Hydrogen Peroxide Generated Extracellularly by Receptor-Ligand Interaction Facilitates Cell Signaling

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 H2O2is 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 H2O2generation. We also found that production of H2O2was diminished in a granulocyte-macrophage colony-stimulating factor receptor mutant unable to bind ligand. Exogenously added H2O2induced signaling in the absence of ligand, whereas catalase and a membrane-bound peroxiredoxin inhibited ligand-dependent signaling. Our results suggest that H2O2produced by receptor-ligand interaction is involved as a chemical mediator that facilitates cell signaling.