action of CnAβ1 and its role in the differentiation of mESCs to the mesodermal lineage.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipEuropean Union's FP7 [CardioNext-ITN-608027, Cardio-NeT-ITN-289600]; Spanish Ministry of Science and Innovation [SAF2012-31451, CP08/00144]; Regional Government of Madrid [2010-BMD-2321]; Spanish Ministry of Economy and Competitiveness; Pro-CNIC Foundation; Severo Ochoa Center of Excellence (MINECO award) [SEV-2015-0505]es_ES
dc.format.number11es_ES
dc.format.page1372-1382es_ES
dc.format.volume23es_ES
dc.identifier.citationCell Chem Biol. 2016; 23(11):1372-1382es_ES
dc.identifier.doi10.1016/j.chembiol.2016.09.010es_ES
dc.identifier.e-issn2451-9448es_ES
dc.identifier.issn24519456es_ES
dc.identifier.journalCell chemical biologyes_ES
dc.identifier.pubmedID27746127es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7971
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/289600/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/608027/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2012-31451es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/CP08/00144es_ES
dc.repisalud.institucionCNICes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Molecular de la Insuficiencia Cardiacaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Señalización por Integrinases_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Células Pluripotenteses_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAktes_ES
dc.subjectCnAβ1es_ES
dc.subjectGolgi apparatuses_ES
dc.subjectRictores_ES
dc.subjectcalcineurines_ES
dc.subjectmTORes_ES
dc.subjectsplicinges_ES
dc.subjectstem cellses_ES
dc.subject.meshAnimalses_ES
dc.subject.meshCalcineurines_ES
dc.subject.meshCell Differentiationes_ES
dc.subject.meshCell Linees_ES
dc.subject.meshGolgi Apparatuses_ES
dc.subject.meshMechanistic Target of Rapamycin Complex 2es_ES
dc.subject.meshMicees_ES
dc.subject.meshMouse Embryonic Stem Cellses_ES
dc.subject.meshMultiprotein Complexeses_ES
dc.subject.meshSignal Transductiones_ES
dc.subject.meshTOR Serine-Threonine Kinaseses_ES
dc.titleThe Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activationes_ES
dc.typejournal articlees_ES
dc.type.hasVersionAMes_ES
dspace.entity.typePublication
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