2024
Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis
Joshi D, Coon B, Chakraborty R, Deng H, Yang Z, Babar M, Fernandez-Tussy P, Meredith E, Attanasio J, Joshi N, Traylor J, Orr A, Fernandez-Hernando C, Libreros S, Schwartz M. Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis. Nature Cardiovascular Research 2024, 3: 1035-1048. PMID: 39232138, PMCID: PMC11399086, DOI: 10.1038/s44161-024-00522-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisCadherin Related ProteinsCadherinsDisease Models, AnimalEndothelial CellsHuman Umbilical Vein Endothelial CellsHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMiceMice, Inbred C57BLMice, KnockoutPlaque, AtheroscleroticReceptors, NotchSignal TransductionConceptsAtherosclerotic cardiovascular diseaseIntracellular domainNotch intracellular domainTranscription factor KLF2Mechanisms of vascular inflammationAnti-inflammatory programVascular endothelial cellsHost defenseCleavage resultsAntibody blockadeGenetic deletionVascular inflammationViral infectionImmune systemEndothelial cellsCardiovascular diseasePromote atherosclerosisBlood flowKLF2KLF4Suppressive signalsEndotheliumMechanistic studies
2023
SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations
Banerjee K, Lin Y, Gahn J, Cordero J, Gupta P, Mohamed I, Graupera M, Dobreva G, Schwartz M, Ola R. SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations. Journal Of Clinical Investigation 2023, 133: e168352. PMID: 37490341, PMCID: PMC10503796, DOI: 10.1172/jci168352.Peer-Reviewed Original ResearchConceptsActivin-like kinase 1Fluid shear stressSMAD family member 4Arterial identityCyclin-dependent kinase inhibitors Cdkn2aVascular network formsEndothelial cellsVascular stabilitySensitivity of ECsBMP signalsPI3K/AktFamily member 4Downstream effectorsProtein 9Kinase 1Vascular developmentBone morphogenic protein 9Mechanism of synergyMorphological responsesSMAD4 deletionEC proliferationMember 4
2019
Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis
Chen PY, Qin L, Li G, Wang Z, Dahlman JE, Malagon-Lopez J, Gujja S, Cilfone N, Kauffman K, Sun L, Sun H, Zhang X, Aryal B, Canfran-Duque A, Liu R, Kusters P, Sehgal A, Jiao Y, Anderson D, Gulcher J, Fernandez-Hernando C, Lutgens E, Schwartz M, Pober J, Chittenden T, Tellides G, Simons M. Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis. Nature Metabolism 2019, 1: 912-926. PMID: 31572976, PMCID: PMC6767930, DOI: 10.1038/s42255-019-0102-3.Peer-Reviewed Original ResearchConceptsTGF-β signalingVascular inflammationDisease progressionPlaque growthProgressive vascular diseaseVessel wall inflammationChronic inflammatory responseSpecific therapeutic interventionsAtherosclerotic plaque growthHyperlipidemic micePlaque inflammationWall inflammationProinflammatory effectsVascular diseaseInflammatory responseVascular permeabilityAtherosclerotic plaquesAbnormal shear stressTherapeutic interventionsInflammationEndothelial TGFΒ signalingVessel wallAtherosclerosisLipid retentionCaveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation
Ramírez CM, Zhang X, Bandyopadhyay C, Rotllan N, Sugiyama MG, Aryal B, Liu X, He S, Kraehling JR, Ulrich V, Lin CS, Velazquez H, Lasunción MA, Li G, Suárez Y, Tellides G, Swirski FK, Lee WL, Schwartz MA, Sessa WC, Fernández-Hernando C. Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation. Circulation 2019, 140: 225-239. PMID: 31154825, PMCID: PMC6778687, DOI: 10.1161/circulationaha.118.038571.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseDiet-induced atherosclerosisNO productionVascular inflammationENOS activationEndothelial nitric oxide synthase activationNitric oxide synthase activationAthero-protective functionsLipid metabolic factorsEndothelial cell inflammationNitric oxide synthaseWild-type miceMice Lacking ExpressionProduction of NOExtracellular matrix remodelingInflammatory primingHyperlipidemic miceInflammatory pathwaysAortic archCell inflammationOxide synthaseMetabolic factorsMouse modelAtherosclerosisInflammation
2018
Local Tension on Talin in Focal Adhesions Correlates with F-Actin Alignment at the Nanometer Scale
