2019
Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis
Yun S, Hu R, Schwaemmle ME, Scherer AN, Zhuang Z, Koleske AJ, Pallas DC, Schwartz MA. Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis. Journal Of Clinical Investigation 2019, 129: 4863-4874. PMID: 31408443, PMCID: PMC6819111, DOI: 10.1172/jci127692.Peer-Reviewed Original ResearchConceptsPP2A regulatory subunit B55αTranscription factor YAPActive PDEComplex assemblyAdapter rolePDE4D5B55αIntegrin α5EC phenotypeCell functionInflammatory signalingAthero-prone regionsActivationComplexesPP2AInflammatory activationWidespread consequencesDephosphorylationProteomicsVascular remodelingPlaque sizeAtherosclerotic plaque sizeSignalingYAPRegulatesMKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation
Hu X, Liu ZZ, Chen X, Schulz VP, Kumar A, Hartman AA, Weinstein J, Johnston JF, Rodriguez EC, Eastman AE, Cheng J, Min L, Zhong M, Carroll C, Gallagher PG, Lu J, Schwartz M, King MC, Krause DS, Guo S. MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation. Nature Communications 2019, 10: 1695. PMID: 30979898, PMCID: PMC6461646, DOI: 10.1038/s41467-019-09636-6.Peer-Reviewed Original ResearchConceptsCell fate reprogrammingChromatin accessibilityActin cytoskeletonSomatic cell reprogrammingPluripotency transcription factorsGlobal chromatin accessibilityGenomic accessibilityCytoskeleton (LINC) complexCell reprogrammingCytoskeletal genesTranscription factorsReprogrammingPluripotencyChromatinCytoskeletonMKL1Unappreciated aspectPathwayNuclear volumeNucleoskeletonSUN2CellsActivationGenesExpression
2014
Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling
Baeyens N, Mulligan-Kehoe MJ, Corti F, Simon DD, Ross TD, Rhodes JM, Wang TZ, Mejean CO, Simons M, Humphrey J, Schwartz MA. Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 17308-17313. PMID: 25404299, PMCID: PMC4260558, DOI: 10.1073/pnas.1413725111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisBlotting, WesternCells, CulturedEndothelial CellsFemaleHuman Umbilical Vein Endothelial CellsHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalNF-kappa BReverse Transcriptase Polymerase Chain ReactionRNA InterferenceSignal TransductionStress, MechanicalSyndecan-4Vascular Endothelial Growth Factor Receptor-2ConceptsHuman umbilical vein endothelial cellsNF-κBProinflammatory NF-κBAtherosclerotic plaque burdenKruppel-like factor 2Umbilical vein endothelial cellsVEGF receptor 2Appearance of plaquesVein endothelial cellsHypercholesterolemic micePlaque burdenAntiinflammatory pathwayThoracic aortaReceptor 2Endothelial cellsEndothelial alignmentFlow correlatesCausal roleAtherosclerosisFactor 2MiceCyclic stretchLocalization correlatesActivationSyndecan-4
2013
Endothelial Cell Sensing of Flow Direction
Wang C, Baker BM, Chen CS, Schwartz MA. Endothelial Cell Sensing of Flow Direction. Arteriosclerosis Thrombosis And Vascular Biology 2013, 33: 2130-2136. PMID: 23814115, PMCID: PMC3812824, DOI: 10.1161/atvbaha.113.301826.Peer-Reviewed Original ResearchMeSH KeywordsActin CytoskeletonAnimalsAtherosclerosisCattleCell Culture TechniquesCell ShapeCells, CulturedEndothelial CellsEnzyme ActivationHemodynamicsInflammationMechanotransduction, CellularNF-kappa BNitric OxideNitric Oxide Synthase Type IIIOscillometryPhosphorylationProto-Oncogene Proteins c-aktReactive Oxygen SpeciesRegional Blood FlowStress, MechanicalTime FactorsConceptsEndothelial cellsEndothelial nitric oxide synthaseEndothelial nitric oxide synthase pathwayNitric oxide synthase pathwayNitric oxide synthaseOxide synthase pathwayAtherosclerosis-prone regionsInflammatory activationInflammatory effectsOxide synthaseEndothelial cell responsesCell responsesReactive oxygen productionDisturbed flowNitric oxideNuclear factorSimilar effectsActivationCellsSynthase pathwayInability of cells
