S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke
Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 4, 2013 (received for review September 6, 2012)
Abstract
Overproduction of nitric oxide (NO) can cause neuronal damage, contributing to the pathogenesis of several neurodegenerative diseases and stroke (i.e., focal cerebral ischemia). NO can mediate neurotoxic effects at least in part via protein S-nitrosylation, a reaction that covalently attaches NO to a cysteine thiol (or thiolate anion) to form an S-nitrosothiol. Recently, the tyrosine phosphatase Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) and its downstream pathways have emerged as important mediators of cell survival. Here we report that in neurons and brain tissue NO can S-nitrosylate SHP-2 at its active site cysteine, forming S-nitrosylated SHP-2 (SNO–SHP-2). We found that NMDA exposure in vitro and transient focal cerebral ischemia in vivo resulted in increased levels of SNO–SHP-2. S-Nitrosylation of SHP-2 inhibited its phosphatase activity, blocking downstream activation of the neuroprotective physiological ERK1/2 pathway, thus increasing susceptibility to NMDA receptor-mediated excitotoxicity. These findings suggest that formation of SNO–SHP-2 represents a key chemical reaction contributing to excitotoxic damage in stroke and potentially other neurological disorders.
Acknowledgments
We thank Traci Fang-Newmeyer for preparing cultures. This work was supported in part by a postdoctoral fellowship of the Spanish Ministry of Education and Science Programa Nacional de Movilidad de Recursos Humanos del Plan Nacional de Investigación, Desarrollo e innovación 2008–2011 (to C.R.S.); and National Institutes of Health Grants R01 EY05477, P01 HD29687, P01 ES016738, and P30 NS076411 (to S.A.L.).
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Cover image: Pictured is a pseudo-colored confocal microscopic image of the trigeminal nerve from a newborn pig. Leah R. Reznikov et al. investigated whether disruption of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which causes cystic fibrosis, directly influences nervous system function. Using a porcine model of cystic fibrosis, the authors found that loss of CFTR resulted in myelin sheath abnormalities, reduced axon density, and slowed nerve conduction velocity—changes that are consistent with reports of neuropathy in people with cystic fibrosis. See the article by Reznikov et al. on pages 3083–3088. Image courtesy of Leah R. Reznikov.
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Published online: February 4, 2013
Published in issue: February 19, 2013
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Acknowledgments
We thank Traci Fang-Newmeyer for preparing cultures. This work was supported in part by a postdoctoral fellowship of the Spanish Ministry of Education and Science Programa Nacional de Movilidad de Recursos Humanos del Plan Nacional de Investigación, Desarrollo e innovación 2008–2011 (to C.R.S.); and National Institutes of Health Grants R01 EY05477, P01 HD29687, P01 ES016738, and P30 NS076411 (to S.A.L.).
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*This Direct Submission article had a prearranged editor.
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The authors declare no conflict of interest.
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