Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 102 (14): 5044-5049

Copyright © 2005 by the National Academy of Sciences.


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}

© 2005 by The National Academy of Sciences of the USA

Induction of oxidative stress by oxidized LDL via meprin{alpha}-activated epidermal growth factor receptor in macrophages.
P. Gao, X.-m. Wang, D.-h. Qian, Z.-X. Qin, J. Jin, Q. Xu, Q.-Y. Yuan, X.-J. Li, and L.-Y. Si (2013)
Cardiovasc Res 97, 533-543
   Abstract »    Full Text »    PDF »
Resveratrol blocks Akt activation in angiotensin II- or EGF-stimulated vascular smooth muscle cells in a redox-independent manner.
C. E. Schreiner, M. Kumerz, J. Gesslbauer, D. Schachner, H. Joa, T. Erker, A. G. Atanasov, E. H. Heiss, and V. M. Dirsch (2011)
Cardiovasc Res 90, 140-147
   Abstract »    Full Text »    PDF »
Reactive oxygen species are indispensable in ovulation.
K. Shkolnik, A. Tadmor, S. Ben-Dor, N. Nevo, D. Galiani, and N. Dekel (2011)
PNAS 108, 1462-1467
   Abstract »    Full Text »    PDF »
Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species.
M. D. Kraaij, N. D. L. Savage, S. W. van der Kooij, K. Koekkoek, J. Wang, J. M. van den Berg, T. H. M. Ottenhoff, T. W. Kuijpers, R. Holmdahl, C. van Kooten, et al. (2010)
PNAS 107, 17686-17691
   Abstract »    Full Text »    PDF »
Immunoglobulin Light Chains Activate Tubular Epithelial Cells through Redox Signaling.
K. Basnayake, W.-Z. Ying, P.-X. Wang, and P. W. Sanders (2010)
J. Am. Soc. Nephrol. 21, 1165-1173
   Abstract »    Full Text »    PDF »
Human IgG1 Hinge Fragmentation as the Result of H2O2-mediated Radical Cleavage.
B. Yan, Z. Yates, A. Balland, and G. R. Kleemann (2009)
J. Biol. Chem. 284, 35390-35402
   Abstract »    Full Text »    PDF »
Glutathione Peroxidase-1 Regulates Mitochondrial Function to Modulate Redox-dependent Cellular Responses.
D. E. Handy, E. Lubos, Y. Yang, J. D. Galbraith, N. Kelly, Y.-Y. Zhang, J. A. Leopold, and J. Loscalzo (2009)
J. Biol. Chem. 284, 11913-11921
   Abstract »    Full Text »    PDF »
Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation.
S. N. Mink, K. Kasian, L. E. Santos Martinez, H. Jacobs, R. Bose, Z.-Q. Cheng, and R. B. Light (2008)
Am J Physiol Heart Circ Physiol 294, H1724-H1735
   Abstract »    Full Text »    PDF »
Response to Lysyl Oxidase Inhibition Is Responsible for the Vascular Elastic Fiber Phenotype.
N. Mercier, K. El Hadri, M. Osborne-Pellegrin, J. Nehme, C. Perret, C. Labat, V. Regnault, J.-M. D. Lamaziere, P. Challande, B. Feve, et al. (2008)
Hypertension 51, e14
   Full Text »    PDF »
Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced c-Jun NH2-terminal Kinase Activation and Apoptosis.
P. J. Nadeau, S. J. Charette, M. B. Toledano, and J. Landry (2007)
Mol. Biol. Cell 18, 3903-3913
   Abstract »    Full Text »    PDF »
Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock.
C.-S. Yang, D.-S. Lee, C.-H. Song, S.-J. An, S. Li, J.-M. Kim, C. S. Kim, D. G. Yoo, B. H. Jeon, H.-Y. Yang, et al. (2007)
J. Exp. Med. 204, 583-594
   Abstract »    Full Text »    PDF »
Diesel exhaust particulate-induced activation of Stat3 requires activities of EGFR and Src in airway epithelial cells.
D. Cao, T. L. Tal, L. M. Graves, I. Gilmour, W. Linak, W. Reed, P. A. Bromberg, and J. M. Samet (2007)
Am J Physiol Lung Cell Mol Physiol 292, L422-L429
   Abstract »    Full Text »    PDF »
Interference between Streptococcus pneumoniae and Staphylococcus aureus: In Vitro Hydrogen Peroxide-Mediated Killing by Streptococcus pneumoniae.
G. Regev-Yochay, K. Trzcinski, C. M. Thompson, R. Malley, and M. Lipsitch (2006)
J. Bacteriol. 188, 4996-5001
   Abstract »    Full Text »    PDF »
Really outside signaling.
W. A. Wells (2005)
J. Cell Biol. 169, 215
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882