Table of Contents
Journal of Signal Transduction
Volume 2011, Article ID 636951, 15 pages
Research Article

Repetitive Peroxide Exposure Reveals Pleiotropic Mitogen-Activated Protein Kinase Signaling Mechanisms

1Receptor Pharmacology Unit, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
2Miller School of Medicine, University of Miami, Miami, FL 33136, USA
3Metabolism Unit, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA

Received 14 August 2010; Accepted 28 September 2010

Academic Editor: Wan-Wan Lin

Copyright © 2011 Wayne Chadwick et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Oxidative stressors such as hydrogen peroxide control the activation of many interconnected signaling systems and are implicated in neurodegenerative disease etiology. Application of hydrogen peroxide to PC12 cells activated multiple tyrosine kinases (c-Src, epidermal growth factor receptor (EGFR), and Pyk2) and the serine-threonine kinase ERK1/2. Peroxide-induced ERK1/2 activation was sensitive to intracellular calcium chelation and EGFR and c-Src kinase inhibition. Acute application and removal of peroxide allowed ERK1/2 activity levels to rapidly subside to basal serum-deprived levels. Using this protocol, we demonstrated that ERK1/2 activation tachyphylaxis developed upon repeated peroxide exposures. This tachyphylaxis was independent of c-Src/Pyk2 tyrosine phosphorylation but was associated with a progressive reduction of peroxide-induced EGFR tyrosine phosphorylation, EGFR interaction with growth factor receptor binding protein 2, and a redistribution of EGFR from the plasma membrane to the cytoplasm. Our data indicates that components of peroxide-induced ERK1/2 cascades are differentially affected by repeated exposures, indicating that oxidative signaling may be contextually variable.