2012
Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels
Batra N, Burra S, Siller-Jackson AJ, Gu S, Xia X, Weber GF, DeSimone D, Bonewald LF, Lafer EM, Sprague E, Schwartz MA, Jiang JX. Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 3359-3364. PMID: 22331870, PMCID: PMC3295295, DOI: 10.1073/pnas.1115967109.Peer-Reviewed Original ResearchMeSH KeywordsAndrostadienesAnimalsCell LineChromonesConnexin 43Extracellular Matrix ProteinsFibronectinsImmunomagnetic SeparationIntegrin alpha5beta1MiceMorpholinesOsteocytesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Interaction MappingRNA, Small InterferingStress, MechanicalWortmannin
2011
JNK2 Promotes Endothelial Cell Alignment under Flow
Hahn C, Wang C, Orr AW, Coon BG, Schwartz MA. JNK2 Promotes Endothelial Cell Alignment under Flow. PLOS ONE 2011, 6: e24338. PMID: 21909388, PMCID: PMC3164210, DOI: 10.1371/journal.pone.0024338.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinase c-Jun N-terminal kinaseProtein kinase c-Jun N-terminal kinaseC-Jun N-terminal kinaseActin stress fibersN-terminal kinaseFocal adhesionsBasement membrane proteinsMembrane proteinsLaminar shear stressStress fibersGene expressionJNK activityIntegrin activationJNK2 activationEndothelial cell alignmentJNK activationActivated JNKExtracellular matrixInflammatory gene expressionCell alignmentUnexpected connectionEndothelial cellsActivationPathwayCells
2009
Focal adhesion kinase modulates activation of NF-κB by flow in endothelial cells
Petzold T, Orr AW, Hahn C, Jhaveri KA, Parsons JT, Schwartz MA. Focal adhesion kinase modulates activation of NF-κB by flow in endothelial cells. American Journal Of Physiology - Cell Physiology 2009, 297: c814-c822. PMID: 19587216, PMCID: PMC2770750, DOI: 10.1152/ajpcell.00226.2009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell NucleusCells, CulturedEndothelial CellsEndothelium, VascularFocal Adhesion Protein-Tyrosine KinasesHydrogen PeroxideI-kappa B KinaseIntegrinsIntercellular Adhesion Molecule-1MiceNF-kappa BPhosphorylationProtein TransportRac GTP-Binding ProteinsReactive Oxygen SpeciesSignal TransductionStress, MechanicalTranscription Factor RelATumor Necrosis Factor-alphaConceptsFocal adhesion kinaseAdhesion kinaseNF-kappaBRac activationTranscriptional activityDependent genesEndothelial cellsIntegrin activationP65 NF-kappaB subunitDegradation of IkappaBReactive oxygen productionFluid shear stressNF-kappaB subunitsSerine 536Phosphorylation of p65Novel mechanismNF-kappaB activationKinaseNF-kappaB phosphorylationPhosphorylationActivationNF-κBOxygen productionHydrogen peroxideCellsSuppression of RhoG activity is mediated by a syndecan 4–synectin–RhoGDI1 complex and is reversed by PKCα in a Rac1 activation pathway
