2013
Neuroprotective Role of a Brain-Enriched Tyrosine Phosphatase, STEP, in Focal Cerebral Ischemia
Deb I, Manhas N, Poddar R, Rajagopal S, Allan AM, Lombroso PJ, Rosenberg GA, Candelario-Jalil E, Paul S. Neuroprotective Role of a Brain-Enriched Tyrosine Phosphatase, STEP, in Focal Cerebral Ischemia. Journal Of Neuroscience 2013, 33: 17814-17826. PMID: 24198371, PMCID: PMC3818554, DOI: 10.1523/jneurosci.2346-12.2013.Peer-Reviewed Original ResearchConceptsIschemic brain damageStriatal-enriched phosphataseBrain damageNeuroprotective roleBrain injuryP38 MAPK activationSustained p38 MAPK activationIschemic brain injuryFocal cerebral ischemiaOnset of reperfusionHypoxia-reoxygenation injuryP38 MAPKMAPK activationIschemic strokeNeurological deficitsCerebral ischemiaStroke therapyKO miceRat modelP38 MAPK pathwayCultured neuronsNeuronal culturesGenetic deletionSecondary activationInjuryCocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP
Chiodi V, Mallozzi C, Ferrante A, Chen JF, Lombroso PJ, Di Stasi AM, Popoli P, Domenici MR. Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP. Neuropsychopharmacology 2013, 39: 569-578. PMID: 23989619, PMCID: PMC3895235, DOI: 10.1038/npp.2013.229.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCerebral CortexCocaineCorpus StriatumDopamine Uptake InhibitorsEnzyme InhibitorsGene Expression RegulationHumansIn Vitro TechniquesInhibitory Postsynaptic PotentialsMaleMiceMice, Inbred C57BLMice, KnockoutNeural PathwaysNeuronsProtein Tyrosine Phosphatases, Non-ReceptorReceptor, Adenosine A2ASynaptic TransmissionSynaptosomesVanadatesConceptsEffects of cocaineSynaptic transmissionAdenosine A2A receptorsStriatal-enriched protein tyrosine phosphatasePharmacological actionsA2A receptorsWhole-cell voltage-clamp recordingsA2AR antagonist ZM241385Excitatory post-synaptic currentsCocaine-induced reductionMedium spiny neuronsCocaine-induced changesVoltage-clamp recordingsPost-synaptic currentsA2AR knockout miceCorticostriatal slicesStriatal slicesPsychomotor effectsSpiny neuronsSynaptic mechanismsAntagonist ZM241385Synaptic depressionClamp recordingsBrain areasStriatum
2012
The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity
Olausson P, Venkitaramani D, Moran T, Salter M, Taylor J, Lombroso P. The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity. Neuroscience 2012, 225: 1-8. PMID: 22885232, PMCID: PMC3725644, DOI: 10.1016/j.neuroscience.2012.07.069.Peer-Reviewed Original ResearchMeSH KeywordsAmygdalaAnalysis of VarianceAnimalsBiophysicsConditioning, OperantElectric StimulationExcitatory Postsynaptic PotentialsFearMaleMAP Kinase Signaling SystemMemoryMiceMice, Inbred C57BLMice, TransgenicNeuronal PlasticityPatch-Clamp TechniquesProtein Tyrosine Phosphatases, Non-ReceptorReinforcement ScheduleReinforcement, PsychologyConceptsSynaptic plasticityExperience-dependent synaptic plasticityAspartic acid (NMDA) receptorsMemory formationLong-term potentiationAdult neuroplasticityAmygdala-dependent memory formationPharmacological treatmentKO miceExperience-induced neuroplasticityTyrosine phosphatase STEPNR2B subunitLateral amygdalaBrain regionsTyrosine kinase FynAcid receptorsStriatal-enriched protein tyrosine phosphataseNeuroplasticityMiceERK phosphorylationReceptor internalizationERK signalingKinase 1/2Detectable expressionSTEP KO miceThe 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 plasticityCalpain 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 localizationGenetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model
