Abstract
The c-Abl and Arg tyrosine kinases are activated in the cellular response to oxidative stress. The present studies demonstrate that c-Abl and Arg associate with glutathione peroxidase 1 (GPx1) and that this interaction is regulated by intracellular oxidant levels. The c-Abl and Arg SH3 domains bind directly to a proline-rich site in GPx1 at amino acids 132-145. GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress. Our findings provide the first evidence that GPx1 is regulated by a signaling pathway that is activated in the oxidative stress response.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Catalytic Domain
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Enzyme Activation
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Glutathione / metabolism
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Glutathione Peroxidase / chemistry
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Glutathione Peroxidase / genetics
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Glutathione Peroxidase / metabolism*
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Glutathione Peroxidase GPX1
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Humans
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In Vitro Techniques
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Mice
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Mice, Knockout
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Mutation
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Oxidative Stress
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-abl / chemistry
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism*
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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src Homology Domains
Substances
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Recombinant Proteins
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Glutathione Peroxidase
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ARG tyrosine kinase
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-abl
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Glutathione
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Glutathione Peroxidase GPX1