The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia
Open accessAbstract
Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1α. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55α, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1α accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55α knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55α, and HIF1α but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Under hypoxia, PP2A/B55α dephosphorylates PHD2 at Ser125, stabilizing HIF1α.
“Under hypoxia, mTOR and p70S6K are inactivated and PP2A/B55α dephosphorylates PHD2 Ser125, leading to HIF1α stabilization (Di Conza et al., 2017).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Di Conza et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 43 · Cited by 119
- Authors
- Di Conza, G., Trusso Cafarello, S., Loroch, S., Mennerich, D., Deschoemaeker, S., Di Matteo, M., Ehling, M., Gevaert, K., Prenen, H., Zahedi, R. P., Sickmann, A., Kietzmann, T., Moretti, F., & Mazzone, M.
- Affiliations
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- University of Oulu (FI)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- KU Leuven (BE)
- University of Aberdeen (GB)
- National Research Council (IT)
- Corresponding author
- Mazzone, Massimiliano
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 18
- Issue
- 7
- Pages
- 1699-1712
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5318657
- OpenAlex
- W2588464299
- Cited by
- 119
- References
- 43
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 10 · 2023: 10 · 2022: 24 · 2021: 20 · 2020: 9 · 2019: 15 · 2018: 7 · 2017: 5
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- RENATE (submittedVersion, cc-by-nc-nd)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- RENATE
- Funders
- Bundesministerium für Bildung und Forschung
- Fonds Wetenschappelijk Onderzoek (1505611N00)
- Vlaamse Liga Tegen Kanker (419.052.173)
- Stichting Tegen Kanker (2010-169)
- Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen (1211413N)
- Deutsche Forschungsgemeinschaft (EH 472/1-1)
- European Resuscitation Council (308459)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PHD2, HIF-1α, mTOR, p70S6K, protein phosphatase 2A, REDD1, hypoxia, colorectal cancer, autophagy, cell survival, protein phosphorylation, tumor growth
- MeSH terms
- Cell Line, Cell Survival, Humans, Phosphorylation, Colorectal Neoplasms, Signal Transduction, Cell Hypoxia, HT29 Cells, Ribosomal Protein S6 Kinases, 70-kDa, Cell Line, Tumor, Cell Proliferation, Hypoxia-Inducible Factor 1, alpha Subunit, Protein Phosphatase 2, HEK293 Cells, TOR Serine-Threonine Kinases, Hypoxia-Inducible Factor-Proline Dioxygenases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
