2024
Mitogen-Activated Protein Kinase Phosphatase-5 is Required for TGF-β Signaling Through a JNK-Dependent Pathway
Dorry S, Perla S, Bennett A. Mitogen-Activated Protein Kinase Phosphatase-5 is Required for TGF-β Signaling Through a JNK-Dependent Pathway. Molecular And Cellular Biology 2024, ahead-of-print: 1-15. PMID: 39607740, DOI: 10.1080/10985549.2024.2426665.Peer-Reviewed Original ResearchMitogen-activated protein kinaseTGF-b signalingMKP-5JNK-dependent pathwayFamily of protein phosphatasesNon-canonical sitesJNK-dependent mannerP38 mitogen-activated protein kinaseMitogen-activated protein kinase phosphatase-5JNK-dependentTranscriptional activityProtein phosphatasesTranscriptome analysisRNA sequencingProtein kinaseJNK inactivationNuclear translocationSignaling activityTGF-bSmad2 phosphorylationPharmacological inhibitionDrivers of fibrosisTissue fibrosisFactor BPathwaySpatiotemporal control of subcellular O-GlcNAc signaling using Opto-OGT
Ong Q, Lim L, Goh C, Liao Y, Chan S, Lim C, Kam V, Yap J, Tseng T, Desrouleaux R, Wang L, Ler S, Lim S, Kim S, Sobota R, Bennett A, Han W, Yang X. Spatiotemporal control of subcellular O-GlcNAc signaling using Opto-OGT. Nature Chemical Biology 2024, 1-9. PMID: 39543398, DOI: 10.1038/s41589-024-01770-7.Peer-Reviewed Original ResearchO-GlcNAc transferaseO-GlcNAcLocalized to specific subcellular sitesResponse to insulin stimulationPost-translational modification of intracellular proteinsModification of intracellular proteinsO-GlcNAc signalingPost-translational modificationsTargeting O-GlcNAc transferaseSpatiotemporal controlMulticellular organismsOGT activityOrganelle functionO-GlcNAcylationSubcellular sitesMTORC activitySignal transductionIntracellular proteinsNutrient-sensing signalsCell signalingInsulin stimulationPlasma membraneGene expressionRegulatory mechanismsAkt phosphorylationmiR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression
Fernández-Tussy P, Cardelo M, Zhang H, Sun J, Price N, Boutagy N, Goedeke L, Cadena-Sandoval M, Xirouchaki C, Brown W, Yang X, Pastor-Rojo O, Haeusler R, Bennett A, Tiganis T, Suárez Y, Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression. JCI Insight 2024, 9: e168476. PMID: 39190492, PMCID: PMC11466198, DOI: 10.1172/jci.insight.168476.Peer-Reviewed Original ResearchMiR-33Regulation of biological processesMitochondrial fatty acid oxidationRegulation of lipid metabolismNon-alcoholic fatty liver diseaseDevelopment of effective therapeuticsFatty acid oxidationLipid synthesisProgression of non-alcoholic fatty liver diseaseMitochondrial functionTarget genesBiological processesComplex diseasesNon-alcoholic steatohepatitisLipid accumulationDeletionDevelopment of non-alcoholic fatty liver diseasePathway activationLipid metabolismProgress to non-alcoholic steatohepatitisAcid oxidationHCC progressionEffective therapeuticsTherapeutic targetHepatocellular carcinomaMAP kinase phosphatase-1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution
