2025
Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics
Bennett A, Tiganis T. Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics. Annual Review Of Physiology 2025, 87: 301-324. PMID: 39531392, DOI: 10.1146/annurev-physiol-022724-105540.Peer-Reviewed Original ResearchProtein tyrosine phosphataseFunction of protein tyrosine phosphatasesActions of protein tyrosine kinasesTyrosine phosphorylation-dependent signalingTyrosine phosphataseType 2 diabetesPhosphorylation-dependent signalingPathophysiology of metabolic diseasesPrevalence of chronic metabolic disordersProtein tyrosine kinasesMetabolic disordersChronic metabolic disorderMetabolic homeostasisTyrosine kinaseIncreased prevalencePharmaceutical strategiesMetabolic diseasesGlucose metabolismMetabolismProteinBody weightObesityPhosphataseComplex interplayDisorders
2020
Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines
Yi JS, Perla S, Enyenihi L, Bennett AM. Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines. JCI Insight 2020, 5 PMID: 32584792, PMCID: PMC7455087, DOI: 10.1172/jci.insight.137753.Peer-Reviewed Original ResearchConceptsProtein tyrosine phosphataseTyrosyl phosphorylationNSML micePhosphorylation-defective mutantPTPN11 mutationsS6 kinase activityPZR tyrosyl phosphorylationTyrosine phosphataseS6 kinasePathophysiological signalingKinase activityShp2 interactionMutant fibroblastsSHP2Transmembrane glycoproteinMultiple lentiginesNoonan syndromeCraniofacial defectsPTPN11 geneHeart lysatesPhosphorylationSHP2 bindingMutationsNF-κB pathwayProtein zero
2017
Glutathione-Responsive Selenosulfide Prodrugs as a Platform Strategy for Potent and Selective Mechanism-Based Inhibition of Protein Tyrosine Phosphatases
Tjin CC, Otley KD, Baguley TD, Kurup P, Xu J, Nairn AC, Lombroso PJ, Ellman JA. Glutathione-Responsive Selenosulfide Prodrugs as a Platform Strategy for Potent and Selective Mechanism-Based Inhibition of Protein Tyrosine Phosphatases. ACS Central Science 2017, 3: 1322-1328. PMID: 29296673, PMCID: PMC5746864, DOI: 10.1021/acscentsci.7b00486.Peer-Reviewed Original ResearchStriatal-enriched protein tyrosine phosphataseProtein tyrosineTyrosine phosphatasePhosphatase inhibitorProtein tyrosine phosphataseProtein tyrosine phosphorylation levelsActive site cysteineProtein tyrosine phosphorylationTyrosine phosphorylation levelsHuman PTPsSite cysteinePTP targetsTyrosine phosphorylationRepresentative cysteine proteaseCysteine proteasesHuman diseasesCellular activitiesPhosphorylation levelsVirulence factorsEssential roleSelective mechanismIntracellular GSH concentrationSelective active sitesNeurodegenerative diseasesPTPX‑ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors
Witten MR, Wissler L, Snow M, Geschwindner S, Read JA, Brandon NJ, Nairn AC, Lombroso PJ, Käck H, Ellman JA. X‑ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors. Journal Of Medicinal Chemistry 2017, 60: 9299-9319. PMID: 29116812, PMCID: PMC5758861, DOI: 10.1021/acs.jmedchem.7b01292.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseProtein tyrosine phosphatase inhibitorProtein tyrosine phosphataseTyrosine phosphatase inhibitorFirst X-ray crystal structureTyrosine phosphatasePhosphatase inhibitorSTEP inhibitorPhosphorylation levelsInhibitor structureSubstrate-based approachNumerous neuropsychiatric disordersX-ray crystal structureDrug discoverySTEP substratesStructural informationPhosphataseInhibitorsMouse modelKnockdownSurprising findingCrystal structureNeuropsychiatric disordersExcessive activityAlzheimer's diseaseAnnexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases
Luo M, Flood EC, Almeida D, Yan L, Berlin DA, Heerdt PM, Hajjar KA. Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases. Journal Of Experimental Medicine 2017, 214: 2535-2545. PMID: 28694388, PMCID: PMC5584111, DOI: 10.1084/jem.20160652.Peer-Reviewed Original ResearchConceptsAlveolar hypoxiaVascular endothelial cadherinMicrovascular integrityPulmonary edemaSrc homology phosphatase 2Vascular integrityEndothelial cellsVascular endothelial growth factorMicrovascular endothelial cellsEndothelial growth factorAdherens junction protein vascular endothelial cadherinEndothelial cadherinAirway obstructionNeutrophil infiltrationPulmonary microvasculatureAnnexin A2 functionsVascular leakLung parenchymaMice displayAltitude sicknessBarrier functionGrowth factorHypoxiaPhospholipid-binding proteinsProtein tyrosine phosphatase
2016
STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit
Tian M, Xu J, Lei G, Lombroso PJ, Jackson MF, MacDonald JF. STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit. Scientific Reports 2016, 6: 36684. PMID: 27857196, PMCID: PMC5114553, DOI: 10.1038/srep36684.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseFamily of kinasesProtein tyrosine phosphataseM1R stimulationN-methyl-D-aspartate receptorsM1 muscarinic acetylcholine receptorSrc recruitmentTyrosine phosphataseSrc regulationNMDAR functionIntracellular Ca2Step activationMuscarinic acetylcholine receptorsGluN2A subunitGαqAcetylcholine receptorsHigh intracellular Ca2Function of NMDARsSynaptic plasticityPhosphataseNMDAR activationActivationReceptorsRecruitmentCa2
2015
Regulation 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 phosphataseChemInform Abstract: Synthesis of Benzopentathiepin Analogues and Their Evaluation as Inhibitors of the Phosphatase STEP.
