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 |
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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. 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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1215501110</identifier><identifier>PMID: 23382182</identifier><identifier>CODEN: PNASA6</identifier><language>eng</language><publisher>Washington, DC: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-02, Vol.110 (8), p.3137-3142</ispartof><rights>2014 INIST-CNRS</rights><rights>Copyright National Academy of Sciences Feb 19, 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-610ed02131fddb3c4bf8009ab1902d55cadb4aa8c95682c862f7253c95315f5a3</citedby><cites>FETCH-LOGICAL-c461t-610ed02131fddb3c4bf8009ab1902d55cadb4aa8c95682c862f7253c95315f5a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/110/8.cover.gif</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581884/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581884/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27205880$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23382182$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SHI, Zhong-Qing</creatorcontrib><creatorcontrib>SUNICO, Carmen R</creatorcontrib><creatorcontrib>MCKERCHER, Scott R</creatorcontrib><creatorcontrib>JIANKUN CUI</creatorcontrib><creatorcontrib>FENG, Gen-Sheng</creatorcontrib><creatorcontrib>NAKAMURA, Tomohiro</creatorcontrib><creatorcontrib>LIPTON, Stuart A</creatorcontrib><title>S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><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.</description><subject>active sites</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Binding sites</subject><subject>Biological and medical sciences</subject><subject>Biological Sciences</subject><subject>brain</subject><subject>Brain Ischemia - physiopathology</subject><subject>cell viability</subject><subject>Cells</subject><subject>chemical reactions</subject><subject>cysteine</subject><subject>Enzyme kinetics</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Immunohistochemistry</subject><subject>ischemia</subject><subject>MAP Kinase Signaling System</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>neurodegenerative diseases</subject><subject>Neurology</subject><subject>neurons</subject><subject>Neurons - pathology</subject><subject>neurotoxicity</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>pathogenesis</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism</subject><subject>protein-tyrosine-phosphatase</subject><subject>Proteins</subject><subject>Receptors, N-Methyl-D-Aspartate - physiology</subject><subject>Stroke</subject><subject>Stroke - physiopathology</subject><subject>thiols</subject><subject>tyrosine</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdks1v1DAQxS0EokvhzA0iISQuaWfsOOtcKlXlo0jlQ1p6thzHaV2y8WI7qPvfM9tdtoWTZfk3b-bNM2MvEY4Q5uJ4NZp0hBylBESER2yG0GBZVw08ZjMAPi9VxasD9iylGwBopIKn7IALoTgqPmPtohx9jiGtB5NdVyzOv5e8sGHM0bdTdqnIofj65f1pEZ11qxxiuXSdv2PdrfU55HDr6VwXfiyMpZLCJ3vtlt4WiYR_uufsSW-G5F7szkN2-fHDj7Pz8uLbp89npxelrWrMZY3gOuAosO-6Vtiq7RUNbFpsgHdSWtO1lTHKNrJW3Kqa93MuBV0Fyl4acchOtrqrqaUZrSMPZtCr6JcmrnUwXv_7MvprfRV-ayEVKlWRwLudQAy_JpeyXpIVNwxmdGFKGhUI2rK4Q9_8h96EKY5kTyNvSE1yAKKOt5SlBafo-v0wCHqTn97kp-_zo4pXDz3s-b-BEfB2B5hkzdBHM1qf7rk5B6nUQ6FNh31b6qu0QDEn4PUW6E3Q5iqSyOWCA9YAWNEnqsUfKqy3JA</recordid><startdate>20130219</startdate><enddate>20130219</enddate><creator>SHI, Zhong-Qing</creator><creator>SUNICO, Carmen R</creator><creator>MCKERCHER, Scott R</creator><creator>JIANKUN CUI</creator><creator>FENG, Gen-Sheng</creator><creator>NAKAMURA, Tomohiro</creator><creator>LIPTON, Stuart A</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20130219</creationdate><title>S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke</title><author>SHI, Zhong-Qing ; SUNICO, Carmen R ; MCKERCHER, Scott R ; JIANKUN CUI ; FENG, Gen-Sheng ; NAKAMURA, Tomohiro ; LIPTON, Stuart A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-610ed02131fddb3c4bf8009ab1902d55cadb4aa8c95682c862f7253c95315f5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>active sites</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Binding sites</topic><topic>Biological and medical sciences</topic><topic>Biological Sciences</topic><topic>brain</topic><topic>Brain Ischemia - physiopathology</topic><topic>cell viability</topic><topic>Cells</topic><topic>chemical reactions</topic><topic>cysteine</topic><topic>Enzyme kinetics</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Immunohistochemistry</topic><topic>ischemia</topic><topic>MAP Kinase Signaling System</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>neurodegenerative diseases</topic><topic>Neurology</topic><topic>neurons</topic><topic>Neurons - pathology</topic><topic>neurotoxicity</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - metabolism</topic><topic>pathogenesis</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism</topic><topic>protein-tyrosine-phosphatase</topic><topic>Proteins</topic><topic>Receptors, N-Methyl-D-Aspartate - physiology</topic><topic>Stroke</topic><topic>Stroke - physiopathology</topic><topic>thiols</topic><topic>tyrosine</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SHI, Zhong-Qing</creatorcontrib><creatorcontrib>SUNICO, Carmen R</creatorcontrib><creatorcontrib>MCKERCHER, Scott R</creatorcontrib><creatorcontrib>JIANKUN CUI</creatorcontrib><creatorcontrib>FENG, Gen-Sheng</creatorcontrib><creatorcontrib>NAKAMURA, Tomohiro</creatorcontrib><creatorcontrib>LIPTON, Stuart A</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SHI, Zhong-Qing</au><au>SUNICO, Carmen R</au><au>MCKERCHER, Scott R</au><au>JIANKUN CUI</au><au>FENG, Gen-Sheng</au><au>NAKAMURA, Tomohiro</au><au>LIPTON, Stuart A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2013-02-19</date><risdate>2013</risdate><volume>110</volume><issue>8</issue><spage>3137</spage><epage>3142</epage><pages>3137-3142</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><coden>PNASA6</coden><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.</abstract><cop>Washington, DC</cop><pub>National Academy of Sciences</pub><pmid>23382182</pmid><doi>10.1073/pnas.1215501110</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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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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