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Cellular Regulation by Hydrogen Peroxide

Sue Goo Rhee^*, Tong-Shin Chang^*, Yun Soo Bae, Seung-Rock Lee and Sang Won Kang

*Laboratory of Cell Signaling, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and Center for Cell Signaling Research and Division of Molecular Life Sciences, Ewha Women’s University, Seodaemoon-gu, Seoul Korea.

Correspondence to Dr. Sue Goo Rhee, Building 50, Room 3523, South Drive, MSC 8015, Bethesda, MD 20892. Phone: 301-496-9646; Fax: 301-480-0357;

ABSTRACT. Substantial evidence suggests that the transient production of H₂O₂ is an important signaling event triggered by the activation of various cell surface receptors. Understanding the intracellular messenger function of H₂O₂ calls for studies of how receptor occupation elicits the production of H₂O₂, what kinds of molecules are targeted by the produced H₂O₂, and how H₂O₂ is eliminated after the completion of its mission. Recent studies suggest that growth factor–induced H₂O₂ production requires the activation of PtdIns 3-kinase. The essential role of PtdIns 3-kinase is likely to provide PI(3,4,5)P₃ that recruits and activates a guanine nucleotide exchange factor of Rac, which is required for the activation of NADPH oxidase. The targets of H₂O₂ action include proteins that contain a reactive Cys residue. Thus, H₂O₂ produced in response to growth factor causes inactivation of protein tyrosine phosphatases in various cells by oxidizing specifically the catalytic Cys. These results, together with other observations, indicate that the activation of a receptor tyrosine kinase per se by binding of the corresponding growth factor might not be sufficient to increase the steady-state level of protein tyrosine phosphorylation in cells. Rather, the concurrent inhibition of protein tyrosine phosphatases by H₂O₂ might also be required. Peroxiredoxins, members of a newly discovered family of peroxidases, efficiently reduced the intracellular level of H₂O₂ produced in the cells stimulated with various cell surface ligands. Furthermore, the activity of peroxiredoxin enzymes seems to be regulated via protein phosphorylation as in the case of many other intracellular messenger metabolizing enzymes. E-mail: sgrhee@nih.gov

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