{"id":"https://openalex.org/W2020583309","doi":"https://doi.org/10.1074/jbc.m410771200","title":"Reversible Oxidation of ERK-directed Protein Phosphatases Drives Oxidative Toxicity in Neurons","display_name":"Reversible Oxidation of ERK-directed Protein Phosphatases Drives Oxidative Toxicity in Neurons","publication_year":2004,"publication_date":"2004-12-04","ids":{"openalex":"https://openalex.org/W2020583309","doi":"https://doi.org/10.1074/jbc.m410771200","mag":"2020583309","pmid":"https://pubmed.ncbi.nlm.nih.gov/15579467"},"language":"en","primary_location":{"id":"doi:10.1074/jbc.m410771200","doi":"https://doi.org/10.1074/jbc.m410771200","is_oa":true,"landing_page_url":"https://doi.org/10.1074/jbc.m410771200","pdf_url":null,"source":{"id":"https://openalex.org/S140251998","display_name":"Journal of Biological Chemistry","issn_l":"0021-9258","issn":["0021-9258","1067-8816","1083-351X"],"is_oa":false,"is_in_doaj":true,"is_core":true,"listed_in":["anvur-scientific","cwts-core","doaj","dongbi-b","doyens","jufo-2","ki-jl-2","medline","norway-2","poland-100","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Biological Chemistry","raw_type":"journal-article"},"volume":null,"type":"article","is_traditional":true,"indexed_in":["crossref","doaj","pubmed"],"open_access":{"is_oa":true,"oa_status":"hybrid","oa_url":"https://doi.org/10.1074/jbc.m410771200","any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5081662349","display_name":"David J. Levinthal","orcid":"https://orcid.org/0000-0001-8453-8382","observed_orcids":["https://orcid.org/0000-0001-8453-8382"]},"institutions":[{"id":"https://openalex.org/I170201317","display_name":"University of Pittsburgh","ror":"https://ror.org/01an3r305","country_code":"US","type":"education","lineage":["https://openalex.org/I170201317"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"David J. Levinthal","raw_affiliation_strings":["Center for Neuroscience and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA","Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Center for Neuroscience and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA","institution_ids":["https://openalex.org/I170201317"]},{"raw_affiliation_string":"Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261","institution_ids":["https://openalex.org/I170201317"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5066345618","display_name":"Donald Benedict DeFranco","orcid":"https://orcid.org/0000-0002-7662-4886","observed_orcids":["https://orcid.org/0000-0002-7662-4886"]},"institutions":[{"id":"https://openalex.org/I170201317","display_name":"University of Pittsburgh","ror":"https://ror.org/01an3r305","country_code":"US","type":"education","lineage":["https://openalex.org/I170201317"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Donald B. DeFranco","raw_affiliation_strings":["Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261","Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261","institution_ids":["https://openalex.org/I170201317"]},{"raw_affiliation_string":"Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261","institution_ids":["https://openalex.org/I170201317"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":["https://openalex.org/A5066345618"],"corresponding_institution_ids":["https://openalex.org/I170201317"],"apc_list":{"value":3430,"currency":"USD","value_usd":3430},"apc_paid":{"value":3430,"currency":"USD","value_usd":3430},"fwci":2.6351,"has_fulltext":false,"cited_by_count":126,"citation_normalized_percentile":{"value":0.90488866,"is_in_top_1_percent":false,"is_in_top_10_percent":true},"cited_by_percentile_year":{"min":88,"max":99},"biblio":{"volume":"280","issue":"7","first_page":"5875","last_page":"5883"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T12104","display_name":"Protein Tyrosine Phosphatases","score":0.8062000274658203,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T12104","display_name":"Protein Tyrosine Phosphatases","score":0.8062000274658203,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11884","display_name":"Redox biology and oxidative stress","score":0.1662999987602234,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10169","display_name":"Protein Kinase Regulation and GTPase