Kumar A, Anderson KL, Swift MF, Hanein D, Volkmann N, Schwartz MA. Local Tension on Talin in Focal Adhesions Correlates with F-Actin Alignment at the Nanometer Scale. Biophysical Journal 2018, 115: 1569-1579. PMID: 30274833, PMCID: PMC6372196, DOI: 10.1016/j.bpj.2018.08.045.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCells, CulturedCytoskeletonFocal AdhesionsMechanotransduction, CellularMiceMice, KnockoutTalinConceptsActin organizationLocal actin organizationTalin tension sensorFocal adhesion dynamicsLinear actin filamentsIndividual focal adhesionsCellular force transmissionF-actin alignmentFocal adhesionsAdhesion dynamicsCell centerVinculin localizationActin intensityActin filamentsF-actinAdhesion centersNormal physiologyTalinSame cellsAdhesion correlatesStable adhesionTension sensor
2017
Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification
Fang JS, Coon BG, Gillis N, Chen Z, Qiu J, Chittenden TW, Burt JM, Schwartz MA, Hirschi KK. Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nature Communications 2017, 8: 2149. PMID: 29247167, PMCID: PMC5732288, DOI: 10.1038/s41467-017-01742-7.Peer-Reviewed Original ResearchConceptsEndothelial cell cycle arrestArterial gene expressionCell cycle arrestArterial specificationGene expressionCycle arrestArterial-venous specificationCell cycle inhibitor CDKN1BEndothelial cell cycleCell cycle inhibitionEmbryonic developmentBlood vessel formationP27 axisFunctional vascular networkCell cycleGrowth controlSpecialized phenotypeFluid shear stressCycle inhibitionVessel formationGrowth inhibitionTissue repairMechanochemical pathwayEndothelial cellsVascular regeneration
2016
Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development
Wang Y, Baeyens N, Corti F, Tanaka K, Fang JS, Zhang J, Jin Y, Coon B, Hirschi KK, Schwartz MA, Simons M. Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development. Development 2016, 143: 4441-4451. PMID: 27789626, PMCID: PMC5201046, DOI: 10.1242/dev.140129.Peer-Reviewed Original ResearchConceptsLymphatic endothelial cellsPlanar cell polarity protein Vangl2Lymphatic vessel remodelingMouse embryonic developmentHuman lymphatic endothelial cellsVangl2 overexpressionVangl2 expressionEmbryonic developmentValve morphogenesisEndothelial cellsVasculature developmentSyndecan-4Lymphatic vasculatureFluid shear stressSDC4Double knockout miceMice resultsHigh expressionVessel remodelingLymphatic vesselsExpressionVangl2RemodelingCellsMorphogenesis
2015
Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization
Dubrac A, Genet G, Ola R, Zhang F, Pibouin-Fragner L, Han J, Zhang J, Thomas JL, Chedotal A, Schwartz MA, Eichmann A. Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization. Circulation 2015, 133: 409-421. PMID: 26659946, PMCID: PMC4729599, DOI: 10.1161/circulationaha.115.017537.Peer-Reviewed Original ResearchConceptsFront-rear polaritySprouting angiogenesisSignal integration mechanismImportant drug targetsNck adaptorsCytoskeletal dynamicsEndothelial cell migrationEmbryonic developmentAngiogenesis defectsPAK2 activationVessel sproutsNumber of diseasesBlood vessel growthDrug targetsCell migrationPostnatal retinaAngiogenic growthNckNck1AdaptorVessel growthKey processesEndothelial cellsPathological ocular neovascularizationInhibits neovascularizationKLF4 is a key determinant in the development and progression of cerebral cavernous malformations
Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini MF, Maddaluno L, Baeyens N, Adams RH, Jain MK, Owens GK, Schwartz M, Lampugnani MG, Dejana E. KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Molecular Medicine 2015, 8: 6-24. PMID: 26612856, PMCID: PMC4718159, DOI: 10.15252/emmm.201505433.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBone Morphogenetic Protein 6Cell ProliferationDisease Models, AnimalDisease ProgressionEndothelial CellsHEK293 CellsHemangioma, Cavernous, Central Nervous SystemHumansKRIT1 ProteinKruppel-Like Factor 4Kruppel-Like Transcription FactorsMiceMice, Inbred C57BLMice, KnockoutMicrotubule-Associated ProteinsMitogen-Activated Protein Kinase 7MutationProto-Oncogene ProteinsRNA InterferenceSignal TransductionSmad1 ProteinTransforming Growth Factor betaConceptsKruppel-like factor 4Cerebral cavernous malformationsEndothelial cellsCavernous malformationsFamilial cerebral cavernous malformationsCentral nervous systemDouble knockout miceGrowth factor-beta/bone morphogenetic protein signalingCerebral hemorrhageMouse mortalityPharmacological treatmentCurrent therapiesVascular malformationsKnockout miceTherapeutic targetNervous systemMesenchymal transitionKLF4 transcriptional activityMalformationsCCM3 genesFactor 4Function mutationsEndMTMorphogenetic protein signalingBone morphogenetic protein (BMP) signalingEndothelial-to-mesenchymal transition drives atherosclerosis progression
