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...

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Detalhes bibliográficos
Autores: 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
Tipo de documento: artigo
Data de publicação:2016
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositório:Repisalud
Idioma:inglês
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7971
Acesso em linha:http://hdl.handle.net/20.500.12105/7971
Access Level:Acceso aberto
Palavra-chave: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
Descrição
Resumo: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.

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