RECEPTOR-LIGAND INTERACTIONS Generating Extracellular Peroxide

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 subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR) either alone or as part of the complete receptor (/ßGMR), GM-CSF stimulated an increase in extracellular H₂O₂. GM-CSF stimulated H₂O₂ production in cells expressing intracellular deletion mutants of the two GMR subunits (/ß) and in fixed cells expressing GMR or /ßGMR but not in cells expressing a binding-defective GMR 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 ßGMR and transcriptional activation of a STAT5-dependent gene reporter in 293T cells expressing /ßGMR. Similarly, 293 cells that expressed peroxiredoxin-5 at the cell membrane, as well as /ßGMR, 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 ßGMR in an in vitro system involving immunoprecipitated ßGMR-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]