2019
Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing
Dedek A, Xu J, Kandegedara CM, Lorenzo LÉ, Godin AG, De Koninck Y, Lombroso PJ, Tsai EC, Hildebrand ME. Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing. Brain 2019, 142: 1535-1546. PMID: 31135041, PMCID: PMC6536915, DOI: 10.1093/brain/awz105.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate receptorsLaminae INMDAR responsesDorsal horn synapsesSpinal pain processingNerve injury modelSpinal dorsal hornSynaptic NMDAR responsesTyrosine phosphatase STEP61Loss of inhibitionBehavioral hypersensitivityInflammatory painNeuropathic painDorsal hornPain statesPathological painPain targetsChronic painPain processingInjury modelAssociated downregulationRodent modelsReceptor potentiationPainSTEP61 activity
2017
Synaptic NMDA Receptor Activation Induces Ubiquitination and Degradation of STEP61
Xu J, Kurup P, Nairn AC, Lombroso PJ. Synaptic NMDA Receptor Activation Induces Ubiquitination and Degradation of STEP61. Molecular Neurobiology 2017, 55: 3096-3111. PMID: 28466270, PMCID: PMC5668205, DOI: 10.1007/s12035-017-0555-x.Peer-Reviewed Original ResearchConceptsMK-801-treated miceProtein tyrosine Phosphatase 61GluN1/GluN2B receptorsNMDA receptor signalingD-serine treatmentMouse frontal cortexNMDAR signalingSynaptic NMDARsCortical samplesHuman schizophreniaTherapeutic effectFrontal cortexGluN2B receptorsSynaptic plasticityNeurological disordersCognitive deficitsReceptor signalingD-serineSTEP61SchizophreniaBicucullineMiceProteasomal degradationSurface localizationSignaling
2016
Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models
Xu J, Hartley BJ, Kurup P, Phillips A, Topol A, Xu M, Ononenyi C, Foscue E, Ho SM, Baguley TD, Carty N, Barros CS, Müller U, Gupta S, Gochman P, Rapoport J, Ellman JA, Pittenger C, Aronow B, Nairn AC, Nestor MW, Lombroso PJ, Brennand KJ. Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Molecular Psychiatry 2016, 23: 271-281. PMID: 27752082, PMCID: PMC5395367, DOI: 10.1038/mp.2016.163.Peer-Reviewed Original ResearchConceptsBrain-specific tyrosine phosphataseDephosphorylation of GluN2BExtracellular signal-regulated kinase 1/2Signal-regulated kinase 1/2Glutamate receptor internalizationPluripotent stem cellsKnockout mouse modelTyrosine phosphataseMouse modelKinase 1/2Receptor internalizationImportant regulatorGenetic reductionLoss of NMDARsStem cellsN-methyl DPharmacological inhibitionProtein levelsSynaptic functionSTEP61Patient cohortForebrain neuronsBehavioral deficitsExcitatory neuronsSchizophrenia model
2015
Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice
Xu J, Kurup P, Baguley TD, Foscue E, Ellman JA, Nairn AC, Lombroso PJ. Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice. Cellular And Molecular Life Sciences 2015, 73: 1503-1514. PMID: 26450419, PMCID: PMC4801664, DOI: 10.1007/s00018-015-2057-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzothiepinsBrain-Derived Neurotrophic FactorCells, CulturedCognition DisordersCREB-Binding ProteinDown-RegulationMaleMiceMice, Inbred C57BLMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Motor ActivityNeuronsPhencyclidinePhosphorylationProtein Tyrosine PhosphatasesReceptors, N-Methyl-D-AspartateRNA InterferenceUbiquitinationConceptsBrain-derived neurotrophic factorBDNF expressionProtein tyrosine Phosphatase 61Cognitive deficitsPCP-induced reductionPCP-treated micePhencyclidine-treated micePCP-induced increasePCP-induced hyperlocomotionTyrosine phosphatase STEP61STEP61 levelsBDNF transcriptionNeurotrophic factorNMDAR antagonistsCortical culturesCortical neuronsCNS disordersSynaptic strengtheningPsychotic episodeRodent modelsBrain disordersPharmacologic inhibitionSTEP61SchizophreniaCognitive functioningRegulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity
Jang SS, Royston SE, Xu J, Cavaretta JP, Vest MO, Lee KY, Lee S, Jeong HG, Lombroso PJ, Chung HJ. Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity. Molecular Brain 2015, 8: 55. PMID: 26391783, PMCID: PMC4578242, DOI: 10.1186/s13041-015-0148-4.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate receptorsHomeostatic synaptic plasticitySynaptic plasticityTyrosine phosphorylationActivity blockadeDephosphorylation of GluN2BSynaptic scalingProtein tyrosine phosphataseLevel of GluN2BProlonged activity blockadeExcitatory synaptic transmissionHippocampal cultured neuronsIsoxazolepropionic acid (AMPA) receptorsNMDAR subunit GluN2BActivity-dependent regulationTyrosine phosphataseSTEP61 levelsHomeostatic stabilizationSynaptic transmissionExcitatory synapsesAMPA receptorsGluA2 expressionPostsynaptic accumulationCultured neuronsAcid receptorsBDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome
