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

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  • 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
    Present address: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia)

  • 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)

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.

Suggested Citation

  • Jason S. L. Yu & Thamil Selvee Ramasamy & Nick Murphy & Marie K. Holt & Rafal Czapiewski & Shi-Khai Wei & Wei Cui, 2015. "PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8212
    DOI: 10.1038/ncomms8212
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