Fortier S, Walker N, Penke L, Baas J, Shen Q, Speth J, Huang S, Zemans R, Bennett A, Peters-Golden M. MAP kinase phosphatase-1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution. Journal Of Clinical Investigation 2024, 134: e172826. PMID: 38512415, PMCID: PMC11093610, DOI: 10.1172/jci172826.Peer-Reviewed Original ResearchConceptsMAPK phosphatase 1Fibrosis resolutionPulmonary fibrosisSpontaneous resolutionLung fibrosisBleomycin-induced lung fibrosisLung fibroblastsProgressive pulmonary fibrosisFibroblast-specific deletionExperimental lung fibrosisCells to apoptosisLung injuryRegulation of MAPK activityApoptosis-resistant myofibroblastsTransgenic miceResident fibroblastsTissue injuryFibrosisLung myofibroblastsLoss-of-function studiesGain- and loss-of-function studiesLungVX-702MyofibroblastsMAPK activationSkeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α
Liu B, Xie D, Huang X, Jin S, Dai Y, Sun X, Li D, Bennett A, Diano S, Huang Y. Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α. Diabetologia 2024, 67: 724-737. PMID: 38216792, PMCID: PMC10904493, DOI: 10.1007/s00125-023-06073-5.Peer-Reviewed Original ResearchConceptsTen-eleven translocationMuscle insulin sensitivityRNA-seqPGC-1aRegulation of muscle insulin sensitivityType 2 diabetesAnalysis of RNA-seqResponse to environmental cuesGenome-wide expression profilingWild-typeHFD-fedHFD-induced insulin resistanceHigh-fat diet (HFD)-inducedExpression levelsMaintenance of glucoseSkeletal muscle insulin sensitivityAccession numbersSkeletal muscleEnhanced glucose toleranceFamily dioxygenasesMitochondrial respirationSkeletal muscle of humansEnvironmental cuesMitochondrial functionBiological processes
2023
Identification of Protein Tyrosine Phosphatase (PTP) Substrates
Perla S, Qiu B, Dorry S, Yi J, Bennett A. Identification of Protein Tyrosine Phosphatase (PTP) Substrates. Methods In Molecular Biology 2023, 2743: 123-133. PMID: 38147212, DOI: 10.1007/978-1-0716-3569-8_8.Peer-Reviewed Original ResearchMKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention
Qiu B, Lawan A, Xirouchaki C, Yi J, Robert M, Zhang L, Brown W, Fernández-Hernando C, Yang X, Tiganis T, Bennett A. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention. Nature Communications 2023, 14: 5405. PMID: 37669951, PMCID: PMC10480499, DOI: 10.1038/s41467-023-41145-5.Peer-Reviewed Original ResearchTeaching an old dog new tricks: A new tool for protein tyrosine phosphatase substrate discovery
Bennett A. Teaching an old dog new tricks: A new tool for protein tyrosine phosphatase substrate discovery. Journal Of Biological Chemistry 2023, 299: 104731. PMID: 37080392, PMCID: PMC10193000, DOI: 10.1016/j.jbc.2023.104731.Peer-Reviewed Original ResearchConceptsIdentification of substratesSubstrate discoveryProtein tyrosineProtein substratesInteraction networksBreast cancer cell modelsCancer cell modelsFunctional interactionNovel targetVersatile new toolNew toolCell modelComplete understandingRecent studiesOld dog new tricksNew tricksInteractorsPTP1B.PTP1BPTPMutationsSubstrateEnzymeTyrosinePathwaySH2 Domain-Containing Phosphatase-SHP2 Attenuates Fibrotic Responses through Negative Regulation of Mitochondrial Metabolism in Lung Fibroblasts
Karampitsakos T, Galaris A, Barbayianni I, DeIuliis G, Ahangari F, Sampsonas F, Sotiropoulou V, Aidinis V, Bennett A, Herazo-Maya J, Xylourgidis N, Bakakos P, Bouros D, Kaminski N, Tzouvelekis A. SH2 Domain-Containing Phosphatase-SHP2 Attenuates Fibrotic Responses through Negative Regulation of Mitochondrial Metabolism in Lung Fibroblasts. Diagnostics 2023, 13: 1166. PMID: 36980473, PMCID: PMC10047203, DOI: 10.3390/diagnostics13061166.Peer-Reviewed Original ResearchMitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?
