PreprintCited by 223TGF-β signaling in diseasesPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

TGF-β inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest

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Petritsch, Claudia, Beug, Hartmut, Balmain, Allan, Oft, Martin·2000·Genes & Development

Abstract

On TGF-beta binding, the TGF-beta receptor directly phosphorylates and activates the transcription factors Smad2/3, leading to G(1) arrest. Here, we present evidence for a second, parallel, TGF-beta-dependent pathway for cell cycle arrest, achieved via inhibition of p70(s6k). TGF-beta induces association of its receptor with protein phosphatase-2A (PP2A)-Balpha. Concomitantly, three PP2A-subunits, Balpha, Abeta, and Calpha, associate with p70(s6k), leading to its dephosphorylation and inactivation. Although either pathway is sufficient to induce G(1) arrest, abrogation of both, the inhibition of p70(s6k), and transcription through Smad proteins is required for release of epithelial cells from TGF-beta-induced G(1) arrest. TGF-beta thereby modulates the translational and posttranscriptional control of cell cycle progression.

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Authors
Petritsch, C., Beug, H., Balmain, A., & Oft, M.
Affiliations
University of California, San Francisco (US)
Venue
Genes & Development
Published
2000-12-15
Volume
14
Issue
24
Pages
3093-3101
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
OpenAlex
W1999086610
Cited by
223
References
39
Citations by year
2026: 4 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 6 · 2014: 8 · 2013: 7 · 2012: 9
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
TGF-beta, p70 S6 kinase, protein phosphatase 2A, G1 cell cycle arrest, Smad2/3 signaling, TGF-beta receptor, protein dephosphorylation, translational regulation, post-transcriptional regulation, cell cycle progression, epithelial cells
MeSH terms
Wortmannin, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Androstadienes, Animals, Cells, Cultured, Chromones, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme Inhibitors, Epithelial Cells, Fibroblasts, Morpholines, Mutation, Phosphoprotein Phosphatases, Phosphorylation, Quinazolines, Protein Biosynthesis, Signal Transduction, Trans-Activators, G1 Phase, S Phase, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Ribosomal Protein S6 Kinases, Sirolimus, Activin Receptors, Type I, Smad2 Protein, Protein Phosphatase 2, ErbB Receptors

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