Chen PY, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, Tellides G, Schwartz MA, Simons M. Endothelial-to-mesenchymal transition drives atherosclerosis progression. Journal Of Clinical Investigation 2015, 125: 4514-4528. PMID: 26517696, PMCID: PMC4665771, DOI: 10.1172/jci82719.Peer-Reviewed Original ResearchConceptsProgression of atherosclerosisTGF-β signalingFGF receptor 1Left main coronary arteryMesenchymal transitionFGFR1 expressionDevelopment of EndMTMain coronary arteryTotal plaque burdenHigh-fat dietCultured human endothelial cellsDouble knockout miceEndothelial-specific deletionEarly time pointsCoronary atherosclerosisCoronary diseaseHuman endothelial cellsAtherosclerosis progressionPlaque burdenAtherosclerotic miceCoronary arteryInflammatory cytokinesAtherosclerotic lesionsNeointima formationClinical relevance
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-4Up-regulation of Thrombospondin-2 in Akt1-null Mice Contributes to Compromised Tissue Repair Due to Abnormalities in Fibroblast Function*
Bancroft T, Bouaouina M, Roberts S, Lee M, Calderwood DA, Schwartz M, Simons M, Sessa WC, Kyriakides TR. Up-regulation of Thrombospondin-2 in Akt1-null Mice Contributes to Compromised Tissue Repair Due to Abnormalities in Fibroblast Function*. Journal Of Biological Chemistry 2014, 290: 409-422. PMID: 25389299, PMCID: PMC4281743, DOI: 10.1074/jbc.m114.618421.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell MovementFibroblastsGene Expression RegulationGenetic Complementation TestIntegrin beta1MiceMice, KnockoutNeuropeptidesNitric Oxide Synthase Type IIIPrimary Cell CultureProto-Oncogene Proteins c-aktRac1 GTP-Binding ProteinRNA, Small InterferingSignal TransductionSkinThrombospondinsWound HealingWounds, Nonpenetrating
2012
The role of p21-activated kinase in the initiation of atherosclerosis
Jhaveri K, Debnath P, Chernoff J, Sanders J, Schwartz M. The role of p21-activated kinase in the initiation of atherosclerosis. BMC Cardiovascular Disorders 2012, 12: 55. PMID: 22824149, PMCID: PMC3489605, DOI: 10.1186/1471-2261-12-55.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAorta, ThoracicAortic DiseasesAtherosclerosisBiomechanical PhenomenaCells, CulturedDisease Models, AnimalEndothelial CellsFibronectinsGalectin 3ImmunohistochemistryInflammation MediatorsIntercellular Adhesion Molecule-1MaleMiceMice, Inbred C57BLMice, KnockoutP21-Activated KinasesRegional Blood FlowTranscription Factor RelBVascular Cell Adhesion Molecule-1ConceptsLesser curvatureNF-κB subunitsInflammatory activationEndothelial cellsAtherosclerosis-prone sitesPro-inflammatory functionsInflammatory marker expressionNormal chow dietArch of aortaInitiation of atherosclerosisInflammatory markersOverall inflammationChow dietInflammatory pathwaysYoung miceAtherosclerosis-susceptible regionsConclusionThese dataICAM-1VCAM-1NF-κBRelA NF-κB subunitMarker expressionLow levelsFibronectin depositionInflammation
2010
Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation
Feaver RE, Gelfand BD, Wang C, Schwartz MA, Blackman BR. Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation. Circulation Research 2010, 106: 1703-1711. PMID: 20378855, PMCID: PMC2891748, DOI: 10.1161/circresaha.109.216283.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortic DiseasesApolipoproteins EAtherosclerosisCells, CulturedDisease Models, AnimalEndothelium, VascularFeedback, PhysiologicalFibronectinsHemodynamicsHumansInflammationMechanotransduction, CellularMiceMice, Inbred C57BLMice, KnockoutNF-kappa BPlatelet Endothelial Cell Adhesion Molecule-1Pulsatile FlowRegional Blood FlowRNA InterferenceStress, MechanicalTime FactorsTransfectionUp-RegulationConceptsFN depositionAtheroprone flowPECAM-1FN expressionTranscription factor NF-kappaB.Platelet endothelial cell adhesion moleculeNF-kappaB activationNF-kappaB activityAtheroprone hemodynamicsHuman endothelial cellsEndothelial inflammationProinflammatory phenotypeAortic archInduction of fibronectinCarotid arteryCell adhesion moleculeExogenous fibronectinInflammatory signalingFN accumulationNF-kappaBSustained increaseNF-kappaB.Nuclear factorTransient increaseEndothelial cells