Goebel‐Goody S, Wilson‐Wallis E, Royston S, Tagliatela S, Naegele J, Lombroso P. Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model. Genes Brain & Behavior 2012, 11: 586-600. PMID: 22405502, PMCID: PMC3922131, DOI: 10.1111/j.1601-183x.2012.00781.x.Peer-Reviewed Original ResearchConceptsFragile X syndromeFragile X syndrome mouse modelProtein tyrosine phosphataseMental retardation proteinMRNAs downstreamControl translationTyrosine phosphataseGenetic manipulationGenetic basisFMR1 geneLoss of stepsX syndromeSyndrome mouse modelFMRPReceptor activationGlutamate receptor activationExcess levelsSynaptic strengthSynaptic strengtheningBasal levelsC-Fos activationActivationTranscriptionFynMouse model
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 modelExpressionStriatal‐enriched protein tyrosine phosphatase (STEP) knockout mice have enhanced hippocampal memory
Venkitaramani DV, Moura PJ, Picciotto MR, Lombroso PJ. Striatal‐enriched protein tyrosine phosphatase (STEP) knockout mice have enhanced hippocampal memory. European Journal Of Neuroscience 2011, 33: 2288-2298. PMID: 21501258, PMCID: PMC3118976, DOI: 10.1111/j.1460-9568.2011.07687.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBehavior, AnimalFocal Adhesion Kinase 2HippocampusMemoryMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3PhosphorylationProtein Tyrosine Phosphatases, Non-ReceptorReceptors, AMPAReceptors, N-Methyl-D-AspartateSynaptic TransmissionConceptsStriatal-enriched protein tyrosine phosphataseSTEP KO miceProtein tyrosine phosphataseBrain-specific phosphataseProline-rich tyrosine kinaseEffect of deletionN-methyl-D-aspartate receptorsERK1/2 substratesNR1/NR2B N‐Methyl‐d‐Aspartate ReceptorsPotential molecular mechanismsTyrosine phosphataseSignaling proteinsTyrosine phosphorylationDownstream effectorsKinase 1/2Molecular mechanismsTyrosine kinaseFunctional importanceKnockout micePhosphorylationSTEP knockout miceSynaptic strengtheningIsoxazole propionic acid (AMPA) receptorsSynaptosomal expressionRegulation
2010
Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer’s disease mouse model
Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ. Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer’s disease mouse model. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 19014-19019. PMID: 20956308, PMCID: PMC2973892, DOI: 10.1073/pnas.1013543107.Peer-Reviewed Original ResearchConceptsStriatal-enriched tyrosine phosphataseTyrosine phosphataseDisease mouse modelStriatal-enriched phosphataseAlzheimer's diseaseCellular deficitsGenetic manipulationNMDA receptorsMouse modelTriple transgenic AD mouse modelIncurable neurodegenerative disorderTransgenic AD mouse modelAlzheimer's disease mouse modelPathophysiology of ADSTEP inhibitorGenetic reductionAD mouse modelHuman AD patientsSoluble Aβ oligomersSynaptic functionPhosphataseNeurodegenerative disordersAD patientsDevastating disorderAnimal modelsAβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61
Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ. Aβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61. Journal Of Neuroscience 2010, 30: 5948-5957. PMID: 20427654, PMCID: PMC2868326, DOI: 10.1523/jneurosci.0157-10.2010.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAnimalsCell LineCells, CulturedCerebral CortexEndocytosisHumansIn Vitro TechniquesMiceMice, KnockoutMice, TransgenicMiddle AgedNeuronsProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateUbiquitinated ProteinsUbiquitinationConceptsAlzheimer's diseaseAbeta treatmentNR2B subunitProtein tyrosine Phosphatase 61Cognitive deficitsNMDA receptor internalizationHuman AD brainsMouse cortical culturesNR1/NR2B receptorsNMDA receptor endocytosisIonotropic glutamate receptorsTyrosine phosphatase STEP61AD brainCortical slicesCortical culturesGlutamate receptorsNR2B receptorsPostsynaptic terminalsPrefrontal cortexNeuronal membranesElevated levelsCortexReceptor internalizationUbiquitin-proteasome systemStep activity
