The Calcineurin Variant CnAβ1 controls mouse embryonic stem cell differentiation by directing mTORC2 membrane localization and activation
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2016-10-13
Date Acceptance
2016-09-02
Citation
Cell Chemical Biology, 2016, 23 (11), pp.1372-1382
ISSN
2451-9456
Publisher
Elsevier: Cell Press
Start Page
1372
End Page
1382
Journal / Book Title
Cell Chemical Biology
Volume
23
Issue
11
Copyright Statement
© 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Commission of the European Communities
Identifier
PII: S2451-9456(16)30308-7
Grant Number
289600
Subjects
Akt
CnAβ1
Golgi apparatus
Rictor
calcineurin
mTOR
splicing
stem cells
Publication Status
Published