Signaling","score":0.017000000923871994,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/erk1-2","display_name":"ERK1/2","score":0.8859999775886536},{"id":"https://openalex.org/keywords/protein-phosphatase","display_name":"protein phosphatase","score":0.859000027179718},{"id":"https://openalex.org/keywords/oxidative-stress","display_name":"oxidative stress","score":0.8899999856948853},{"id":"https://openalex.org/keywords/glutamate-excitotoxicity","display_name":"glutamate excitotoxicity","score":0.7440000176429749},{"id":"https://openalex.org/keywords/glutathione-depletion","display_name":"glutathione depletion","score":0.8420000076293945},{"id":"https://openalex.org/keywords/mkp-3","display_name":"MKP-3","score":0.949999988079071},{"id":"https://openalex.org/keywords/erk-nuclear-translocation","display_name":"ERK nuclear translocation","score":0.7490000128746033},{"id":"https://openalex.org/keywords/neuroprotection","display_name":"neuroprotection","score":0.7599999904632568},{"id":"https://openalex.org/keywords/neuronal-death","display_name":"neuronal cell death","score":0.6850000023841858},{"id":"https://openalex.org/keywords/reactive-oxygen-species","display_name":"reactive oxygen species","score":0.703000009059906},{"id":"https://openalex.org/keywords/mapk-signaling","display_name":"MAPK signaling","score":0.5450000166893005}],"concepts":[{"id":"https://openalex.org/C57600042","wikidata":"https://www.wikidata.org/wiki/Q227564","display_name":"Oxidative phosphorylation","level":2,"score":0.6575330495834351},{"id":"https://openalex.org/C178666793","wikidata":"https://www.wikidata.org/wiki/Q422476","display_name":"Phosphatase","level":3,"score":0.6139017939567566},{"id":"https://openalex.org/C57074206","wikidata":"https://www.wikidata.org/wiki/Q14197552","display_name":"MAPK/ERK pathway","level":3,"score":0.5688261389732361},{"id":"https://openalex.org/C29730261","wikidata":"https://www.wikidata.org/wiki/Q274160","display_name":"Toxicity","level":2,"score":0.5605491399765015},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.4966636300086975},{"id":"https://openalex.org/C2776151105","wikidata":"https://www.wikidata.org/wiki/Q898814","display_name":"Oxidative stress","level":2,"score":0.4889909029006958},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.4135971963405609},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.3989151418209076},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.31025177240371704},{"id":"https://openalex.org/C11960822","wikidata":"https://www.wikidata.org/wiki/Q242736","display_name":"Phosphorylation","level":2,"score":0.26981645822525024},{"id":"https://openalex.org/C178790620","wikidata":"https://www.wikidata.org/wiki/Q11351","display_name":"Organic chemistry","level":1,"score":0.0}],"mesh":[{"descriptor_ui":"D000818","descriptor_name":"Animals","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D002460","descriptor_name":"Cell Line","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D002478","descriptor_name":"Cells, Cultured","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D002540","descriptor_name":"Cerebral Cortex","qualifier_ui":"Q000166","qualifier_name":"cytology","is_major_topic":false},{"descriptor_ui":"D009474","descriptor_name":"Neurons","qualifier_ui":"Q000166","qualifier_name":"cytology","is_major_topic":false},{"descriptor_ui":"D009474","descriptor_name":"Neurons","qualifier_ui":"Q000187","qualifier_name":"drug effects","is_major_topic":false},{"descriptor_ui":"D009474","descriptor_name":"Neurons","qualifier_ui":"Q000201","qualifier_name":"enzymology","is_major_topic":false},{"descriptor_ui":"D009474","descriptor_name":"Neurons","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D010084","descriptor_name":"Oxidation-Reduction","qualifier_ui":"Q000187","qualifier_name":"drug effects","is_major_topic":false},{"descriptor_ui":"D010749","descriptor_name":"Phosphoprotein Phosphatases","qualifier_ui":"Q000037","qualifier_name":"antagonists & inhibitors","is_major_topic":false},{"descriptor_ui":"D010749","descriptor_name":"Phosphoprotein Phosphatases","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D010766","descriptor_name":"Phosphorylation","qualifier_ui":"Q000187","qualifier_name":"drug effects","is_major_topic":false},{"descriptor_ui":"D014638","descriptor_name":"Vanadates","qualifier_ui":"Q000494","qualifier_name":"pharmacology","is_major_topic":false},{"descriptor_ui":"D017027","descriptor_name":"Protein