Baguley T, Nairn A, Lombroso P, Ellman J. ChemInform Abstract: Synthesis of Benzopentathiepin Analogues and Their Evaluation as Inhibitors of the Phosphatase STEP. ChemInform 2015, 46: no-no. DOI: 10.1002/chin.201526245.Peer-Reviewed Original ResearchStriatal-enriched protein tyrosine phosphataseProtein tyrosine phosphataseTyrosine phosphataseNovel inhibitorsInhibitorsPhosphataseStriatal‐enriched protein tyrosine phosphatase regulates the PTPα/Fyn signaling pathway
Xu J, Kurup P, Foscue E, Lombroso PJ. Striatal‐enriched protein tyrosine phosphatase regulates the PTPα/Fyn signaling pathway. Journal Of Neurochemistry 2015, 134: 629-641. PMID: 25951993, PMCID: PMC4516628, DOI: 10.1111/jnc.13160.Peer-Reviewed Original ResearchConceptsProtein tyrosine phosphataseProtein kinase ARegulation of FynTyrosine phosphataseReceptor-type protein tyrosine phosphatase alphaProtein tyrosine phosphatase alphaStriatal-enriched protein tyrosine phosphataseRegulatory tyrosine residuesActivation of FynTyrosine kinase FynRegulatory tyrosineProtein tyrosinePTPαKinase FynSynaptic membranesKinase ATyrosine residuesFyn activityFynNovel substratePrimary neuronal culturesSTEP61Synergistic regulationMolecular techniquesNovel mechanismSynthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP
Baguley TD, Nairn AC, Lombroso PJ, Ellman JA. Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP. Bioorganic & Medicinal Chemistry Letters 2015, 25: 1044-1046. PMID: 25666825, PMCID: PMC4334692, DOI: 10.1016/j.bmcl.2015.01.020.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseProtein tyrosine phosphataseTyrosine phosphataseSpecific protein tyrosine phosphataseInhibitor potencyNeurodegenerative diseasesPotent inhibitorReporter groupPhosphataseStructural featuresInhibitorsConvenient handleSubstitutionAlzheimer's diseaseCellsInhibitionSTEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease
Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC. STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 1202-1207. PMID: 25583483, PMCID: PMC4313846, DOI: 10.1073/pnas.1417423112.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCorpus StriatumCyclic AMP Response Element-Binding ProteinDown-RegulationGene Expression Regulation, EnzymologicHEK293 CellsHumansMAP Kinase Signaling SystemMiceMice, KnockoutMitogen-Activated Protein Kinase 3MPTP PoisoningProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyUbiquitin-Protein LigasesUbiquitinationUp-RegulationConceptsE3 ubiquitin ligase ParkinSubstantia nigra pars compactaPathophysiology of PDProtein tyrosine phosphataseUbiquitin ligase ParkinSporadic Parkinson's diseaseE3 ligase ParkinRegulation of ParkinParkinson's diseaseTyrosine phosphataseParkin mutantsE3 ligaseProteasome systemDopaminergic neuronsDownstream targetsAutosomal recessive juvenile parkinsonismNovel substrateSTEP61ParkinCellular modelSTEP61 levelsSNc dopaminergic neuronsProtein levelsFunction contributesERK1/2
2014
Correction to Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase
Baguley T, Xu H, Chatterjee M, Nairn A, Lombroso P, Ellman J. Correction to Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase. Journal Of Medicinal Chemistry 2014, 57: 10564-10564. PMCID: PMC4364512, DOI: 10.1021/jm5018847.Peer-Reviewed Original Research
2013
Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase
Baguley TD, Xu HC, Chatterjee M, Nairn AC, Lombroso PJ, Ellman JA. Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase. Journal Of Medicinal Chemistry 2013, 56: 7636-7650. PMID: 24083656, PMCID: PMC3875168, DOI: 10.1021/jm401037h.