S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke

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...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (8), p.3137-3142
Hauptverfasser: SHI, Zhong-Qing, SUNICO, Carmen R, MCKERCHER, Scott R, JIANKUN CUI, FENG, Gen-Sheng, NAKAMURA, Tomohiro, LIPTON, Stuart A
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container_issue 8
container_start_page 3137
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 110
creator SHI, Zhong-Qing
SUNICO, Carmen R
MCKERCHER, Scott R
JIANKUN CUI
FENG, Gen-Sheng
NAKAMURA, Tomohiro
LIPTON, Stuart A
description 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.
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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. 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subjects active sites
Amino acids
Animals
Apoptosis
Binding sites
Biological and medical sciences
Biological Sciences
brain
Brain Ischemia - physiopathology
cell viability
Cells
chemical reactions
cysteine
Enzyme kinetics
Fundamental and applied biological sciences. Psychology
Immunohistochemistry
ischemia
MAP Kinase Signaling System
Medical sciences
Mice
neurodegenerative diseases
Neurology
neurons
Neurons - pathology
neurotoxicity
Nitric oxide
Nitric Oxide - metabolism
pathogenesis
Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism
protein-tyrosine-phosphatase
Proteins
Receptors, N-Methyl-D-Aspartate - physiology
Stroke
Stroke - physiopathology
thiols
tyrosine
Vascular diseases and vascular malformations of the nervous system
Vertebrates: nervous system and sense organs
title S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke
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