2009
Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-Mediated Cleavage of STEP
Xu J, Kurup P, Zhang Y, Goebel-Goody SM, Wu PH, Hawasli AH, Baum ML, Bibb JA, Lombroso PJ. Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-Mediated Cleavage of STEP. Journal Of Neuroscience 2009, 29: 9330-9343. PMID: 19625523, PMCID: PMC2737362, DOI: 10.1523/jneurosci.2212-09.2009.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsBrainCalpainCell DeathCells, CulturedCyclin-Dependent Kinase 5EndocytosisGlutamic AcidIn Vitro TechniquesMiceMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3NeuronsP38 Mitogen-Activated Protein KinasesProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateSynapsesConceptsStriatal-enriched protein tyrosine phosphataseCalpain cleavage sitesP38 activationCell deathCleavage siteExtracellular signal-regulated kinase 1/2Protein tyrosine phosphataseSignal-regulated kinase 1/2Promotes cell survivalActivation of p38Tyrosine phosphataseSubstrate bindingKinase 1/2ERK1/2 activationCalpain cleavageCell survivalNovel mechanismCalpain-mediated proteolysisReceptors coupleP38NMDAR stimulationPostsynaptic terminalsValid targetCleavage productsSTEP substrates
2008
The Tyrosine Phosphatase STEP Mediates AMPA Receptor Endocytosis after Metabotropic Glutamate Receptor Stimulation
Zhang Y, Venkitaramani DV, Gladding CM, Zhang Y, Kurup P, Molnar E, Collingridge GL, Lombroso PJ. The Tyrosine Phosphatase STEP Mediates AMPA Receptor Endocytosis after Metabotropic Glutamate Receptor Stimulation. Journal Of Neuroscience 2008, 28: 10561-10566. PMID: 18923032, PMCID: PMC2586105, DOI: 10.1523/jneurosci.2666-08.2008.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseProtein tyrosine phosphataseTyrosine phosphataseAMPAR internalizationMitogen-activated protein kinasePhosphoinositide-3-kinase (PI3K) pathwayAMPA receptor endocytosisTyrosine dephosphorylationAMPA receptor traffickingReceptor endocytosisProtein kinaseKinase pathwayStimulation of mGluR5Receptor traffickingNMDAR endocytosisAMPAR traffickingEndocytosisMetabotropic glutamate receptor stimulationTraffickingSurface expressionInternalizationGlutamate receptor stimulationSynaptic plasticityCentral eventPhosphatase
2007
Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase
Choi YS, Lin SL, Lee B, Kurup P, Cho HY, Naegele JR, Lombroso PJ, Obrietan K. Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase. Journal Of Neuroscience 2007, 27: 2999-3009. PMID: 17360923, PMCID: PMC2701360, DOI: 10.1523/jneurosci.4913-06.2007.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseERK/MAPK activationProtein tyrosine phosphataseCell deathTyrosine phosphataseExtracellular signal-regulated kinase/mitogen-activated protein kinase pathwayKinase/mitogen-activated protein kinase pathwayMAPK activationMAPK pathwayERK/MAPK signalingMitogen-activated protein kinase pathwayStriatal enriched protein tyrosine phosphataseProtein kinase pathwayNeuroprotective responseKinase pathwayImmediate early gene expressionKey regulatorMAPK signalingGene expressionMolecular mechanismsVivo disruptionSignificant rescuePathwayPhosphataseActivation
2005
Regulation of NMDA receptor trafficking by amyloid-β
