2023
An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells
Zhou W, Li W, Wang S, Salovska B, Hu Z, Tao B, Di Y, Punyamurtula U, Turk B, Sessa W, Liu Y. An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells. Nature Communications 2023, 14: 3803. PMID: 37365174, PMCID: PMC10293293, DOI: 10.1038/s41467-023-39514-1.Peer-Reviewed Original ResearchMeSH KeywordsEndothelial CellsHumansOptogeneticsPhosphorylationProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktSignal TransductionConceptsPhosphorylation sitesSerine/threonine kinase AktMass spectrometry-based phosphoproteomicsThreonine kinase AktAkt-dependent phosphorylationAberrant Akt activationEndothelial cellsKinase substrateKinase AktCell signalingPhosphorylation profilePhenotypic outcomesDownstream signalingAkt activationAkt1 phosphorylationHuman diseasesSystem-level analysisAKT1Vascular endothelial cellsRich resourcePhosphorylationSignalingGrowth factorAktCellsAcetate controls endothelial-to-mesenchymal transition
Zhu X, Wang Y, Soaita I, Lee H, Bae H, Boutagy N, Bostwick A, Zhang R, Bowman C, Xu Y, Trefely S, Chen Y, Qin L, Sessa W, Tellides G, Jang C, Snyder N, Yu L, Arany Z, Simons M. Acetate controls endothelial-to-mesenchymal transition. Cell Metabolism 2023, 35: 1163-1178.e10. PMID: 37327791, PMCID: PMC10529701, DOI: 10.1016/j.cmet.2023.05.010.Peer-Reviewed Original ResearchMeSH KeywordsEndothelial CellsEndotheliumHumansSignal TransductionTransforming Growth Factor betaVascular DiseasesConceptsTGF-β signalingChronic vascular diseaseTGF-β receptor ALK5Mesenchymal transitionInduction of EndMTVascular diseaseMolecular basisPositive feedback loopReceptor ALK5Cellular levelSMADs 2Novel targetEndMT inductionMetabolic modulationMetabolic basisFibrotic stateSignalingPotential treatmentEndMTTGFDiseaseActivationInductionACSS2PDK4
2001
Distinction between signaling mechanisms in lipid rafts vs. caveolae
Sowa G, Pypaert M, Sessa W. Distinction between signaling mechanisms in lipid rafts vs. caveolae. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 14072-14077. PMID: 11707586, PMCID: PMC61169, DOI: 10.1073/pnas.241409998.Peer-Reviewed Original ResearchConceptsCav-1Raft domainsLipid raftsCholesterol-rich lipid raft domainsLipid raft domainsCaveolae assemblyEndothelial nitric oxide synthaseCaveolae biogenesisAcylated proteinsSignal transductionSpatial regulationPlasma membraneNegative regulationCaveolin-1CaveolaeFirst clear exampleRaftsPhysical interactionProteinCellsRegulationENOS functionBiogenesisDomainClear exampleAkt-Mediated Phosphorylation of the G Protein-Coupled Receptor EDG-1 Is Required for Endothelial Cell Chemotaxis
Lee M, Thangada S, Paik J, Sapkota G, Ancellin N, Chae S, Wu M, Morales-Ruiz M, Sessa W, Alessi D, Hla T. Akt-Mediated Phosphorylation of the G Protein-Coupled Receptor EDG-1 Is Required for Endothelial Cell Chemotaxis. Molecular Cell 2001, 8: 693-704. PMID: 11583630, DOI: 10.1016/s1097-2765(01)00324-0.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell LineChemotaxisEndothelium, VascularEnzyme ActivationHumansImmediate-Early ProteinsLysophospholipidsModels, BiologicalNeovascularization, PhysiologicPhosphorylationProtein BindingProtein Serine-Threonine KinasesProtein Structure, TertiaryProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRac GTP-Binding ProteinsReceptors, Cell SurfaceReceptors, G-Protein-CoupledReceptors, LysophospholipidRecombinant Fusion ProteinsSignal TransductionSphingosineConceptsG protein-coupled receptor Edg-1EDG-1Cell migrationRac activationAkt-Mediated PhosphorylationCortical actin assemblyProtein kinase AktThird intracellular loopAkt bindsActin assemblyEndothelial cell migrationKinase AktSpecificity switchEndothelial cell chemotaxisCellular phenomenaDependent signalingIntracellular loopAktCell chemotaxisTransactivationPhosphorylationGPCRsChemotaxisActivationMutantsAkt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells*
