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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