Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Becaplermin
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Cell Line
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Epidermal Growth Factor / pharmacology*
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Gene Expression
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HeLa Cells
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Humans
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Hydrogen Peroxide / metabolism
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Insulin / pharmacology
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Mice
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Models, Biological
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NADH, NADPH Oxidoreductases / genetics
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NADH, NADPH Oxidoreductases / metabolism
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NADPH Oxidase 1
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NIH 3T3 Cells
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Oxidation-Reduction
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PTEN Phosphohydrolase
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Peroxidases / genetics
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Peroxidases / metabolism
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Peroxiredoxins
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Phosphatidylinositol Phosphates / biosynthesis
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Phosphoric Monoester Hydrolases / antagonists & inhibitors*
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism*
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Platelet-Derived Growth Factor / pharmacology*
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Proto-Oncogene Proteins c-sis
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Recombinant Proteins / pharmacology
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Signal Transduction
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Transfection
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Tumor Suppressor Proteins / antagonists & inhibitors*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Insulin
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Phosphatidylinositol Phosphates
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Recombinant Proteins
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Tumor Suppressor Proteins
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phosphatidylinositol 3,4,5-triphosphate
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Becaplermin
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Epidermal Growth Factor
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Hydrogen Peroxide
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Peroxidases
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Peroxiredoxins
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NADH, NADPH Oxidoreductases
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NADPH Oxidase 1
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Phosphoric Monoester Hydrolases
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Protein Tyrosine Phosphatases
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PTEN Phosphohydrolase
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PTEN protein, human
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Pten protein, mouse