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PNAS 102 (14): 5044-5049

Copyright © 2005 by the National Academy of Sciences.


CELL BIOLOGY

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

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

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

Communicated by Thomas Maniatis, Harvard University, Cambridge, MA, February 11, 2005

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


Author contributions: J.M.C. and D.W.G. designed research; G.J.D., O.B.-O., and C.C.S. performed research; G.J.D., O.B.-O., and C.C.S. contributed new reagents/analytic tools; G.J.D., J.M.C., and D.W.G. analyzed data; and G.J.D., J.M.C., and D.W.G. wrote the paper.

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; {alpha}GMRx, extracellular domain of {alpha}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.

© 2005 by The National Academy of Sciences of the USA


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