Generating Extracellular Peroxide

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Science's STKE  12 Apr 2005:
Vol. 2005, Issue 279, pp. tw139
DOI: 10.1126/stke.2792005tw139

Although H2O2 and other reactive oxygen species are known to act as intracellular signaling molecules, DeYulia et al. have now provided evidence suggesting an unexpected role in initiating cell signaling for extracellular H2O2 generated through receptor-ligand interactions. In 293T human kidney epithelial cells transfected with the ligand-binding α subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (αGMR) either alone or as part of the complete receptor (α/βGMR), GM-CSF stimulated an increase in extracellular H2O2. GM-CSF stimulated H2O2 production in cells expressing intracellular deletion mutants of the two GMR subunits (αΔ/βΔ) and in fixed cells expressing αGMR or α/βGMR but not in cells expressing a binding-defective αGMR mutant. Extracellular catalase inhibited GM-CSF-dependent proliferation of cytokine-dependent MO7e (human megakaryocytic leukemia) cells, GM-CSF-stimulated phosphorylation of p44 and 42-mitogen-activated protein kinases (p44/42 MAPK) in MO7e and U937 (human histiocytic lymphoma) cells, and both GM-CSF-dependent phosphorylation of βGMR and transcriptional activation of a STAT5-dependent gene reporter in 293T cells expressing α/βGMR. Similarly, 293 cells that expressed peroxiredoxin-5 at the cell membrane, as well as α/βGMR, showed a decrease in GM-CSF-dependent STAT5 signaling. H2O2 stimulated phosphorylation of Janus family tyrosine kinase 2 (Jak2) and p44/42 MAPK in U937 cells and of βGMR in an in vitro system involving immunoprecipitated βGMR-associated proteins. Epidermal growth factor (EGF)-EGF receptor (EGFR) interaction also produced extracellular H2O2, as did interactions between GM-CSF, EGF, and various other cytokines and their respective receptors in cell-free systems. Thus, the authors propose that ligand-receptor interactions elicit the production of extracellular H2O2, which diffuses into the cell locally to facilitate cell signaling.

G. J. DeYulia Jr., J. M. Cárcamo, O. Bórquez-Ojeda, C. C. Shelton, D. W. Golde, Hydrogen peroxide generated extracellularly by receptor-ligand interaction facilitates cell signaling. Proc. Natl. Acad. Sci. U.S.A. 102, 5044-5049 (2005). [Abstract] [Full Text]

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