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neuroscience 2005, 8: 1051-1058. PMID: 16025111, DOI: 10.1038/nn1503.Peer-Reviewed Original ResearchMeSH KeywordsAlpha7 Nicotinic Acetylcholine ReceptorAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsCalcineurinCell MembraneCerebral CortexCREB-Binding ProteinDisease Models, AnimalElectric ConductivityEndocytosisEnzyme ActivationMiceNeuronsN-MethylaspartateNuclear ProteinsPeptide FragmentsProtein TransportProtein Tyrosine PhosphatasesProtein Tyrosine Phosphatases, Non-ReceptorReceptors, NicotinicReceptors, N-Methyl-D-AspartateSignal TransductionSynapsesTrans-ActivatorsConceptsNMDA receptorsCortical neuronsAlzheimer's diseaseBrains of patientsAlzheimer's disease pathologyNMDA receptor traffickingGenetic mouse modelsΓ-secretase inhibitorApplication of amyloidSurface NMDA receptorsGlutamatergic transmissionSynaptic dysfunctionPersistent depressionTyrosine phosphatase STEPNicotinic receptorsMouse modelDisease processSynaptic plasticityDisease pathologyNeuronsReceptorsAmyloidSurface expressionUnderlying mechanismReceptor trafficking
1998
Development of the Cerebral Cortex: III. The Reeler Mutation
LOMBROSO P. Development of the Cerebral Cortex: III. The Reeler Mutation. Journal Of The American Academy Of Child & Adolescent Psychiatry 1998, 37: 333-334. PMID: 9519640, DOI: 10.1097/00004583-199803000-00020.Peer-Reviewed Original Research
1995
Molecular Cloning of the Human Homolog of a Striatum-Enriched Phosphatase (STEP) Gene and Chromosomal Mapping of the Human and Murine Loci
Li X, Luna J, Lombroso P, Francke U. Molecular Cloning of the Human Homolog of a Striatum-Enriched Phosphatase (STEP) Gene and Chromosomal Mapping of the Human and Murine Loci. Genomics 1995, 28: 442-449. PMID: 7490079, DOI: 10.1006/geno.1995.1173.Peer-Reviewed Original ResearchConceptsSrc homology domain 3STEP geneTyrosine phosphataseSomatic cell hybrid analysisHuman fetal brain cDNA libraryFetal brain cDNA libraryPhosphatase catalytic domainCell hybrid analysisProtein tyrosine phosphataseAmino acid domainProline-rich regionCandidate disease genesBrain cDNA libraryUsher syndrome type 1CAmino acid levelsChromosomal mappingPhosphatase geneMutant lociHuman homologTrue homologsMolecular cloningCatalytic domainAcid domainMurine locusCDNA libraryIdentification of two alternatively spliced transcripts of STEP: a subfamily of brain-enriched protein tyrosine phosphatases
Sharma E, Zhao F, Bult A, Lombroso P. Identification of two alternatively spliced transcripts of STEP: a subfamily of brain-enriched protein tyrosine phosphatases. Brain Research 1995, 32: 87-93. PMID: 7494467, DOI: 10.1016/0169-328x(95)00066-2.Peer-Reviewed Original ResearchConceptsTyrosine phosphatase domainPhosphatase domainProtein tyrosineSpliced transcriptsExon-intron organizationProtein tyrosine phosphataseOpen reading frameTyrosine phosphataseReading frameDistinct functionsGenomic DNANorthern analysisSTEP geneSTEP isoformsMolecular massTranscriptsSTEP61ProteinMouse brainTyrosineCentral nervous systemSubfamiliesGenesNervous systemMonoclonal antibodiesCellular and molecular characterization of a brain-enriched protein tyrosine phosphatase
Boulanger L, Lombroso P, Raghunathan A, During M, Wahle P, Naegele. Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase. Journal Of Neuroscience 1995, 15: 1532-1544. PMID: 7869116, PMCID: PMC6577844, DOI: 10.1523/jneurosci.15-02-01532.1995.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalAxonsBlotting, WesternBrainCerebral CortexCorpus StriatumImmunohistochemistryIn Situ HybridizationMiceMice, Inbred BALB CNeuronsPeptide FragmentsProtein Tyrosine PhosphatasesProtein Tyrosine Phosphatases, Non-ReceptorRatsRNA, MessengerSynaptic TransmissionTissue DistributionConceptsSubstantia nigraAdult rat brainCombination of immunocytochemistrySitu hybridization studiesProjection neuronsBasal gangliaCaudate putamenPresynaptic axonsStriatal enriched protein tyrosine phosphataseRat brainBrain regionsImmunocytochemical stainingLesion experimentsWestern blotLesion studiesWestern blottingMonoclonal antibodiesMRNA expression patternsImmunoreactive formsImmunoreactive bandsProtein tyrosine phosphataseNigraSitu hybridizationHybridization studiesSTEP isoforms