Gratton J, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa W. Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells*. Journal Of Biological Chemistry 2001, 276: 30359-30365. PMID: 11387313, DOI: 10.1074/jbc.m009698200.Peer-Reviewed Original ResearchMeSH KeywordsAdenoviridaeAnimalsApoptosisBlotting, WesternCattleCell DeathCell LineCell SurvivalCells, CulturedDose-Response Relationship, DrugDown-RegulationEndothelial Growth FactorsEndothelium, VascularEnzyme ActivationEnzyme InhibitorsFlow CytometryHumansImidazolesLymphokinesMitogen-Activated Protein KinasesP38 Mitogen-Activated Protein KinasesPhosphatidylinositol 3-KinasesPhosphorylationProtein BindingProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktPyridinesSignal TransductionTime FactorsUmbilical VeinsVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsConceptsMEKK3 phosphorylationP38 activationMEKK3 kinase activityMitogen-activated protein kinaseP38 mitogen-activated protein kinaseP38-dependent apoptosisP38 MAPK inhibitor SB203580Dominant-negative RacInhibition of PIActivation of MKK3/6Vascular endothelial growth factorMAPK inhibitor SB203580P38 MAPK pathwayP38 MAPK activationEndothelial cellsEndothelial cell survivalGrowth factorRac activationProtein kinaseActive AktPro-apoptotic effectsKinase activityInhibitor SB203580MAPK activationP38 signalingSphingosine 1-Phosphate Activates Akt, Nitric Oxide Production, and Chemotaxis through a GiProtein/Phosphoinositide 3-Kinase Pathway in Endothelial Cells*
Morales-Ruiz M, Lee M, Zöllner S, Gratton J, Scotland R, Shiojima I, Walsh K, Hla T, Sessa W. Sphingosine 1-Phosphate Activates Akt, Nitric Oxide Production, and Chemotaxis through a GiProtein/Phosphoinositide 3-Kinase Pathway in Endothelial Cells*. Journal Of Biological Chemistry 2001, 276: 19672-19677. PMID: 11278592, DOI: 10.1074/jbc.m009993200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, NorthernBlotting, WesternCattleCell MovementChemotaxisCulture Media, Serum-FreeDose-Response Relationship, DrugEndothelial Growth FactorsEndothelium, VascularEnzyme ActivationGenes, DominantGTP-Binding Protein alpha Subunits, Gi-GoLungLymphokinesLysophospholipidsNeovascularization, PhysiologicNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IIIPhosphatidylinositol 3-KinasesPhosphorylationProtein BindingProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptors, Cell SurfaceSignal TransductionSphingosineTime FactorsVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVirulence Factors, BordetellaConceptsEndothelial differentiation gene familySerine/threonine kinase AktHeterotrimeric G proteinsThreonine kinase AktEDG-1 receptorGene familyAkt substrateKinase AktEndothelial cell chemotaxisActivates AktENOS phosphorylationAkt activationG proteinsCell survivalEndothelial nitric oxide synthasePhosphorylationAktCell chemotaxisSppSignalingGrowth factorVascular endothelial growth factorChemotaxisEndothelial cellsSphingosineThe Sonic Hedgehog Receptor Patched Associates with Caveolin-1 in Cholesterol-rich Microdomains of the Plasma Membrane* 210
Karpen H, Bukowski J, Hughes T, Gratton J, Sessa W, Gailani M. The Sonic Hedgehog Receptor Patched Associates with Caveolin-1 in Cholesterol-rich Microdomains of the Plasma Membrane* 210. Journal Of Biological Chemistry 2001, 276: 19503-19511. PMID: 11278759, DOI: 10.1074/jbc.m010832200.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBinding SitesBlotting, WesternCaveolin 1CaveolinsCell MembraneCholesterolCOS CellsDNA, ComplementaryDrosophila ProteinsElectrophoresis, Polyacrylamide GelGlutathione TransferaseHumansImmunohistochemistryMembrane MicrodomainsMembrane ProteinsMicroscopy, ConfocalModels, BiologicalMolecular Sequence DataMutationPatched ReceptorsPrecipitin TestsProtein BindingProtein Structure, TertiaryProtein TransportReceptors, Cell SurfaceReceptors, G-Protein-CoupledRecombinant Fusion ProteinsSignal TransductionSmoothened ReceptorSubcellular FractionsTime FactorsConceptsCholesterol-rich microdomainsRaft microdomainsCaveolin-1Receptor complexEarly embryonic patterningFractionation studiesHedgehog receptor complexCaveolin-enriched microdomainsBuoyant density fractionsEmbryonic patterningHh proteinsLipid raftsSubcellular localizationPlasma membranePatchedPlasmalemmal cholesterolProtein experimentsImmunoprecipitation studiesSmoothenedMicrodomainsConfocal microscopyImmunocytochemistry dataComplexesMembraneDrosophila
2000
Membrane Estrogen Receptor Engagement Activates Endothelial Nitric Oxide Synthase via the PI3-Kinase–Akt Pathway in Human Endothelial Cells