Saavedra A, Puigdellívol M, Tyebji S, Kurup P, Xu J, Ginés S, Alberch J, Lombroso PJ, Pérez-Navarro E. BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome. Molecular Neurobiology 2015, 53: 4261-4273. PMID: 26223799, PMCID: PMC4738169, DOI: 10.1007/s12035-015-9335-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain-Derived Neurotrophic FactorCerebral CortexExtracellular Signal-Regulated MAP KinasesHippocampusMembrane PotentialsMiceNeostriatumNerve Growth FactorNeuronsNeurotrophin 3Phospholipase C gammaPhosphorylationProteasome Endopeptidase ComplexProtein Tyrosine Phosphatases, Non-ReceptorProteolysisReceptors, N-Methyl-D-AspartateUbiquitinationConceptsBrain-derived neurotrophic factorSTEP61 levelsCortical neuronsUbiquitin-proteasome systemStriatal-enriched protein tyrosine phosphatasePrimary cortical neuronsLevels/activitiesNerve growth factorNeurotrophic factorNeurotrophin-3Cultured striatalHippocampal neuronsCell depolarizationGrowth factorERK1/2 phosphorylationNeuronsStriatalTyrosine kinasePhospholipase C-gammaC gammaDifferent mechanismsLevelsBlockadeGluN2BProtein tyrosine phosphatase
2014
Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease
Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, Kanyo J, Zhang Y, Seyb K, Ononenyi C, Foscue E, Anderson GM, Gresack J, Cuny GD, Glicksman MA, Greengard P, Lam TT, Tautz L, Nairn AC, Ellman JA, Lombroso PJ. Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease. PLOS Biology 2014, 12: e1001923. PMID: 25093460, PMCID: PMC4122355, DOI: 10.1371/journal.pbio.1001923.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmino Acid SequenceAnimalsBenzothiepinsCatalytic DomainCell DeathCerebral CortexCognition DisordersCysteineDisease Models, AnimalEnzyme InhibitorsHigh-Throughput Screening AssaysHumansMaleMice, Inbred C57BLMice, KnockoutMolecular Sequence DataNeuronsPhosphorylationPhosphotyrosineProtein Tyrosine Phosphatases, Non-ReceptorSubstrate SpecificityConceptsInhibitors of stepsSpecificity of inhibitorsIsoxazolepropionic acid receptor (AMPAR) traffickingCatalytic cysteinePTP inhibitorsTyrosine phosphataseTyrosine phosphorylationSecondary assaysSTEP KO miceReceptor traffickingFirst large-scale effortN-methyl-D-aspartate receptorsPyk2 activitySTEP inhibitorLarge-scale effortsNovel therapeutic targetSynaptic functionAlzheimer's diseaseNeurodegenerative disordersCortical cellsTherapeutic targetERK1/2Specificity experimentsPhosphataseInhibitorsInhibition of striatal‐enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption
Darcq E, Hamida SB, Wu S, Phamluong K, Kharazia V, Xu J, Lombroso P, Ron D. Inhibition of striatal‐enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption. Journal Of Neurochemistry 2014, 129: 1024-1034. PMID: 24588427, PMCID: PMC4055745, DOI: 10.1111/jnc.12701.Peer-Reviewed Original ResearchMeSH KeywordsAlcohol DrinkingAnimalsAntibodies, BlockingBlotting, WesternChoice BehaviorDown-RegulationEnzyme InhibitorsGene Knockdown TechniquesImmunohistochemistryLentivirusMaleMiceMice, Inbred C57BLMotor ActivityNeostriatumPhosphorylationProtein Tyrosine PhosphatasesQuinineRNA, Small InterferingSaccharin
2012
The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications
Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ. The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Translational Psychiatry 2012, 2: e137-e137. PMID: 22781170, PMCID: PMC3410627, DOI: 10.1038/tp.2012.63.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate receptorsSTEP61 levelsSurface expressionPostmortem anterior cingulate cortexGluN2B-containing N-methyl-D-aspartate receptorsGluN1/GluN2B receptorsMK-801 treatmentPathophysiology of schizophreniaAnterior cingulate cortexSTEP knockout miceDorsolateral prefrontal cortexChronic administrationChronic treatmentNeuroleptic treatmentAntipsychotic medicationGlutamatergic functionMK-801Glutamate hypothesisMedications resultsTyrosine phosphatase STEPGlutamatergic signalingKnockout miceGluN2B receptorsCingulate cortexSynaptic plasticityStriatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity*
