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

Jason S. L. Yu, Thamil Selvee Ramasamy, Nick Murphy, Marie K. Holt, Rafal Czapiewski, Shi-Khai Wei and Wei Cui ()
Additional contact information
Jason S. L. Yu: Institute of Reproductive and Developmental Biology, Imperial College London
Thamil Selvee Ramasamy: Institute of Reproductive and Developmental Biology, Imperial College London
Nick Murphy: Institute of Reproductive and Developmental Biology, Imperial College London
Marie K. Holt: Institute of Reproductive and Developmental Biology, Imperial College London
Rafal Czapiewski: Institute of Reproductive and Developmental Biology, Imperial College London
Shi-Khai Wei: Institute of Reproductive and Developmental Biology, Imperial College London
Wei Cui: Institute of Reproductive and Developmental Biology, Imperial College London

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms8212 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8212

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms8212

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().