Haynes M, Sinha D, Russell K, Collinge M, Fulton D, Morales-Ruiz M, Sessa W, Bender J. Membrane Estrogen Receptor Engagement Activates Endothelial Nitric Oxide Synthase via the PI3-Kinase–Akt Pathway in Human Endothelial Cells. Circulation Research 2000, 87: 677-682. PMID: 11029403, DOI: 10.1161/01.res.87.8.677.Peer-Reviewed Original ResearchMeSH KeywordsAdenoviridaeBinding SitesCell MembraneCells, CulturedChromonesEndothelium, VascularEnzyme InhibitorsEstradiolGenes, DominantHumansMorpholinesNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IIIPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptors, EstrogenSerum Albumin, BovineSignal TransductionTransduction, GeneticConceptsPI3-kinaseKinase-Akt pathwayDominant-negative AktPI3-kinase inhibitorRapid eNOS phosphorylationRapid Akt phosphorylationActivation of eNOSAkt-dependent pathwayEndothelial nitric oxide synthaseAkt substratePhosphatidylinositol 3ENOS phosphorylationCritical residuesSerine 473Human endothelial cellsEstrogen receptor antagonist ICI 182Cell membrane sitesHuman endothelial cell lineAkt pathwayAkt phosphorylationPhosphorylationReceptor engagementEndothelial cell lineActivation eventsFunctional involvementGeldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti‐inflammatory effects and interacts with glucocorticoid receptor in vivo
Bucci M, Roviezzo F, Cicala C, Sessa W, Cirino G. Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti‐inflammatory effects and interacts with glucocorticoid receptor in vivo. British Journal Of Pharmacology 2000, 131: 13-16. PMID: 10960063, PMCID: PMC1572305, DOI: 10.1038/sj.bjp.0703549.Peer-Reviewed Original ResearchConceptsAnti-inflammatory effectsAnti-inflammatory actionEdema formationRU 486Heat shock protein 90Shock protein 90Endothelial nitric oxide synthaseEndothelium-dependent relaxationAnti-inflammatory dosePotential anti-inflammatory drugsVascular endothelial growth factorNitric oxide synthaseAnti-inflammatory drugsEndothelial growth factorDose-dependent mannerProtein 90Specific inhibitorIntact blood vesselsIntraplantar administrationPaw edemaMiddle arteryOxide synthaseRat aortaTherapeutic rationaleGlucocorticoid receptorThe HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.
Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer D, Sessa W, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nature Medicine 2000, 6: 1004-1010. PMID: 10973320, PMCID: PMC2828689, DOI: 10.1038/79510.Peer-Reviewed Original ResearchConceptsProtein kinase Akt/PKBKinase Akt/PKBProtein kinase AktAkt/PKBAkt-dependent mannerVascular structure formationActivation of AktKinase AktVascular endothelial growth factor treatmentEnhanced phosphorylationBlood vessel growthNew blood vessel growthAktGrowth factor treatmentVessel growthEndothelial cellsEndothelial nitric oxide synthaseRecent studiesHMG-CoA reductase inhibitor simvastatinAngiogenesisPKBFactor treatmentPhosphorylationReductase inhibitor simvastatinApoptosisVascular Endothelial Growth Factor–Stimulated Actin Reorganization and Migration of Endothelial Cells Is Regulated via the Serine/Threonine Kinase Akt
Morales-Ruiz M, Fulton D, Sowa G, Languino L, Fujio Y, Walsh K, Sessa W. Vascular Endothelial Growth Factor–Stimulated Actin Reorganization and Migration of Endothelial Cells Is Regulated via the Serine/Threonine Kinase Akt. Circulation Research 2000, 86: 892-896. PMID: 10785512, DOI: 10.1161/01.res.86.8.892.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCattleCell MovementCells, CulturedCytoskeletonEndothelium, VascularProtein Serine-Threonine KinasesSignal TransductionConceptsSignal transduction mechanismsCell migrationActin reorganizationActive AktMyr-AktSerine/threonine kinase AktCell signal transduction mechanismsTransduction mechanismsThreonine kinase AktVascular endothelial growth factorDominant-negative AktDistinct signal transduction mechanismsBovine lung microvascular endothelial cellsEndothelial cellsAbsence of VEGFActin cytoskeletonGrowth factorMicrovascular endothelial cellsKinase AktActin rearrangementStress fibersF-actinCell locomotionEndothelial growth factorEndothelial cell proliferation
1999
