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TGF-β inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest
Open accessAbstract
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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“In the PI3K/AKT pathway, both PI3K and AKT downstream signaling factors are substrates of PP2A (Kuo et al., 2008; Petritsch et al., 2000).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Petritsch et al., 2000
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Metadata
- Authors
- Petritsch, C., Beug, H., Balmain, A., & Oft, M.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-12-15
- Volume
- 14
- Issue
- 24
- Pages
- 3093-3101
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317138
- 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
- bronze
- doi.org
- 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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