2024
MAP 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
Mitogen-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 siteDephosphorylationAn 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-9
2020
An 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 screenInhibitorsTreatmentInhibition
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 kinaseRole of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis
Xylourgidis N, Min K, Ahangari F, Yu G, Herazo-Maya JD, Karampitsakos T, Aidinis V, Binzenhöfer L, Bouros D, Bennett AM, Kaminski N, Tzouvelekis A. Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2019, 317: l678-l689. PMID: 31483681, PMCID: PMC6879900, DOI: 10.1152/ajplung.00264.2018.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibiotics, AntineoplasticBleomycinDual-Specificity PhosphatasesFemaleFibroblastsHumansMAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase PhosphatasesPhosphorylationPulmonary FibrosisSignal TransductionTransforming Growth Factor beta1ConceptsPulmonary fibrosisLung fibrosisFibrogenic genesLung fibroblastsM1 macrophage phenotypeIdiopathic pulmonary fibrosisHuman lung fibrosisGrowth factor-β1Levels of hydroxyprolineProtein kinase phosphatase 5IPF lungsReduced fibrosisMuscle fibrosisProfibrogenic effectsTGF-β1Smad7 levelsTherapeutic targetAnimal modelsFactor-β1FibrosisSmad3 phosphorylationEnhanced p38 MAPK activityP38 MAPK activityMyofibroblast differentiationMKP-5 expression
2018
Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function
Levy AD, Xiao X, Shaw JE, Devi S, Katrancha SM, Bennett AM, Greer CA, Howe JR, Machida K, Koleske AJ. Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function. Cell Reports 2018, 24: 1523-1535. PMID: 30089263, PMCID: PMC6234505, DOI: 10.1016/j.celrep.2018.07.006.Peer-Reviewed Original ResearchConceptsTyrosine phosphatase SHP2Noonan syndromePhosphatase SHP2Regulatory proteinsSHP2Recombinant GluN1Nck2Receptor functionNMDA receptor functionNMDAR functionGluN2B functionMutationsNMDAR dysfunctionNeuron functionNS miceGluN1ProteinAllelesNMDA receptorsDiheteromersReceptor kineticsReduced contributionsFunctionHyperactivationMiceDUSPs, twists and turns in the Journey to Vascular Inflammation
Bennett AM. DUSPs, twists and turns in the Journey to Vascular Inflammation. The FEBS Journal 2018, 285: 1589-1592. PMID: 29682902, DOI: 10.1111/febs.14461.Peer-Reviewed Original Research
2017
Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism
Lawan A, Bennett AM. Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends In Endocrinology And Metabolism 2017, 28: 868-878. PMID: 29128158, PMCID: PMC5774993, DOI: 10.1016/j.tem.2017.10.007.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseMitogen-activated protein kinaseHepatic metabolismLipid metabolismType 2 diabetes mellitusFatty liver diseaseHepatic mitogen-activated protein kinaseHepatic metabolic functionDiabetes mellitusLiver diseaseLiver metabolismMetabolic diseasesInsulin actionPathophysiological conditionsDiseaseMetabolismMetabolic functionsRecent insightsMellitusObesityProtein kinase
2014
Mining the function of protein tyrosine phosphatases in health and disease
Lee H, Yi JS, Lawan A, Min K, Bennett AM. Mining the function of protein tyrosine phosphatases in health and disease. Seminars In Cell And Developmental Biology 2014, 37: 66-72. PMID: 25263013, PMCID: PMC4339398, DOI: 10.1016/j.semcdb.2014.09.021.Peer-Reviewed Original ResearchConceptsPTP functionProtein tyrosineHuman diseasesProteomic approachNon-biased approachUnanticipated roleProteomic techniquesProteomic technologiesNovel therapeutic targetPTPTherapeutic targetTyrosineFundamental cellCrucial roleHuman healthDiscoveryRegulationRoleElucidationFunctionCellsCutting-edge technologiesTarget
2000
Differential Role of β1C and β1AIntegrin Cytoplasmic Variants in Modulating Focal Adhesion Kinase, Protein Kinase B/AKT, and Ras/Mitogen-activated Protein Kinase Pathways