Tyrosine Phosphatases","qualifier_ui":"Q000235","qualifier_name":"genetics","is_major_topic":false},{"descriptor_ui":"D017027","descriptor_name":"Protein Tyrosine Phosphatases","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D017207","descriptor_name":"Rats, Sprague-Dawley","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D018384","descriptor_name":"Oxidative Stress","qualifier_ui":"Q000187","qualifier_name":"drug effects","is_major_topic":true},{"descriptor_ui":"D018698","descriptor_name":"Glutamic Acid","qualifier_ui":"Q000494","qualifier_name":"pharmacology","is_major_topic":false},{"descriptor_ui":"D019319","descriptor_name":"Okadaic Acid","qualifier_ui":"Q000494","qualifier_name":"pharmacology","is_major_topic":false},{"descriptor_ui":"D048049","descriptor_name":"Extracellular Signal-Regulated MAP Kinases","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D051381","descriptor_name":"Rats","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false}],"locations_count":2,"locations":[{"id":"doi:10.1074/jbc.m410771200","doi":"https://doi.org/10.1074/jbc.m410771200","is_oa":true,"landing_page_url":"https://doi.org/10.1074/jbc.m410771200","pdf_url":null,"source":{"id":"https://openalex.org/S140251998","display_name":"Journal of Biological Chemistry","issn_l":"0021-9258","issn":["0021-9258","1067-8816","1083-351X"],"is_oa":false,"is_in_doaj":true,"is_core":true,"listed_in":["anvur-scientific","cwts-core","doaj","dongbi-b","doyens","jufo-2","ki-jl-2","medline","norway-2","poland-100","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Biological Chemistry","raw_type":"journal-article"},{"id":"pmid:15579467","doi":null,"is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/15579467","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"The Journal of biological chemistry","raw_type":"Journal Article"}],"best_oa_location":{"id":"doi:10.1074/jbc.m410771200","doi":"https://doi.org/10.1074/jbc.m410771200","is_oa":true,"landing_page_url":"https://doi.org/10.1074/jbc.m410771200","pdf_url":null,"source":{"id":"https://openalex.org/S140251998","display_name":"Journal of Biological Chemistry","issn_l":"0021-9258","issn":["0021-9258","1067-8816","1083-351X"],"is_oa":false,"is_in_doaj":true,"is_core":true,"listed_in":["anvur-scientific","cwts-core","doaj","dongbi-b","doyens","jufo-2","ki-jl-2","medline","norway-2","poland-100","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Biological Chemistry","raw_type":"journal-article"},"sustainable_development_goals":[{"display_name":"Good health and well-being","id":"https://metadata.un.org/sdg/3","score":0.5683000087738037}],"study_designs":[],"awards":[{"id":"https://openalex.org/G1125377667","display_name":"OXIDATIVE STRESS AND NEURODEGENERATION","funder_award_id":"R01NS038319","funder_id":"https://openalex.org/F4320337359","funder_display_name":"National Institute of Neurological Disorders and Stroke"},{"id":"https://openalex.org/G5371498421","display_name":"The Role of MKPs in Oxidative Neuronal Cell Death","funder_award_id":"F30NS043824","funder_id":"https://openalex.org/F4320337359","funder_display_name":"National Institute of Neurological Disorders and Stroke"}],"funders":[{"id":"https://openalex.org/F4320337359","display_name":"National Institute of Neurological Disorders and Stroke","ror":"https://ror.org/01s5ya894"}],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":42,"referenced_works":["https://openalex.org/W1517407659","https://openalex.org/W1525431558","https://openalex.org/W1597498191","https://openalex.org/W1852105575","https://openalex.org/W1922083656","https://openalex.org/W1969294711","https://openalex.org/W1984875486","https://openalex.org/W1984909573","https://openalex.org/W1990362370","https://openalex.org/W1994148496","https://openalex.org/W1994662389","https://openalex.org/W2009940961","https://openalex.org/W2010522496","https://openalex.org/W2011371104","https://openalex.org/W2016003408","https://openalex.org/W2016293448","https://openalex.org/W2021346058","https://openalex.org/W2023847928","https://openalex.org/W2028407281","https://openalex.org/W2043549608","https://openalex.org/W2046431926","https://openalex.org/W2048996120","https://openalex.org/W2050252881","https://openalex.org/W2051095677","https://openalex.org/W2052464531","