Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7971
The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation
Gomez-Salinero, Jesus M. CNIC | Lopez-Olaneta, Marina CNIC | Ortiz-Sanchez, Paula CNIC | Larrasa-Alonso, Javier CNIC | Gatto, Alberto CNIC | Felkin, Leanne E | Barton, Paul J R | Navarro-Lerida, Inmaculada CNIC | del Pozo, Miguel Angel CNIC | García-Pavía, Pablo | Sundararaman, Balaji | Giovinazo, Giovanna CNIC | Yeo, Gene W | Lara-Pezzi, Enrique CNIC
Cell Chem Biol. 2016; 23(11):1372-1382
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.
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
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