ArticleNature communications2015
PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation.
Article in Nature communications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 95 citations in OpenAlex.
- Mechanotransduction Failure and Molecular Rescue in Gastric Cancer: Kinetotherapy Across the IL-6/STAT3-Myostatin/ACVR2B-Akt/mTOR Axis.Medical sciences (Basel, Switzerland) · 2026Review
- E3 ligase SMURF2 promotes adipogenesis and improves obesity complications by suppressing TGF-β signaling.Journal of lipid research · 2026Article
- Therapeutic targeting of AREL1 in hepatic stellate cells attenuates MASH-related liver fibrosis.Nature communications · 2026Article
- Transcriptome Analysis of TGFBI Knockdown vs Normal Corneal Epithelial Cells: Implications for TGFBI Corneal Dystrophy Treatment.Biochemical genetics · 2026Article
- Quality control strategy for differentiating induced pluripotent stem cells into pancreatic β-cells before transplantation.Regenerative medicine · 2026Review
- Endothelial epigenetic senescence driven microglial activation mediates cardio-retinal neuroinflammation in heart failure.Theranostics · 2026Article
- Mulberry-derived carbon dots attenuate kidney fibrosis through direct inhibition of PI3K.Materials today. Bio · 2025Article
- mTORC2-mediated cell-cell interactions promote BMP4-induced WNT activation and mesoderm differentiation.Stem cell reports · 2025Article
- Type III interferon primes pDCs for TLR7 activation and antagonizes immune suppression mediated by TGF-β and PGE2.Nature communications · 2025Article
- Activin A affects colorectal cancer progression and immunomodulation in a stage dependent manner.Scientific reports · 2025Article
- Combating chronic kidney disease-associated cachexia: A literature review of recent therapeutic approaches.BMC nephrology · 2025Review
- OCT4 translationally promotes AKT signaling as an RNA-binding protein in stressed pluripotent stem cells.Stem cell research & therapy · 2025Article
- Article
- The Upregulation of Leucine-Rich Repeat Containing 1 Expression Activates Hepatic Stellate Cells and Promotes Liver Fibrosis by Stabilizing Phosphorylated Smad2/3.International journal of molecular sciences · 2024Article
- Lysicamine Reduces Protein Kinase B (AKT) Activation and Promotes Necrosis in Anaplastic Thyroid Cancer.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Extracellular matrix modulates the spatial hepatic features in hepatocyte-like cells derived from human embryonic stem cells.Stem cell research & therapy · 2023Article
- FGFR-mediated ERK1/2 signaling contributes to mesendoderm and definitive endoderm formationiScience · 2023Article
- Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema.Experimental & molecular medicine · 2023Article
- Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia.International journal of molecular sciences · 2023Review
- Shear stress induces autophagy in Schlemm's canal cells via primary cilia-mediated SMAD2/3 signaling pathway.Autophagy reports · 2023Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.