https://openalex.org/W2056470407","https://openalex.org/W2057593147","https://openalex.org/W2064298888","https://openalex.org/W2065568194","https://openalex.org/W2083076387","https://openalex.org/W2083875726","https://openalex.org/W2090741482","https://openalex.org/W2091864083","https://openalex.org/W2101744311","https://openalex.org/W2101803513","https://openalex.org/W2109734459","https://openalex.org/W2132951626","https://openalex.org/W2135250775","https://openalex.org/W2136095930","https://openalex.org/W2137324819","https://openalex.org/W2149884899","https://openalex.org/W2161667640"],"related_works":["https://openalex.org/W93358848","https://openalex.org/W58084357","https://openalex.org/W2146267072","https://openalex.org/W1994148496","https://openalex.org/W7096526530","https://openalex.org/W1990362370","https://openalex.org/W2135250775","https://openalex.org/W1988264669","https://openalex.org/W2004950881","https://openalex.org/W2230330403"],"abstract_inverted_index":{"Oxidative":[0],"stress":[1],"links":[2],"diverse":[3],"neuropathological":[4],"conditions":[5],"that":[6,23,72,109,130,231],"include":[7],"stroke,":[8],"Parkinson's":[9],"disease,":[10],"and":[11,14,41,119,124,148,160,172,185,237],"Alzheimer's":[12],"disease":[13],"has":[15],"been":[16],"modeled":[17],"in":[18,49,95,151,155,161,180,216,243],"vitro":[19],"with":[20],"various":[21],"paradigms":[22],"lead":[24],"to":[25,51,233],"neuronal":[26,157],"cell":[27,47,158],"death":[28,48],"following":[29],"the":[30,54,80,87,117,134,140,167,192,206,222],"increased":[31],"accumulation":[32,239],"of":[33,53,63,79,115,136,142,166,191,224],"reactive":[34],"oxygen":[35],"species.":[36],"For":[37],"example,":[38],"immortalized":[39],"neurons":[40,45,98,152],"immature":[42],"primary":[43,162,186],"cortical":[44,163],"undergo":[46],"response":[50],"depletion":[52],"antioxidant":[55],"glutathione,":[56],"which":[57,90,196],"can":[58],"be":[59],"elicited":[60],"by":[61,89],"administration":[62],"glutamate":[64],"at":[65],"high":[66],"concentrations.":[67],"We":[68],"have":[69],"demonstrated":[70],"previously":[71],"this":[73,91,105],"glutamate-induced":[74],"oxidative":[75,111,149,214,241],"toxicity":[76,150,215,242],"requires":[77],"activation":[78,92,147,236],"mitogen-activated":[81],"protein":[82],"kinase":[83],"member":[84],"ERK1/2,":[85],"but":[86,200],"mechanisms":[88],"takes":[93],"place":[94],"oxidatively":[96],"stressed":[97],"are":[99,122],"still":[100],"not":[101],"fully":[102],"known.":[103],"In":[104],"study,":[106],"we":[107],"demonstrate":[108],"during":[110,240],"stress,":[112],"ERK-directed":[113,143,226],"phosphatases":[114,144,227],"both":[116],"serine/threonine-":[118],"tyrosine-directed":[120],"classes":[121],"selectively":[123],"reversibly":[125],"inhibited":[126],"via":[127],"a":[128,156,229],"mechanism":[129,230],"is":[131],"dependent":[132],"upon":[133],"oxidation":[135],"cysteine":[137],"thiols.":[138],"Furthermore,":[139],"impact":[141],"on":[145],"ERK1/2":[146,198,210,235],"was":[153],"tested":[154],"line":[159],"cultures.":[164],"Overexpression":[165],"highly":[168],"ERK-specific":[169],"phosphatase":[170],"MKP3":[171,176,193],"its":[173,202],"catalytic":[174],"mutant,":[175,195],"C293S,":[177],"were":[178],"neuroprotective":[179,189],"transiently":[181],"transfected":[182],"HT22":[183],"cells":[184],"neurons.":[187,217,244],"The":[188],"effect":[190],"C293S":[194],"enhances":[197],"phosphorylation":[199],"blocks":[201],"nuclear":[203,211,238],"translocation,":[204],"demonstrates":[205],"necessity":[207],"for":[208,213],"active":[209],"localization":[212],"Together,":[218],"these":[219],"data":[220],"implicate":[221],"inhibition":[223],"endogenous":[225],"as":[228],"leads":[232],"aberrant":[234]},"counts_by_year":[{"year":2026,"cited_by_count":2},{"year":2025,"cited_by_count":2},{"year":2024,"cited_by_count":1},{"year":2023,"cited_by_count":2},{"year":2022,"cited_by_count":4},{"year":2021,"cited_by_count":7},{"year":2020,"cited_by_count":3},{"year":2019,"cited_by_count":3},{"year":2018,"cited_by_count":5},{"year":2017,"cited_by_count":4},{"year":2016,"cited_by_count":3},{"year":2015,"cited_by_count":3},{"year":2014,"cited_by_count":6},{"year":2013,"cited_by_count":9},{"year":2012,"cited_by_count":5}],"updated_date":"2026-11-07T11:25:07.637180","created_date":"2016-06-24T00:00:00"}