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
MKP1 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 Research
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
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 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 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 contributionsFunctionHyperactivationMice
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 kinaseLoss of MKP-5 promotes myofiber survival by activating STAT3/Bcl-2 signaling during regenerative myogenesis
Min K, Lawan A, Bennett AM. Loss of MKP-5 promotes myofiber survival by activating STAT3/Bcl-2 signaling during regenerative myogenesis. Skeletal Muscle 2017, 7: 21. PMID: 29047406, PMCID: PMC5648478, DOI: 10.1186/s13395-017-0137-7.Peer-Reviewed Original ResearchConceptsMAPK phosphatase-5Mitogen-activated protein kinaseRegenerative myogenesisApoptotic signalingMyofiber survivalMAPK/JNK signalingMuscle regenerationSkeletal muscleP38 mitogen-activated protein kinaseMitochondrial apoptotic pathwaySkeletal muscle regenerationSkeletal muscle survivalDegenerative muscle diseasePhosphatase 5Expression of catalaseProtein kinaseSTAT3/BclSignal transducerJNK signalingWild typeExpression exhibitTranscription 3Apoptotic pathwayMitochondrial functionSignalingA Phosphoproteomic Screen Identifies a Guanine Nucleotide Exchange Factor for Rab3A Protein as a Mitogen-activated Protein (MAP) Kinase Phosphatase-5-regulated MAP Kinase Target in Interleukin 6 (IL-6) Secretion and Myogenesis*
Lee H, Min K, Yi JS, Shi H, Chang W, Jackson L, Bennett AM. A Phosphoproteomic Screen Identifies a Guanine Nucleotide Exchange Factor for Rab3A Protein as a Mitogen-activated Protein (MAP) Kinase Phosphatase-5-regulated MAP Kinase Target in Interleukin 6 (IL-6) Secretion and Myogenesis*. Journal Of Biological Chemistry 2017, 292: 3581-3590. PMID: 28096466, PMCID: PMC5339744, DOI: 10.1074/jbc.m116.769208.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAnimalsCell MovementCell ProliferationDual-Specificity PhosphatasesGene Expression Regulation, EnzymologicGuanine Nucleotide Exchange FactorsInterleukin-6MAP Kinase Signaling SystemMiceMice, KnockoutMuscle DevelopmentMuscle, SkeletalMutationMyoblastsPhosphorylationProteomicsRab3A GTP-Binding ProteinRegenerationSerineConceptsMitogen-activated protein kinaseMAPK phosphatase-5MAPK substratesExchange factorSer-169Guanine nucleotide exchange factorsNucleotide exchange factorsPhosphorylation-defective mutantSkeletal muscleP38 mitogen-activated protein kinaseC-Jun N-terminal kinaseMAPK-dependent signalingN-terminal kinaseSkeletal muscle functionSubstrate screenMAPK targetsSerine 169Rab3A proteinScreen identifiesRegenerative myogenesisPhosphatase 5Protein kinaseKinase targetsC2C12 myoblastsNegative regulator
2016
Low-dose dasatinib rescues cardiac function in Noonan syndrome
Yi JS, Huang Y, Kwaczala AT, Kuo IY, Ehrlich BE, Campbell SG, Giordano FJ, Bennett AM. Low-dose dasatinib rescues cardiac function in Noonan syndrome. JCI Insight 2016, 1: e90220. PMID: 27942593, PMCID: PMC5135272, DOI: 10.1172/jci.insight.90220.Peer-Reviewed Original ResearchConceptsNoonan syndromeSrc homology 2 domain-containing protein tyrosine phosphatase 2NS miceLow-dose dasatinib treatmentLow-dose dasatinibTyrosine kinase inhibitorsHearts of miceAutosomal dominant disorderCommon targetCardiac fibrosisDasatinib treatmentCardiac functionCardiomyocyte contractilityLow doseCardiac abnormalitiesShort statureNS casesNSML miceCommon autosomal dominant disorderMultiple lentiginesCraniofacial dysmorphismKinase inhibitorsMiceDasatinibProtein zero
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
2013
Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5
Shi H, Verma M, Zhang L, Dong C, Flavell RA, Bennett AM. Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5. Journal Of Clinical Investigation 2013, 123: 2064-2077. PMID: 23543058, PMCID: PMC3635719, DOI: 10.1172/jci64375.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationCrosses, GeneticDual-Specificity PhosphatasesDystrophinFemaleMaleMAP Kinase Kinase 4MAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, KnockoutMuscle, SkeletalMusclesMuscular Dystrophy, DuchenneMutationP38 Mitogen-Activated Protein KinasesRegenerationStem CellsConceptsMuscle stem cell functionMitogen-activated protein kinaseStem cell functionMKP-5MAPK phosphataseSkeletal muscle diseasesRegenerative myogenesisCell functionMuscle stem cell proliferationP38 mitogen-activated protein kinaseMuscle stem cellsDegenerative skeletal muscle diseaseStem cell proliferationEssential negative regulatorProtein kinaseMuscle diseaseNegative regulatorMAPK activityGenetic lossMKP5Muscle phenotypeDystrophic muscle phenotypeStem cellsMuscular dystrophyCell proliferation
