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PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation

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Title: PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation
Authors: Yu, JS
Ramasamy, TS
Murphy, N
Holt, MK
Czapiewski, R
Wei, SK
Cui, W
Item Type: Journal Article
Abstract: Crosstalk between the phosphatidylinositol 3-kinase (PI3K) and the transforming growth factor-β signalling pathways play an important role in regulating many cellular functions. However, the molecular mechanisms underpinning this crosstalk remain unclear. Here, we report that PI3K signalling antagonizes the Activin-induced definitive endoderm (DE) differentiation of human embryonic stem cells by attenuating the duration of Smad2/3 activation via the mechanistic target of rapamycin complex 2 (mTORC2). Activation of mTORC2 regulates the phosphorylation of the Smad2/3-T220/T179 linker residue independent of Akt, CDK and Erk activity. This phosphorylation primes receptor-activated Smad2/3 for recruitment of the E3 ubiquitin ligase Nedd4L, which in turn leads to their degradation. Inhibition of PI3K/mTORC2 reduces this phosphorylation and increases the duration of Smad2/3 activity, promoting a more robust mesendoderm and endoderm differentiation. These findings present a new and direct crosstalk mechanism between these two pathways in which mTORC2 functions as a novel and critical mediator.
Issue Date: 22-May-2015
Date of Acceptance: 20-Apr-2015
URI: http://hdl.handle.net/10044/1/23306
DOI: 10.1038/ncomms8212
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 6
Issue: 4
Copyright Statement: © 2015, Rights Managed by Nature Publishing Group. The article for which you have requested permission has been distributed under a Creative Commons CC-BY license (please see the article itself for the license version number). You may reuse this material without obtaining permission from Nature Publishing Group, providing that the author and the original source of publication are fully acknowledged, as per the terms of the license.
Sponsor/Funder: Genesis Research Trust
Medical Research Council (MRC)
Funder's Grant Number: N/A
G0802537
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
EMBRYONIC STEM-CELLS
SELF-RENEWAL
EFFICIENT DIFFERENTIATION
DEFINITIVE ENDODERM
MTOR
PROTEIN
AKT
ACTIVATION
KINASE
GROWTH
Activins
Cell Differentiation
Cell Line, Tumor
Embryonic Stem Cells
Endoderm
HEK293 Cells
Humans
Mechanistic Target of Rapamycin Complex 2
Multiprotein Complexes
Phosphatidylinositol 3-Kinases
Phosphorylation
Receptor Cross-Talk
Smad Proteins, Receptor-Regulated
TOR Serine-Threonine Kinases
Transforming Growth Factor beta
Cell Line, Tumor
Endoderm
Humans
Multiprotein Complexes
Activins
Transforming Growth Factor beta
Cell Differentiation
Receptor Cross-Talk
Phosphorylation
Smad Proteins, Receptor-Regulated
Embryonic Stem Cells
Phosphatidylinositol 3-Kinases
HEK293 Cells
TOR Serine-Threonine Kinases
Mechanistic Target of Rapamycin Complex 2
Publication Status: Published
Article Number: ARTN 7212
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons