Hydrogen peroxide generated extracellularly by receptor–ligand interaction facilitates cell signaling

Garrett J. DeYulia, Jr. ^*, , Juan M. Cárcamo ^, , Oriana Bórquez-Ojeda , Christopher C. Shelton ^*, , and David W. Golde ^{*, , ¶ ||}

^*Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021; and Program in Molecular Pharmacology and Chemistry and Departments of Clinical Laboratories and ^¶Medicine, Memorial Sloan–Kettering Cancer Center, New York, NY 10021

Received for publication April 19, 2004.

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.

Key Words: reactive oxygen species • kinase • cytokine hematopoietin

Abbreviations: ROS, reactive oxygen species; GM-CSF, granulocyte–macrophage colony-stimulating factor; GMR, GM-CSF receptor; EGFR, EGF receptor; Jak2, Janus family tyrosine kinase 2; STAT, signal transducers and activators of transcription; MAPK, mitogen-activated protein kinase; GH, human growth hormone; ProL, prolactin; Prdx5, peroxiredoxin-5; GMRx, extracellular domain of GMR.

^|| Deceased August 9, 2004.

To whom correspondence should be addressed at: Memorial Sloan–Kettering Cancer Center, P.O. Box 451, 1275 York Avenue, New York, NY 10021. E-mail: carcamoj{at}mskcc.org.

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