Related Experiment Video

Updated: Apr 12, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

14.9K

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

Jason S L Yu1, Thamil Selvee Ramasamy1, Nick Murphy1

  • 1Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London W12 0NN, UK.

Nature Communications
|May 23, 2015
PubMed

Insights

Phosphatidylinositol 3-kinase (PI3K) signaling hinders embryonic stem cell differentiation by shortening Smad2/3 activation via mTORC2. Inhibiting this pathway promotes robust endoderm development.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Molecular Biology

Background:

  • The phosphatidylinositol 3-kinase (PI3K) and transforming growth factor-β (TGF-β) signaling pathways are crucial for cellular functions.
  • The precise molecular mechanisms governing the crosstalk between PI3K and TGF-β pathways are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms of crosstalk between PI3K and TGF-β signaling pathways.
  • To investigate the role of mechanistic target of rapamycin complex 2 (mTORC2) in regulating Activin-induced definitive endoderm differentiation.

Main Methods:

  • Utilized human embryonic stem cells.
  • Investigated the effects of PI3K signaling on Smad2/3 activation and degradation.
  • Examined the role of mTORC2 in Smad2/3 phosphorylation and its interaction with Nedd4L.

Main Results:

  • PI3K signaling antagonizes definitive endoderm differentiation by reducing Smad2/3 activation duration through mTORC2.
  • mTORC2-mediated Smad2/3 phosphorylation at T220/T179, independent of Akt, CDK, and Erk.
  • This phosphorylation facilitates Nedd4L recruitment and Smad2/3 degradation.
  • Inhibition of PI3K/mTORC2 enhances Smad2/3 activity duration, promoting mesendoderm and endoderm differentiation.

Conclusions:

  • A novel crosstalk mechanism between PI3K and TGF-β pathways is identified.
  • mTORC2 acts as a critical mediator in this crosstalk, regulating Smad2/3 stability.
  • Targeting the PI3K/mTORC2 axis offers a potential strategy to enhance stem cell differentiation.

More Related Videos

Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay11:38

Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay

Published on: September 14, 2021

3.9K
Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation09:40

Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation

Published on: June 27, 2017

8.4K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.4K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
11.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.1K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.7K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
14.1K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
19.6K