Xu J, Kurup P, Bartos JA, Patriarchi T, Hell JW, Lombroso PJ. Striatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity*. Journal Of Biological Chemistry 2012, 287: 20942-20956. PMID: 22544749, PMCID: PMC3375518, DOI: 10.1074/jbc.m112.368654.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseProtein tyrosine phosphataseN-Methyl-d-aspartate (NMDA) Receptor TraffickingFocal adhesion kinase familyPyk2 activationProline-rich tyrosine kinase 2Pyk2 kinase activityTyrosine kinase 2Kinase familyKinase membersCytoskeletal reorganizationDiverse functionsKinase activitySTEP KO miceReceptor traffickingKinase 2Tyrosine sitesPyk2 activityEnhanced phosphorylationCell adhesionPyk2PhosphorylationFunctional studiesHematopoietic cellsPostsynaptic densityCalpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model
Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA. Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model. Human Molecular Genetics 2012, 21: 3739-3752. PMID: 22523092, PMCID: PMC3412376, DOI: 10.1093/hmg/dds154.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalpainCoculture TechniquesDisease Models, AnimalEnzyme ActivationEnzyme InhibitorsHuntington DiseaseIon Channel GatingMiceModels, BiologicalNeostriatumNeuronsPhosphorylationPhosphotyrosineProtein TransportProtein Tyrosine Phosphatases, Non-ReceptorReceptors, N-Methyl-D-AspartateSynapsesConceptsYAC128 striatumProtein tyrosine phosphatase activationNMDAR localizationCalpain cleavageProtein tyrosine phosphataseTyrosine phosphatase activationEarly synaptic defectsWhole-cell NMDAR currentsDisease mouse modelGluN2B expressionNMDA receptor traffickingMutant huntingtin proteinCalpain inhibitionTyrosine phosphataseHuntington's diseaseFull-length mhttPlasma membranePhosphatase activationC-terminusReceptor traffickingNMDAR traffickingPolyglutamine repeatsMouse modelHuntingtin proteinNMDA receptor localization
2011
Striatal-Enriched Protein Tyrosine Phosphatase Expression and Activity in Huntington's Disease: A STEP in the Resistance to Excitotoxicity
Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas JJ, Lombroso PJ, Alberch J, Pérez-Navarro E. Striatal-Enriched Protein Tyrosine Phosphatase Expression and Activity in Huntington's Disease: A STEP in the Resistance to Excitotoxicity. Journal Of Neuroscience 2011, 31: 8150-8162. PMID: 21632937, PMCID: PMC3472648, DOI: 10.1523/jneurosci.3446-10.2011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCalcineurinCell DeathDisease Models, AnimalGene Expression RegulationGene Products, tatHuntingtin ProteinHuntington DiseaseMiceMice, Neurologic MutantsMice, TransgenicMicroinjectionsNerve Tissue ProteinsNuclear ProteinsPhosphorylationProtein Tyrosine Phosphatases, Non-ReceptorQuinolinic AcidSignal TransductionConceptsStriatal-enriched protein tyrosine phosphataseCell deathSTEP expressionPhosphorylation levelsProtein Tyrosine Phosphatase ExpressionProtein tyrosine phosphataseSTEP phosphorylationTyrosine phosphataseProtein kinasePhosphorylated ERK2Phosphatase expressionHuntington's diseaseSTEP proteinMutant huntingtinCalcineurin activityPhosphorylationExon 1STEP protein levelsDisease mouse modelProtein levelsMouse modelMouse striatumTAT-STEPHuntington's disease mouse modelExpression
2008
Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia
Braithwaite SP, Xu J, Leung J, Urfer R, Nikolich K, Oksenberg D, Lombroso PJ, Shamloo M. Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia. European Journal Of Neuroscience 2008, 27: 2444-2452. PMID: 18445231, PMCID: PMC2738830, DOI: 10.1111/j.1460-9568.2008.06209.x.Peer-Reviewed Original ResearchConceptsStriatal enriched protein tyrosine phosphataseProtein tyrosine phosphataseTyrosine phosphatasePost-transcriptional levelNovel speciesPhosphorylation stateImportant proteinsMature formKey substrateNMDA receptor subunitsReceptor subunitsActive formSynaptic functionComplex cascadeCritical roleERKMRNA levelsProteinMRNAPERKPhosphataseCleavageCentral nervous systemNervous systemSubunits