2009
Suppression 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
Endothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice
Harry BL, Sanders JM, Feaver RE, Lansey M, Deem TL, Zarbock A, Bruce AC, Pryor AW, Gelfand BD, Blackman BR, Schwartz MA, Ley K. Endothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice. Arteriosclerosis Thrombosis And Vascular Biology 2008, 28: 2003-2008. PMID: 18688018, PMCID: PMC2651147, DOI: 10.1161/atvbaha.108.164707.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAorta, AbdominalAorta, ThoracicApolipoproteins EAtherosclerosisBone Marrow CellsBone Marrow TransplantationCells, CulturedDietary FatsDisease Models, AnimalDisease ProgressionEndothelial CellsHumansMacrophagesMiceMice, Inbred C57BLMice, KnockoutNF-kappa BPlatelet Endothelial Cell Adhesion Molecule-1Regional Blood FlowRNA InterferenceRNA, Small InterferingStress, MechanicalVascular Cell Adhesion Molecule-1ConceptsEndothelial PECAM-1PECAM-1Aortic archAbdominal aortaNF-kappaBVascular cell adhesion molecule-1 expressionCell adhesion molecule-1 expressionAdhesion molecule-1 expressionCell adhesion molecule-1ApoE-deficient miceAtherosclerotic lesion sizeBone marrow transplantationAtherosclerotic lesion formationMolecule-1 expressionVCAM-1 expressionAdhesion molecule-1Endothelial cell adhesion molecule-1NF-kappaB activityNuclear NF-kappaBDisturbed flowMarrow transplantationMacrophage infiltrationLesser curvatureWestern dietDeficient mice
2006
Integrin-mediated adhesion regulates membrane order
Gaus K, Le Lay S, Balasubramanian N, Schwartz MA. Integrin-mediated adhesion regulates membrane order. Journal Of Cell Biology 2006, 174: 725-734. PMID: 16943184, PMCID: PMC2064315, DOI: 10.1083/jcb.200603034.Peer-Reviewed Original ResearchConceptsFocal adhesionsMembrane orderCholesterol-dependent domainsSpecific protein complexesLipid raft propertiesIntegrin-mediated adhesionFluorescent probe LaurdanProtein complexesRaft componentsDetachment of cellsRaft propertiesCell adhesionCell membraneSubunit BProbe LaurdanCaveolinCaveolaeAdhesionDomainImportant consequencesTyr14Caveolin1PhosphorylationTraffickingTwo-photon microscopy
2005
A mechanosensory complex that mediates the endothelial cell response to fluid shear stress
Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 2005, 437: 426-431. PMID: 16163360, DOI: 10.1038/nature03952.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDCadherinsCattleCell AdhesionCells, CulturedEndothelial CellsFemaleGene DeletionMechanotransduction, CellularMiceMice, KnockoutMultiprotein ComplexesNF-kappa BPlatelet Endothelial Cell Adhesion Molecule-1RatsStress, MechanicalVascular Endothelial Growth Factor Receptor-2ConceptsDownstream inflammatory genesPECAM-1 knockout miceVascular endothelial cell cadherinVascular remodellingHigh-affinity stateInflammatory genesNF-κBVascular homeostasisEndothelial cell responsesCell responsesMechanosensory complexPECAM-1Heterologous cellsPathway upstreamCardiac developmentIntegrin activationAtherogenesisMechanism of transductionPathwayMicePhospho-caveolin-1 mediates integrin-regulated membrane domain internalization
del Pozo MA, Balasubramanian N, Alderson NB, Kiosses WB, Grande-García A, Anderson RG, Schwartz MA. Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nature Cell Biology 2005, 7: 901-908. PMID: 16113676, PMCID: PMC1351395, DOI: 10.1038/ncb1293.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCaveolaeCaveolin 1CaveolinsCell AdhesionCell ProliferationDynamin IIEndocytosisExtracellular MatrixExtracellular Signal-Regulated MAP KinasesFocal AdhesionsIntegrinsMembrane MicrodomainsMiceMice, KnockoutMicroscopy, Electron, TransmissionNeoplasm InvasivenessNeoplasmsNIH 3T3 CellsPhosphatidylinositol 3-KinasesPhosphorylationRac GTP-Binding ProteinsConceptsCaveolin-1Cholesterol-enriched membrane microdomainsPhosphatidylinositol-3-OH kinaseCell detachmentNovel molecular mechanismCholesterol-rich domainsInhibition of ERKMembrane microdomainsFocal adhesionsDynamin 2Plasma membraneMolecular mechanismsTumor suppressionTyr-14Multiple pathwaysNormal cellsInternalizationERKRacPathwayCaveolaeKinasePhosphorylationAdhesionMicrodomains