Shillingford S, Bennett A. Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable? The Annual Review Of Pharmacology And Toxicology 2023, 63: 617-636. PMID: 36662585, PMCID: PMC10127142, DOI: 10.1146/annurev-pharmtox-051921-121923.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseSmall molecule inhibitionProtein kinaseCritical cellular functionsInhibition of PTPsProtein tyrosineCellular functionsProtein substratesPhosphorylated proteinsCell signalingTyrosine residuesAttractive therapeutic targetCellular effectsKinaseNumerous diseasesPTPDiscovery toolTherapeutic developmentTherapeutic targetMetabolic diseasesInhibitionDephosphorylationSignalingMKPProtein
2022
A novel site on dual-specificity phosphatase MKP7/DUSP16 is required for catalysis and MAPK binding
Shillingford S, Zhang L, Surovtseva Y, Dorry S, Lolis E, Bennett AM. A novel site on dual-specificity phosphatase MKP7/DUSP16 is required for catalysis and MAPK binding. Journal Of Biological Chemistry 2022, 298: 102617. PMID: 36272649, PMCID: PMC9676401, DOI: 10.1016/j.jbc.2022.102617.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseP38 mitogen-activated protein kinaseMAPK bindingRegulatory mechanismsAllosteric siteMKP family membersNovel allosteric siteSmall molecule targetingMAPK/JNKAdditional regulatory mechanismsPhosphatase functionPhosphatase domainP38 MAPK/JNKProtein kinaseMKP7Site mutantsMAPK signalingAllosteric pocketMolecule targetingMAPK dephosphorylationMutantsNovel siteJNKCatalytic siteDephosphorylationDefining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors
Gannam Z, Jamali H, Kweon OS, Herrington J, Shillingford SR, Papini C, Gentzel E, Lolis E, Bennett AM, Ellman JA, Anderson KS. Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors. European Journal Of Medicinal Chemistry 2022, 243: 114712. PMID: 36116232, PMCID: PMC9830533, DOI: 10.1016/j.ejmech.2022.114712.Peer-Reviewed Original ResearchMeSH KeywordsStructure-Activity RelationshipConceptsStress-responsive MAPKsEnzyme-inhibitor complexDystrophic muscle diseasePhosphatase 5Muscle diseaseAllosteric inhibitorsNumber of diseasesNovel classProtein kinase phosphatase 5Structure-activity relationshipsPotential therapeutic targetMKP5X-ray crystal structureTherapeutic targetPotential therapeuticsInhibitorsLead compoundsInhibitionProper positioningMAPKCrystal structureMitogenTyr435Derivative compoundsInteractionAn Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies
Yi JS, Perla S, Bennett AM. An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies. Cardiovascular Drugs And Therapy 2022, 37: 1193-1204. PMID: 35156148, DOI: 10.1007/s10557-022-07324-0.Peer-Reviewed Original ResearchConceptsRAS-MAPK pathwayRAS/mitogen-activated protein kinase (MAPK) pathwayMitogen-activated protein kinase pathwayPost-developmental processesProtein kinase pathwayHypertrophic cardiomyopathyKinase pathwayRASopathy patientsDevelopmental diseasesNoonan syndromeTreatment of HCMRASopathiesCardiofaciocutaneous syndromePathwayNeurofibromatosis type 1Cardiovascular defectsValvular abnormalitiesCardiovascular manifestationsHeart diseaseClinical informationCostello syndromeCongenital heartMultiple lentiginesTherapeutic landscapeAntineoplastic drugs
2021
MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis
Zhong C, Min K, Zhao Z, Zhang C, Gao E, Huang Y, Zhang X, Baldini M, Roy R, Yang X, Koch WJ, Bennett AM, Yu J. MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis. Frontiers In Immunology 2021, 12: 790511. PMID: 34992607, PMCID: PMC8724134, DOI: 10.3389/fimmu.2021.790511.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood PressureCardiomegalyCells, CulturedDisease Models, AnimalDual-Specificity PhosphatasesEchocardiographyFibrosisHeartHeart FailureHumansInterleukin-4MacrophagesMaleMAP Kinase Signaling SystemMatrix Metalloproteinase 9MiceMice, KnockoutMyocardiumPhosphorylationPrimary Cell CultureVentricular RemodelingConceptsMitogen-activated protein kinase phosphatase 5Transverse aortic constrictionCardiac fibrosisMMP-9 expressionPressure overloadCardiac hypertrophyPressure overload-induced cardiac fibrosisOverload-induced cardiac fibrosisTAC-induced cardiac hypertrophyExcessive extracellular matrix depositionPro-fibrotic macrophagesCardiac pressure overloadP38 MAPKMatrix metalloproteinase-9Regulation of MMPsProtein kinase phosphatase 5JNK/ERKIL-4 stimulationExtracellular matrix depositionCardiac injuryAortic constrictionMyocardial fibrosisHeart diseaseFibrotic remodelingMetalloproteinase-9Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines
Yi JS, Perla S, Huang Y, Mizuno K, Giordano FJ, Vinks AA, Bennett AM. Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines. Cardiovascular Drugs And Therapy 2021, 36: 589-604. PMID: 33689087, PMCID: PMC9270274, DOI: 10.1007/s10557-021-07169-z.Peer-Reviewed Original ResearchConceptsHypertrophic cardiomyopathyNSML miceDasatinib treatmentLow-dose dasatinib treatmentPK propertiesMultiple lentiginesHeart tissueDasatinib-treated miceExposure-dependent inhibitionSrc homology 2 domain-containing protein tyrosine phosphatase 2Development of HCMAssessment of markersAutosomal dominant disorderNSML patientsDasatinib administrationCardiac fibrosisEffective target engagementEffective therapyConclusionThese dataMouse modelPharmacodynamic propertiesPK parametersHCM progressionDasatinibNoonan syndrome
2020
Improving Obesity and Insulin Resistance by Targeting Skeletal Muscle MKP-1.
