Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors
Open accessAbstract
Stimulation of cells with various peptide growth factors induces the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) through activation of phosphatidylinositol 3-kinase. The action of this enzyme is reversed by that of the tumor suppressor PTEN. With the use of cells overexpressing NADPH oxidase 1 or peroxiredoxin II, we have now shown that H2O2 produced in response to stimulation of cells with epidermal growth factor or platelet-derived growth factor potentiates PIP3 generation and activation of the protein kinase Akt induced by these growth factors. We also show that a small fraction of PTEN molecules is transiently inactivated as a result of oxidation of the essential cysteine residue of this phosphatase in various cell types stimulated with epidermal growth factor, platelet-derived growth factor, or insulin. These results suggest that the activation of phosphatidylinositol 3-kinase by growth factors might not be sufficient to induce the accumulation of PIP3 because of the opposing activity of PTEN and that the concomitant local inactivation of PTEN by H2O2 might be needed to increase the concentration of PIP3 sufficiently to trigger downstream signaling events. Furthermore, together with previous observations, our data indicate that peroxiredoxin likely participates in PIP3 signaling by modulating the local concentration of H2O2.
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H2O2 inactivates PTEN through disulfide bonds between catalytic cysteines and unlocks PI3-K-dependent recruitment of Akt.
“through the formation of disulfide bonds between catalytic cysteines, H2O2 inactivates phosphatase and tensin homolog phosphatase (PTEN) and unlocks the phosphoinositide 3-kinase (PI3-K)-dependent recruitment of its downstream kinases, such as protein kinase B (Akt)16”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [16]
The paper states that H2O2 oxidation inactivates PTEN and can increase PIP3 and Akt activation; it identifies the disulfide as forming between catalytic-site Cys-124 and Cys-71 (introductory section; page unavailable). It does not describe both cysteines as catalytic or demonstrate Akt recruitment specifically, and its Discussion frames PTEN inactivation as a possible contributor to downstream signaling rather than an established mechanism that ‘unlocks’ recruitment. (LLM, conf=0.86)
Experimental — accuracy not yet measuredROS have been shown to inhibit other classes of phosphatases, including PTEN and MAPK phosphatases.
“Since then, ROS have been shown to inhibit other classes of phosphatases, including phosphatase and tensin homolog (PTEN, lipid phosphatase) and MAPK phosphatases 51–53.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [51]
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- Authors
- Kwon, J., Lee, S.-R., Yang, K.-S., Ahn, Y., Kim, Y. J., Stadtman, E. R., & Rhee, S. G.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Rhee, Sue Goo
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-11-08
- Volume
- 101
- Issue
- 47
- Pages
- 16419-16424
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC534546
- OpenAlex
- W2037813091
- Cited by
- 631
- References
- 34
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 18 · 2023: 15 · 2022: 19 · 2021: 36 · 2020: 40 · 2019: 23 · 2018: 27 · 2017: 28 · 2016: 34 · 2015: 32 · 2014: 61 · 2013: 29 · 2012: 29
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- 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
- PTEN, tumor suppressor inactivation, protein oxidation, hydrogen peroxide, phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-kinase, Akt activation, epidermal growth factor, platelet-derived growth factor, insulin signaling, NOX1, peroxiredoxin 2, cysteine oxidation, redox signaling
- MeSH terms
- NADPH Oxidase 1, Becaplermin, Animals, Cell Line, Epidermal Growth Factor, HeLa Cells, Humans, Hydrogen Peroxide, Insulin, Models, Biological, NADH, NADPH Oxidoreductases, Oxidation-Reduction, Peroxidases, Phosphoric Monoester Hydrolases, Platelet-Derived Growth Factor, Recombinant Proteins, Transfection, Signal Transduction, Gene Expression, Protein Tyrosine Phosphatases, Phosphatidylinositol Phosphates, Proto-Oncogene Proteins c-sis, Tumor Suppressor Proteins, NIH 3T3 Cells, PTEN Phosphohydrolase, Mice, Peroxiredoxins
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