Elfenbein A, Rhodes JM, Meller J, Schwartz MA, Matsuda M, Simons M. Suppression of RhoG activity is mediated by a syndecan 4–synectin–RhoGDI1 complex and is reversed by PKCα in a Rac1 activation pathway. Journal Of Cell Biology 2009, 186: 75-83. PMID: 19581409, PMCID: PMC2712988, DOI: 10.1083/jcb.200810179.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsCluster AnalysisEnzyme ActivationFibroblast Growth Factor 2GTP PhosphohydrolasesGuanine Nucleotide Dissociation InhibitorsHeLa CellsHumansMiceMice, KnockoutModels, BiologicalPhosphorylationPhosphoserineProtein Kinase C-alphaRac1 GTP-Binding ProteinRatsRho GTP-Binding ProteinsRho-Specific Guanine Nucleotide Dissociation InhibitorsSyndecan-4ConceptsFibroblast growth factor-2Polarized activationRac1 activationSmall guanosine triphosphatase Rac1Activation pathwayProtein complexesRac activationPlasma membranePhysiological defectsSyndecan-4RhoGDI1Major regulatorInactive stateGrowth factor 2RhoGRhoG activityProteoglycan receptorsEndothelial migrationTernary complexFactor 2Genetic deletionSynectinRac1PKCalphaActivationThe Subendothelial Extracellular Matrix Modulates JNK Activation by Flow
Hahn C, Orr AW, Sanders JM, Jhaveri KA, Schwartz MA. The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow. Circulation Research 2009, 104: 995-1003. PMID: 19286608, PMCID: PMC2702158, DOI: 10.1161/circresaha.108.186486.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApolipoproteins EAtherosclerosisBasement MembraneCattleCell Culture TechniquesCells, CulturedCollagenDisease Models, AnimalEndothelial CellsEnzyme ActivationExtracellular MatrixFibronectinsHemorheologyInflammationIntegrinsJNK Mitogen-Activated Protein KinasesMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase KinasesOscillometryP21-Activated KinasesPhosphorylationRegional Blood FlowStress, Mechanical
2008
p21-Activated Kinase Signaling Regulates Oxidant-Dependent NF-&kgr;B Activation by Flow
Orr AW, Hahn C, Blackman BR, Schwartz MA. p21-Activated Kinase Signaling Regulates Oxidant-Dependent NF-&kgr;B Activation by Flow. Circulation Research 2008, 103: 671-679. PMID: 18669917, PMCID: PMC2697905, DOI: 10.1161/circresaha.108.182097.Peer-Reviewed Original ResearchConceptsNF-kappaB activationReactive oxygen speciesProinflammatory transcription factor nuclear factorTranscription factor nuclear factorInflammatory gene expressionNF-kappaB pathwayAbility of ROSP21-activated kinaseDisturbed blood flowBlood flowSensitivity of cellsNuclear factorEndothelial cellsROS productionActivationOxygen speciesCellsDisturbed flowGene expressionCollagenEndogenous RhoG is dispensable for integrin-mediated cell spreading but contributes to Rac-independent migration
Meller J, Vidali L, Schwartz MA. Endogenous RhoG is dispensable for integrin-mediated cell spreading but contributes to Rac-independent migration. Journal Of Cell Science 2008, 121: 1981-1989. PMID: 18505794, PMCID: PMC2759683, DOI: 10.1242/jcs.025130.Peer-Reviewed Original Research
2007
Matrix‐specific PAK activation regulates vascular permeability in atherosclerosis
Orr A, Stockton R, Simmers M, Sanders J, Blackman B, Schwartz M. Matrix‐specific PAK activation regulates vascular permeability in atherosclerosis. The FASEB Journal 2007, 21: a268-a268. DOI: 10.1096/fasebj.21.5.a268-d.Peer-Reviewed Original ResearchPAK activationAtherosclerosis-prone regionsCell-cell junctionsActivation of PAKMembrane proteinsPAK phosphorylationBasement membrane proteinsPro-atherosclerotic cytokinesEndothelial permeabilityPAKActivationFibronectinSubendothelial monocytesVivoKinasePhosphorylationProteinP21Vascular permeabilityRecruitmentMatrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis
Orr AW, Stockton R, Simmers MB, Sanders JM, Sarembock IJ, Blackman BR, Schwartz MA. Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis. Journal Of Cell Biology 2007, 176: 719-727. PMID: 17312022, PMCID: PMC2064028, DOI: 10.1083/jcb.200609008.Peer-Reviewed Original ResearchConceptsP21-activated kinaseP21-activated kinase activationAtherosclerosis-prone regionsCell-cell junctionsBasement membrane proteinsMembrane proteinsPAK phosphorylationActivation of PAKKinase activationPAK activationEndothelial permeabilityFibronectinActivationSubendothelial monocytesVivoKinasePhosphorylationProteinVascular permeabilityAtherogenesisRecruitmentCells
2006
In Vivo Dynamics of Rac-Membrane Interactions
Moissoglu K, Slepchenko BM, Meller N, Horwitz AF, Schwartz MA. In Vivo Dynamics of Rac-Membrane Interactions. Molecular Biology Of The Cell 2006, 17: 2770-2779. PMID: 16597700, PMCID: PMC1474787, DOI: 10.1091/mbc.e06-01-0005.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAnimalsCell MembraneComputer SimulationDiffusionGenes, ReporterGuanine Nucleotide Dissociation InhibitorsKineticsMiceMicroscopy, ConfocalModels, TheoreticalPlasmidsProtein TransportRac GTP-Binding ProteinsRecombinant Fusion ProteinsRecombinant ProteinsRho-Specific Guanine Nucleotide Dissociation InhibitorsConceptsGuanine Nucleotide Dissociation InhibitorGTPase-activating proteinsGTP-RacNucleotide exchange factorsVivo dynamicsSmall hairpin RNADissociation inhibitorMembrane associationExchange factorRac functionGEF Tiam1Hairpin RNARhoGDIPhotobleaching methodRacCytosolOverexpressionMajor routeDissociation rate constantsTiam1RNAProteinDetectable rateMembraneActivationA mechanosensory complex that mediates the endothelial cell response to fluid shear stress
Tzima E, Irani‐Tehrani M, Kiosses W, Dejana E, Schultz D, Engelhardt B, Cao G, DeLisser H, Schwartz M. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. The FASEB Journal 2006, 20: a1378-a1378. DOI: 10.1096/fasebj.20.5.a1378-c.Peer-Reviewed Original ResearchPECAM-1-null miceDownstream inflammatory genesPECAM-1VE-cadherinDevelopment of atherosclerosisICAM-1 expressionNF-kB activationInitiation of atherosclerosisBlood pressureVascular remodelingHigh-affinity stateInflammatory genesNF-κBCell responsesEndothelial cell responsesNull miceMechanosensory complexIntegrin activationAffinity stateAtherosclerosisVEGFR2Heterologous cellsPathway upstreamActivationSrc family kinases
2005
The subendothelial extracellular matrix modulates NF-κB activation by flow
Orr AW, Sanders JM, Bevard M, Coleman E, Sarembock IJ, Schwartz MA. The subendothelial extracellular matrix modulates NF-κB activation by flow. Journal Of Cell Biology 2005, 169: 191-202. PMID: 15809308, PMCID: PMC2171897, DOI: 10.1083/jcb.200410073.Peer-Reviewed Original ResearchConceptsNF-kappaB activationSubendothelial extracellular matrixAtherosclerosis-prone sitesEarly monocyte recruitmentSigns of atherosclerosisFatty streak formationNovel therapeutic strategiesNF-κB activationSuppress NF-kappaB activationExtracellular matrixMonocyte recruitmentICAM-1VCAM-1Plaque formTherapeutic strategiesE-selectinP38-dependent pathwayNF-kappaBEndothelial cellsAtherosclerosisP38 activationNew integrinActivationStreak formationIntegrin alpha2beta1Integrin Activation and Matrix Binding Mediate Cellular Responses to Mechanical Stretch*