Fornaro M, Steger C, Bennett A, Wu J, Languino L. Differential Role of β1C and β1AIntegrin Cytoplasmic Variants in Modulating Focal Adhesion Kinase, Protein Kinase B/AKT, and Ras/Mitogen-activated Protein Kinase Pathways. Molecular Biology Of The Cell 2000, 11: 2235-2249. PMID: 10888665, PMCID: PMC14916, DOI: 10.1091/mbc.11.7.2235.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell AdhesionCHO CellsCricetinaeCytoplasmEnzyme ActivationFibronectinsFocal Adhesion Kinase 1Focal Adhesion Protein-Tyrosine KinasesGene ExpressionHumansIntegrin beta1IntegrinsMitogen-Activated Protein Kinase 1PhosphorylationProtein Serine-Threonine KinasesProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRabbitsRas ProteinsSignal TransductionConceptsStable cell linesMAP kinase pathwayKinase pathwayRas activationERK2 activationRas/MAP kinase pathwayCell proliferationProtein kinase B/Akt activitySurvival signalsProtein kinase B/AktRas/mitogen-activated protein kinase pathwayExtracellular signal-regulated kinase 2 activationCell linesProtein kinase B/Akt phosphorylationMitogen-activated protein kinase pathwayFocal adhesion kinase phosphorylationUnique signaling mechanismVariant cytoplasmic domainKinase 2 activationFocal adhesion kinaseProtein kinase pathwayModulates cell proliferationMAPK kinaseCytoplasmic domainAdhesion kinase
1998
Epidermal Growth Factor Receptor and the Adaptor Protein p52Shc Are Specific Substrates of T-Cell Protein Tyrosine Phosphatase
Tiganis T, Bennett A, Ravichandran K, Tonks N. Epidermal Growth Factor Receptor and the Adaptor Protein p52Shc Are Specific Substrates of T-Cell Protein Tyrosine Phosphatase. Molecular And Cellular Biology 1998, 18: 1622-1634. PMID: 9488479, PMCID: PMC108877, DOI: 10.1128/mcb.18.3.1622.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAdaptor Proteins, Signal TransducingAdaptor Proteins, Vesicular TransportAnimalsBinding SitesCalcium-Calmodulin-Dependent Protein KinasesCell NucleusCOS CellsCytoplasmEndoplasmic ReticulumEpidermal Growth FactorErbB ReceptorsGRB2 Adaptor ProteinHeLa CellsHumansMiceMitogen-Activated Protein Kinase 1MutagenesisPhosphorylationPhosphotyrosineProtein Tyrosine Phosphatase, Non-Receptor Type 2Protein Tyrosine PhosphatasesProteinsProtein-Tyrosine KinasesShc Signaling Adaptor ProteinsSrc Homology 2 Domain-Containing, Transforming Protein 1Substrate SpecificityTyrosineConceptsT-cell protein tyrosine phosphataseSubstrate-trapping mutantEpidermal growth factor receptorProtein tyrosine phosphatasePTyr proteinsTyrosine phosphataseGrowth factor receptorPTP active siteTyrosine phosphorylated proteinsEGF-induced activationFactor receptorAlternative splicingCellular contextCOS cellsP52ShcNuclear formTC45Endoplasmic reticulumCatalytic acidSpecific substratesProteinMutantsComplex formationSpecific sitesEGF
1994
Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras.
Bennett A, Tang T, Sugimoto S, Walsh C, Neel B. Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras. Proceedings Of The National Academy Of Sciences Of The United States Of America 1994, 91: 7335-7339. PMID: 8041791, PMCID: PMC44394, DOI: 10.1073/pnas.91.15.7335.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAnimalsBase SequenceBinding SitesCell LineDNAGenes, rasHumansIntracellular Signaling Peptides and ProteinsMiceMice, Inbred BALB CMolecular Sequence DataPhosphorylationProtein Tyrosine Phosphatase, Non-Receptor Type 11Protein Tyrosine Phosphatase, Non-Receptor Type 6Protein Tyrosine PhosphatasesReceptors, Platelet-Derived Growth FactorSH2 Domain-Containing Protein Tyrosine PhosphatasesSignal TransductionConceptsPlatelet-derived growth factor receptor betaGrowth factor receptor betaPDGF stimulationPositive signalingReceptor tyrosine kinasesSH2 domainRas activationGrowth factor receptorReceptor betaTyrosine phosphorylationSHPTP2Gene productsTyrosine kinaseGrb2Vivo sitesFactor receptorPhosphorylationSignalingPositive signalsSOS1RAHomologuesKinaseSite displayBeta
1993
Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor.
Lechleider R, Sugimoto S, Bennett A, Kashishian A, Cooper J, Shoelson S, Walsh C, Neel B. Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor. Journal Of Biological Chemistry 1993, 268: 21478-21481. PMID: 7691811, DOI: 10.1016/s0021-9258(20)80562-6.Peer-Reviewed Original ResearchConceptsSH-PTP2Platelet-derived growth factor receptorGrowth factor receptorPhosphotyrosyl peptidesFactor receptorSrc homology 2 domainHuman platelet-derived growth factor receptorIntrinsic tyrosine kinase activityPeptide competition assaysTyrosine kinase activitySH2 domainPhosphorylation sitesSignal transductionKinase activityMajor binding siteImmunoprecipitation studiesCompetition assaysTyrosyl residuesBinding sitesEarly eventsProteinLigand additionActivity 5ReceptorsDocking point