title: Hydrogen peroxide generated extracellularly by receptor-ligand interaction facilitates cell signaling.
abstract: Reactive oxygen species (ROS) are key components of postreceptor intracellular signaling pathways; however, the role of ROS in signal initiation is uncertain. We discovered that receptor-ligand interaction caused the generation of hydrogen peroxide (H2O2). Using members of the hematopoietin receptor superfamily, as well as EGF receptor, we show that H2O2 is generated by specific receptor-ligand interaction in cells and in cell-free systems. With cognate ligand, the extracellular domain of the receptor was sufficient for H2O2 generation. We also found that production of H2O2 was diminished in a granulocyte-macrophage colony-stimulating factor receptor mutant unable to bind ligand. Exogenously added H2O2 induced signaling in the absence of ligand, whereas catalase and a membrane-bound peroxiredoxin inhibited ligand-dependent signaling. Our results suggest that H2O2 produced by receptor-ligand interaction is involved as a chemical mediator that facilitates cell signaling.
authors.affiliation: Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: DeYulia
authors.forename: Juan M
authors.initials: JM
authors.lastname: Cárcamo
authors.forename: Oriana
authors.initials: O
authors.lastname: Bórquez-Ojeda
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Shelton
authors.forename: David W
authors.initials: DW
authors.lastname: Golde
mesh_terms: D001483:Base Sequence; D002374:Catalase / Q000494:pharmacology; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D066298:In Vitro Techniques; D008024:Ligands; D008954:Models, Biological; D009154:Mutation; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism; D054464:Peroxiredoxins; D021122:Protein Subunits; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D008024:Ligands; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006861:Hydrogen Peroxide; D010544:Peroxidases; D054464:Peroxiredoxins; D002374:Catalase; D066246:ErbB Receptors