Katsumi A, Naoe T, Matsushita T, Kaibuchi K, Schwartz MA. Integrin Activation and Matrix Binding Mediate Cellular Responses to Mechanical Stretch*. Journal Of Biological Chemistry 2005, 280: 16546-16549. PMID: 15760908, DOI: 10.1074/jbc.c400455200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell AdhesionEnzyme ActivationEnzyme InhibitorsExtracellular MatrixExtracellular Signal-Regulated MAP KinasesIntegrin alphaVbeta3IntegrinsJNK Mitogen-Activated Protein KinasesLigandsMAP Kinase Kinase 4MiceMitogen-Activated Protein Kinase KinasesNIH 3T3 CellsPhosphatidylinositol 3-KinasesPhosphorylationProtein ConformationSignal TransductionStress, MechanicalTime FactorsConceptsIntegrin activationExtracellular matrix proteinsRole of integrinsConformational activationBiochemical signalsNIH3T3 cellsMolecular mechanismsCellular responsesMatrix proteinsExtracellular matrixCell growthMechanical stretch stimulationIntegrin alphavbeta3IntegrinsMechanical tensionMechanical stretchCritical determinantStretch stimulationActivationPhosphoinositolMechanotransductionJNKProteinApoptosisDifferentiation
2003
Localized Cdc42 Activation, Detected Using a Novel Assay, Mediates Microtubule Organizing Center Positioning in Endothelial Cells in Response to Fluid Shear Stress*
Tzima E, Kiosses WB, del Pozo MA, Schwartz MA. Localized Cdc42 Activation, Detected Using a Novel Assay, Mediates Microtubule Organizing Center Positioning in Endothelial Cells in Response to Fluid Shear Stress*. Journal Of Biological Chemistry 2003, 278: 31020-31023. PMID: 12754216, DOI: 10.1074/jbc.m301179200.Peer-Reviewed Original ResearchConceptsMicrotubule organizing centerCdc42 activityCdc42 activationFluid shear stressSmall GTPase Cdc42Protein kinase CzetaGTPase Cdc42Early embryosEndothelial cellsIntegrin dynamicsOrganizing centerCdc42Extracellular matrixLocalized activationFluorescence energy transferMTOC localizationVascular endothelial cellsSingle cellsNovel assayCellsActivationPar6CzetaGolgiEmbryos
2001
Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression
Assoian R, Schwartz M. Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression. Current Opinion In Genetics & Development 2001, 11: 48-53. PMID: 11163150, DOI: 10.1016/s0959-437x(00)00155-6.Peer-Reviewed Original ResearchConceptsCell cycle progressionReceptor tyrosine kinasesG1 phase cyclinsDependent kinasesTyrosine kinasePhase cell cycle progressionG1 phase cell cycle progressionExtracellular matrix proteinsSoluble growth factorsRho GTPasesGrowth factor receptorRegulated signalingMatrix proteinsKinaseG1 phaseCell proliferationIntegrinsCyclinGrowth factorRecent studiesGTPasesActivationReceptorsSignalingERK
2000
Localized Rac Activation Dynamics Visualized in Living Cells
Kraynov V, Chamberlain C, Bokoch G, Schwartz M, Slabaugh S, Hahn K. Localized Rac Activation Dynamics Visualized in Living Cells. Science 2000, 290: 333-337. PMID: 11030651, DOI: 10.1126/science.290.5490.333.Peer-Reviewed Original ResearchConceptsSmall guanosine triphosphatasesSpatio-temporal controlMembrane rufflesGuanosine triphosphatasesSubcellular localizationNucleotide stateRac activationProtein activityDownstream targetsMotile cellsLiving cellsSpatial controlSpatio-temporal dynamicsGradient of activationCellsActivation dynamicsActivationRufflesTriphosphatasesPrecise spatial controlProteinRacLeading edgeApplicable approachLocalized effect