ArticleThe Journal of biological chemistry2010
Hypoxia-activated Smad3-specific dephosphorylation by PP2A.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 63 citations in OpenAlex.
- Anticancer agent FTY720 upregulates cell cycle regulator BTG2 via the SET/TAF-Iβ -PP2A-SMAD3 signaling pathway and induces G2/M arrest in leukemia.Genes & genomics · 2026Article
- BRG1 exacerbates myocardial fibrosis after myocardial infarction by interacting with ZEB1.Frontiers in pharmacology · 2026Article
- Acetylation-regulated DUSP1 deficiency contributes to renal fibrosis progression.Theranostics · 2025Article
- Article
- Small-molecule α-lipoic acid targets ELK1 to balance human neutrophil and erythrocyte differentiation.Stem cell research & therapy · 2024Article
- TGF-β signaling in health, disease, and therapeutics.Signal transduction and targeted therapy · 2024Review
- Harnessing the effects of hypoxia-like inhibition on homology-directed DNA repair.Seminars in cancer biology · 2024Review
- Direct conversion of human umbilical cord mesenchymal stem cells into retinal pigment epithelial cells for treatment of retinal degeneration.Cell death & disease · 2022Article
- Exendin-4 Attenuates Remodeling in the Remote Myocardium of Rats After an Acute Myocardial Infarction by Activating β-Arrestin-2, Protein Phosphatase 2A, and Glycogen Synthase Kinase-3 and Inhibiting β-Catenin.Cardiovascular drugs and therapy · 2021Article
- TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
- Modeling Cellular Response in Large-Scale Radiogenomic Databases to Advance Precision Radiotherapy.Cancer research · 2019Article
- Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression.Redox biology · 2019Review
- Mesenchymal stem cells of Systemic Sclerosis patients, derived from different sources, show a profibrotic microRNA profiling.Scientific reports · 2019Article
- Phosphatase PP2A is essential for TProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Simvastatin reduces TGF-β1-induced SMAD2/3-dependent human ventricular fibroblasts differentiation: Role of protein phosphatase activation.International journal of cardiology · 2018Article
- Hypoxia Downregulates MAPK/ERK but Not STAT3 Signaling in ROS-Dependent and HIF-1-Independent Manners in Mouse Embryonic Stem Cells.Oxidative medicine and cellular longevity · 2017Article
- Posttranslational Regulation of Smads.Cold Spring Harbor perspectives in biology · 2016Review
- The broken "Off" switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance.BBA clinical · 2016Review
- LB-100 sensitizes hepatocellular carcinoma cells to the effects of sorafenib during hypoxia by activation of Smad3 phosphorylation.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Transforming growth factor-β signaling enhancement by long-term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells.Cancer science · 2015Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The transforming growth factor-beta (TGF-beta) maintains epithelial homeostasis and suppresses early tumor formation, but paradoxically at later stages of tumor progression, TGF-beta promotes malignancy. TGF-beta activates phosphorylation of Smad2 and -3 effectors. Smad2 and -3 are known to have different functions, but differential regulation of their phosphorylation has not been described. Here we show that upon hypoxia, the TGF-beta-induced phosphorylation of Smad3 was inhibited, although Smad2 remained phosphorylated. The inhibition of Smad3 phosphorylation was not due to TGF-beta receptor inactivation. We show that Smad3 was dephosphorylated by PP2A (protein phosphatase 2A) specifically under hypoxic conditions. The hypoxic Smad3 dephosphorylation required intact expression of the essential scaffold component PR65 of PP2A. PP2A physically interacted with Smad3 that occurred only in hypoxia. Accordingly, Smad3-associated PP2A activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of TGF-beta-induced Smad3 but did not affect Smad2. Moreover, the influence of TGF-beta on a set of Smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical PP2A inhibition. Our data demonstrate the existence of a Smad3-specific phosphatase and identify a novel role for PP2A. Moreover, our data implicate a novel mechanism by which hypoxia regulates growth factor responses.
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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.