2011
Loss of Mitogen-activated Protein Kinase Phosphatase-1 Protects from Hepatic Steatosis by Repression of Cell Death-inducing DNA Fragmentation Factor A (DFFA)-like Effector C (CIDEC)/Fat-specific Protein 27*
Flach RJ, Qin H, Zhang L, Bennett AM. Loss of Mitogen-activated Protein Kinase Phosphatase-1 Protects from Hepatic Steatosis by Repression of Cell Death-inducing DNA Fragmentation Factor A (DFFA)-like Effector C (CIDEC)/Fat-specific Protein 27*. Journal Of Biological Chemistry 2011, 286: 22195-22202. PMID: 21521693, PMCID: PMC3121364, DOI: 10.1074/jbc.m110.210237.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinase phosphatase-1Hepatic lipid homeostasisFatty acid oxidationLipid homeostasisMKP-1-deficient miceProtein kinase phosphatase-1MAPK-dependent phosphorylationFat-specific protein 27Like effector CPeroxisome proliferator-activated receptor-γ target genesProtein 27Kinase phosphatase-1Lipid droplet formationPhosphatase 1Acid oxidationLipogenic gene expressionSerine 112Target genesHepatic lipogenic gene expressionGene expressionPPARγ functionMetabolic signalsInhibitory residuesFactor AHepatic fatty acid oxidation
2010
The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching
Jeanneteau F, Deinhardt K, Miyoshi G, Bennett AM, Chao MV. The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nature Neuroscience 2010, 13: 1373-1379. PMID: 20935641, PMCID: PMC2971689, DOI: 10.1038/nn.2655.Peer-Reviewed Original ResearchAnimalsAxonsBrain-Derived Neurotrophic FactorCells, CulturedCerebral CortexDual Specificity Phosphatase 1ElectroporationEmbryo, MammalianFemaleGene Expression Regulation, EnzymologicGreen Fluorescent ProteinsHomeodomain ProteinsJNK Mitogen-Activated Protein KinasesMiceMice, TransgenicMicrotubulesNeuronsPregnancyRatsRats, Sprague-DawleyTransfection
2009
MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice
Roth RJ, Le AM, Zhang L, Kahn M, Samuel VT, Shulman GI, Bennett AM. MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice. Journal Of Clinical Investigation 2009, 119: 3817-3829. PMID: 19920356, PMCID: PMC2786792, DOI: 10.1172/jci39054.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceDietary FatsDNA PrimersDual Specificity Phosphatase 1Energy MetabolismMAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, KnockoutModels, BiologicalMuscle Fibers, Slow-TwitchObesityP38 Mitogen-Activated Protein KinasesPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaRNA, MessengerTrans-ActivatorsTranscription FactorsUp-Regulation
2001
SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis.
Kontaridis M, Liu X, Zhang L, Bennett A. SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis. Journal Of Cell Science 2001, 114: 2187-98. PMID: 11493654, DOI: 10.1242/jcs.114.11.2187.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsAntigens, DifferentiationCell DifferentiationCell LineFibroblastsInsulinIntracellular Signaling Peptides and ProteinsMembrane GlycoproteinsMiceMitogen-Activated Protein KinasesMolecular WeightMuscle, SkeletalMyoD ProteinNeural Cell Adhesion Molecule L1Neural Cell Adhesion MoleculesP38 Mitogen-Activated Protein KinasesPhosphoproteinsPhosphorylationPhosphotyrosineProtein BindingProtein Tyrosine Phosphatase, Non-Receptor Type 11Protein Tyrosine Phosphatase, Non-Receptor Type 6Protein Tyrosine PhosphatasesReceptors, ImmunologicSH2 Domain-Containing Protein Tyrosine PhosphatasesSignal TransductionSomatomedinsConceptsSHP-2Tyrosyl phosphorylationSH2 domain-containing tyrosine phosphataseC2C12 myoblastsSubstrate-1MyoD-responsive genesMitogen-activated protein kinase activityP38 mitogen-activated protein kinase activityMuscle-specific genesProtein tyrosine kinasesSkeletal muscle differentiationProtein kinase activityExpression of MyoD.Cell-cell recognitionComplex formationInvolvement of tyrosineTyrosine phosphataseGab-1C2C12 myogenesisMuscle differentiationBinder 1Kinase activityInducible activationMyoD expressionTyrosine kinase