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

Yu, J.S.L. and Ramasamy, T.S. and Murphy, N. and Holt, M.K. and Czapiewski, R. and Wei, S.K. and Cui, W. (2015) PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation. Nature Communications, 6 (1). p. 7212. ISSN 2041-1723, DOI https://doi.org/10.1038/ncomms8212.

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Official URL: http://dx.doi.org/10.1038/ncomms8212


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.

Item Type: Article
Uncontrolled Keywords: Activins; Cell Differentiation; Cell Line, Tumor; Embryonic Stem Cells; Endoderm; HEK293 Cells; Humans; Multiprotein Complexes; Phosphatidylinositol 3-Kinases; Phosphorylation; Receptor Cross-Talk; Smad Proteins, Receptor-Regulated; TOR Serine-Threonine Kinases; Transforming Growth Factor beta
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 20 Sep 2018 07:07
Last Modified: 20 Sep 2018 07:07
URI: http://eprints.um.edu.my/id/eprint/19339

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