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 activation
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 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 ResearchMeSH KeywordsAnimalsFemaleHumansLiver CirrhosisMaleMiceMice, KnockoutN-AcetylglucosaminyltransferasesNecroptosisConceptsReceptor-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
2017
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*
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
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
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