The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation
Embryonic 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 r...
| Autores: | , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/7971 |
| Acceso en línea: | http://hdl.handle.net/20.500.12105/7971 |
| Access Level: | acceso abierto |
| Palabra clave: | Animals Calcineurin Cell Differentiation Cell Line Golgi Apparatus Mechanistic Target of Rapamycin Complex 2 Mice Mouse Embryonic Stem Cells Multiprotein Complexes Signal Transduction TOR Serine-Threonine Kinases |
| id |
ES_f56b96ff399ca3a1fa44bcab8ab8ae39 |
|---|---|
| oai_identifier_str |
oai:repisalud.isciii.es:20.500.12105/7971 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and ActivationGomez-Salinero, Jesus M.Lopez-Olaneta, MarinaOrtiz-Sanchez, PaulaLarrasa-Alonso, JavierGatto, AlbertoFelkin, Leanne EBarton, Paul J RNavarro-Lerida, Inmaculadadel Pozo, Miguel AngelGarcía-Pavía, PabloSundararaman, BalajiGiovinazzo, GiovannaYeo, Gene WLara-Pezzi, EnriqueAnimalsCalcineurinCell DifferentiationCell LineGolgi ApparatusMechanistic Target of Rapamycin Complex 2MiceMouse Embryonic Stem CellsMultiprotein ComplexesSignal TransductionTOR Serine-Threonine KinasesEmbryonic 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.ElsevierUnión Europea. Comisión EuropeaMinisterio de Ciencia e Innovación (España)Comunidad de Madrid (España)Ministerio de Economía y Competitividad (España)Fundación ProCNIC20192019-07-2920162016-11-1720162016-11-17journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/7971reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 289600European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 608027ES SEV-2015-0505 Not availableES SAF2012-31451 Not availableES CP08 00144open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/79712026-06-12T12:43:37Z |
| dc.title.none.fl_str_mv |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation |
| title |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation |
| spellingShingle |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation Gomez-Salinero, Jesus M. Animals Calcineurin Cell Differentiation Cell Line Golgi Apparatus Mechanistic Target of Rapamycin Complex 2 Mice Mouse Embryonic Stem Cells Multiprotein Complexes Signal Transduction TOR Serine-Threonine Kinases |
| title_short |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation |
| title_full |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation |
| title_fullStr |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation |
| title_full_unstemmed |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation |
| title_sort |
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation |
| dc.creator.none.fl_str_mv |
Gomez-Salinero, Jesus M. Lopez-Olaneta, Marina Ortiz-Sanchez, Paula Larrasa-Alonso, Javier Gatto, Alberto Felkin, Leanne E Barton, Paul J R Navarro-Lerida, Inmaculada del Pozo, Miguel Angel García-Pavía, Pablo Sundararaman, Balaji Giovinazzo, Giovanna Yeo, Gene W Lara-Pezzi, Enrique |
| author |
Gomez-Salinero, Jesus M. |
| author_facet |
Gomez-Salinero, Jesus M. Lopez-Olaneta, Marina Ortiz-Sanchez, Paula Larrasa-Alonso, Javier Gatto, Alberto Felkin, Leanne E Barton, Paul J R Navarro-Lerida, Inmaculada del Pozo, Miguel Angel García-Pavía, Pablo Sundararaman, Balaji Giovinazzo, Giovanna Yeo, Gene W Lara-Pezzi, Enrique |
| author_role |
author |
| author2 |
Lopez-Olaneta, Marina Ortiz-Sanchez, Paula Larrasa-Alonso, Javier Gatto, Alberto Felkin, Leanne E Barton, Paul J R Navarro-Lerida, Inmaculada del Pozo, Miguel Angel García-Pavía, Pablo Sundararaman, Balaji Giovinazzo, Giovanna Yeo, Gene W Lara-Pezzi, Enrique |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Unión Europea. Comisión Europea Ministerio de Ciencia e Innovación (España) Comunidad de Madrid (España) Ministerio de Economía y Competitividad (España) Fundación ProCNIC |
| dc.subject.none.fl_str_mv |
Animals Calcineurin Cell Differentiation Cell Line Golgi Apparatus Mechanistic Target of Rapamycin Complex 2 Mice Mouse Embryonic Stem Cells Multiprotein Complexes Signal Transduction TOR Serine-Threonine Kinases |
| topic |
Animals Calcineurin Cell Differentiation Cell Line Golgi Apparatus Mechanistic Target of Rapamycin Complex 2 Mice Mouse Embryonic Stem Cells Multiprotein Complexes Signal Transduction TOR Serine-Threonine Kinases |
| description |
Embryonic 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. |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2016 2016-11-17 2016 2016-11-17 2019 2019-07-29 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 AM http://purl.org/coar/version/c_ab4af688f83e57aa |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/20.500.12105/7971 |
| url |
http://hdl.handle.net/20.500.12105/7971 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 289600 European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 608027 ES SEV-2015-0505 Not available ES SAF2012-31451 Not available ES CP08 00144 |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
| dc.source.none.fl_str_mv |
reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII) |
| instname_str |
Instituto de Salud Carlos III (ISCIII) |
| reponame_str |
Repisalud |
| collection |
Repisalud |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869424588127993856 |
| score |
15,811543 |