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiphenyl CompoundsBlood-Brain BarrierBoronic AcidsCells, CulturedCerebral CortexHumansNeuronsPermeabilityPhosphorous AcidsProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleySmall Molecule LibrariesStereoisomerismStructure-Activity RelationshipSubstrate SpecificityConceptsSubstrate Activity ScreeningProtein tyrosine phosphatase activityProtein tyrosine phosphataseTyrosine phosphatase activityGlutamate receptor internalizationOptimization of fragmentsTyrosine phosphataseDual specificityReceptor internalizationDevelopment of SelectiveSTEP inhibitorPhosphatase activityAlzheimer's diseaseIonotropic glutamate receptorsSubstrate-based approachNonpeptidic inhibitorsPotential targetAD mouse modelDrug discoveryRat cortical neuronsActivity screeningCortical neuronsGlutamate receptorsMouse modelNeuropsychiatric disordersStriatal-Enriched Protein Tyrosine Phosphatase—STEPs Toward Understanding Chronic Stress-Induced Activation of Corticotrophin Releasing Factor Neurons in the Rat Bed Nucleus of the Stria Terminalis
Dabrowska J, Hazra R, Guo JD, Li C, DeWitt S, Xu J, Lombroso PJ, Rainnie DG. Striatal-Enriched Protein Tyrosine Phosphatase—STEPs Toward Understanding Chronic Stress-Induced Activation of Corticotrophin Releasing Factor Neurons in the Rat Bed Nucleus of the Stria Terminalis. Biological Psychiatry 2013, 74: 817-826. PMID: 24012328, PMCID: PMC3818357, DOI: 10.1016/j.biopsych.2013.07.032.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseLong-term potentiationProtein tyrosine phosphataseCRF neuronsReverse transcriptase-polymerase chain reactionTranscriptase-polymerase chain reactionRestraint stressTyrosine phosphatasePolymerase chain reactionBed nucleusFactor neuronsStria terminalisWhole-cell patch-clamp electrophysiologyInduction of LTPRole of STEPQuantitative reverse transcriptase-polymerase chain reactionChain reactionNovel treatment strategiesStress-induced anxiety disordersAnxiety-like behaviorSingle-cell reverse transcriptase-polymerase chain reactionPatch-clamp electrophysiologyStress-Induced ActivationRat bed nucleusTyrosine phosphatase STEPLow-copy piggyBac transposon mutagenesis in mice identifies genes driving melanoma
Ni TK, Landrette SF, Bjornson RD, Bosenberg MW, Xu T. Low-copy piggyBac transposon mutagenesis in mice identifies genes driving melanoma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: e3640-e3649. PMID: 24003131, PMCID: PMC3780872, DOI: 10.1073/pnas.1314435110.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternDNA PrimersDNA Transposable ElementsGene Expression Regulation, NeoplasticGenetic TestingHEK293 CellsHumansImmunohistochemistryMAP Kinase Kinase Kinase 1MelanomaMiceMice, TransgenicMutagenesis, InsertionalReverse Transcriptase Polymerase Chain ReactionSignal TransductionSpecies SpecificityConceptsCancer-driving genesMitogen-activated protein kinase kinase kinase 1Membrane associated guanylate kinaseProtein kinase kinase kinase 1Kinase kinase kinase 1Protein tyrosine phosphataseTransposon mutagenesis approachKinase kinase 1Transposon mutagenesis screenHuman melanomaBackground mutation rateMelanoma driver genesUndescribed genesIdentifies genesMutagenesis screenPDZ domainGuanylate kinaseTyrosine phosphataseTransposon mutagenesisCellular transformationMutagenesis approachKinase 1Mutation rateERK signalingDriver genes
2012
Striatal-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 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 modelInhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation
Tautz L, Sergienko E, Xu J, Liu W, Dahl R, Critton D, Su Y, Brown B, Chan X, Yang L, Bobkova E, Vasile S, Yuan H, Rascon J, Colayco S, Sidique S, Cosford N, Chung T, Mustelin T, Page R, Lombroso P. Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation. The FASEB Journal 2012, 26: 766.12-766.12. DOI: 10.1096/fasebj.26.1_supplement.766.12.Peer-Reviewed Original ResearchHematopoietic protein tyrosine phosphataseP38 activationProtein tyrosine phosphataseUnique amino acid residuesAmino acid residuesNew drug targetsCell cycle arrestMAP kinases ERK1/2Activation of ERK1/2Tyrosine phosphataseHePTPMutagenesis experimentsMAP kinaseKinases ERK1/2Acid residuesCatalytic pocketDrug targetsTransient activationCycle arrestT-cell acute lymphoblastic leukemiaERK1/2Prolonged activationHuman T cellsPharmacological inhibitionCancer cells
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