Bennett AM, Lawan A. Improving Obesity and Insulin Resistance by Targeting Skeletal Muscle MKP-1. Journal Of Cellular Signaling 2020, 1: 160-168. PMID: 33179019, PMCID: PMC7654974, DOI: 10.33696/signaling.1.025.Peer-Reviewed Original ResearchType 2 diabetesInsulin resistanceSkeletal muscleMetabolic diseasesTreatment of T2DMKP-1Chronic upregulationPharmacological treatmentTherapeutic strategiesObesityGlobal epidemicCalorie restrictionT2DDiabetesCurrent interventionsDiseaseMusclePotential targetingTreatmentPotential strategyUrgent needPatientsPathogenesisStress responseUpregulationAn allosteric site on MKP5 reveals a strategy for small-molecule inhibition
Gannam Z, Min K, Shillingford SR, Zhang L, Herrington J, Abriola L, Gareiss PC, Pantouris G, Tzouvelekis A, Kaminski N, Zhang X, Yu J, Jamali H, Ellman JA, Lolis E, Anderson KS, Bennett AM. An allosteric site on MKP5 reveals a strategy for small-molecule inhibition. Science Signaling 2020, 13 PMID: 32843541, PMCID: PMC7569488, DOI: 10.1126/scisignal.aba3043.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric SiteAmino Acid SequenceAnimalsCell DifferentiationCell LineDual-Specificity PhosphatasesEnzyme InhibitorsFemaleHigh-Throughput Screening AssaysHumansKineticsMiceMice, KnockoutMitogen-Activated Protein Kinase PhosphatasesMyoblastsProtein BindingSequence Homology, Amino AcidSignal TransductionSmall Molecule LibrariesConceptsDystrophic muscle diseaseMitogen-activated protein kinaseMuscle diseaseTGF-β1Promising therapeutic targetP38 mitogen-activated protein kinaseTherapeutic strategiesTherapeutic targetSmall molecule inhibitionSmad2 phosphorylationDiseasePotential targetSmall-molecule screenInhibitorsTreatmentInhibitionTyrosyl 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
2019
O-GlcNAc transferase suppresses necroptosis and liver fibrosis
Zhang B, Li MD, Yin R, Liu Y, Yang Y, Mitchell-Richards KA, Nam JH, Li R, Wang L, Iwakiri Y, Chung D, Robert ME, Ehrlich BE, Bennett AM, Yu J, Nathanson MH, Yang X. O-GlcNAc transferase suppresses necroptosis and liver fibrosis. JCI Insight 2019, 4: e127709. PMID: 31672932, PMCID: PMC6948774, DOI: 10.1172/jci.insight.127709.Peer-Reviewed Original ResearchConceptsReceptor-interacting protein kinase 3Liver fibrosisLiver diseaseHepatocyte necroptosisEthanol-induced liver injuryAlcoholic liver cirrhosisChronic liver diseaseMultiple liver diseasesWeeks of ageProtein expression levelsPortal inflammationLiver cirrhosisLiver injuryBallooning degenerationElevated protein expression levelsSpontaneous genetic modelFibrosisKey suppressorKey mediatorMiceProtein kinase 3CirrhosisExpression levelsGlcNAc levelsMixed lineage kinaseSH2 domain-containing Phosphatase-(SHP)-2 blunts fibrotic responses through regulation of fibroblast mitochondrial metabolism and autophagy
Tzouvelekis A, Yu G, Ahangari F, Bennett A, Karampitsakos T, Bouros D, Bouros E, Kaminski N. SH2 domain-containing Phosphatase-(SHP)-2 blunts fibrotic responses through regulation of fibroblast mitochondrial metabolism and autophagy. 2019, pa583. DOI: 10.1183/13993003.congress-2019.pa583.Peer-Reviewed Original Research