Caveolins, Liquid-Ordered Domains, and Signal Transduction
Smart E, Graf G, McNiven M, Sessa W, Engelman J, Scherer P, Okamoto T, Lisanti M. Caveolins, Liquid-Ordered Domains, and Signal Transduction. Molecular And Cellular Biology 1999, 19: 7289-7304. PMID: 10523618, PMCID: PMC84723, DOI: 10.1128/mcb.19.11.7289.Peer-Reviewed Original ResearchRegulation of endothelium-derived nitric oxide production by the protein kinase Akt
Fulton D, Gratton J, McCabe T, Fontana J, Fujio Y, Walsh K, Franke T, Papapetropoulos A, Sessa W. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999, 399: 597-601. PMID: 10376602, PMCID: PMC3637917, DOI: 10.1038/21218.Peer-Reviewed Original ResearchConceptsProtein kinase AktKinase AktSerine/threonine protein kinase AktMutant eNOSRole of phosphorylationEndothelial nitric oxide synthaseSerine 1179Akt substrateSignal transductionGene transferAktAdenovirus-mediated gene transferPhosphorylationGrowth factorVascular endothelial growth factorEndothelial cellsRegulationSynthase isoformsEndothelial growth factorNitric oxide productionTransductionVascular remodellingOxide productionIsoformsProductionA vascular bed–specific pathway regulates cardiac expression of endothelial nitric oxide synthase
Guillot P, Guan J, Liu L, Kuivenhoven J, Rosenberg R, Sessa W, Aird W. A vascular bed–specific pathway regulates cardiac expression of endothelial nitric oxide synthase. Journal Of Clinical Investigation 1999, 103: 799-805. PMID: 10079100, PMCID: PMC408151, DOI: 10.1172/jci6017.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthase geneEndothelial nitric oxide synthaseMurine endothelial progenitor cellsGrowth factor antibodyNitric oxide synthase geneNitric oxide synthaseEndothelial progenitor cellsOxide synthase geneFactor antibodyOxide synthaseVascular bedResponse elementCardiac expressionTransgenic micePDGF-ABCardiac endotheliumEno expressionCardiac myocytesSkeletal muscleProgenitor cellsSkeletal myocytesEndotheliumMiceBrainBeta-galactosidase activityInduction of Nitric Oxide Synthase mRNA by Shear Stress Requires Intracellular Calcium and G-protein Signals and Is Modulated by PI 3 Kinase
Malek A, Jiang L, Lee I, Sessa W, Izumo S, Alper S. Induction of Nitric Oxide Synthase mRNA by Shear Stress Requires Intracellular Calcium and G-protein Signals and Is Modulated by PI 3 Kinase. Biochemical And Biophysical Research Communications 1999, 254: 231-242. PMID: 9920763, DOI: 10.1006/bbrc.1998.9921.Peer-Reviewed Original ResearchConceptsNitric oxide synthase mRNAPTX-sensitive G proteinsENOS mRNA levelsENOS mRNABovine aortic endothelial cellsIntracellular calciumPertussis toxinMRNA upregulationEndothelial nitric oxide synthase (eNOS) mRNAMRNA levelsEndothelin-1 mRNACalmodulin inhibitor WENOS gene promoterG proteinsSynthase mRNAAortic endothelial cellsTime-dependent increaseTyrosine kinase inhibitor herbimycin ACalcium entryBAPTA-AMInhibitor WEndothelial cellsTyrosine kinase activityMicrotubule integrityLaminar fluid shear stress
1998
Dynamic activation of endothelial nitric oxide synthase by Hsp90
García-Cardeña G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa W. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 1998, 392: 821-824. PMID: 9580552, DOI: 10.1038/33934.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibiotics, AntineoplasticAortaBenzoquinonesCattleCell LineCOS CellsEndothelial Growth FactorsEndothelium, VascularEnzyme ActivationHistamineHSP90 Heat-Shock ProteinsHumansLactams, MacrocyclicLymphokinesMuscle RelaxationNitric OxideNitric Oxide SynthasePrecipitin TestsQuinonesRatsSignal TransductionStress, MechanicalTransfectionVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsConceptsActivation of eNOSCellular targetsHeat shock protein 90Binding of HSP90Specific cellular targetsEndothelial nitric oxide synthaseMolecular chaperonesHsp90 associatesSignaling proteinsProtein foldingProtein 90Mechanotransduction pathwaysENOS complexG proteinsFluid shear stressHsp90Activation statePrecise roleGrowth factorDynamic activationVascular endothelial growth factorSynthaseNitric oxide synthaseEndothelial growth factorActivation
1997
17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization.
Caulin-Glaser T, García-Cardeña G, Sarrel P, Sessa W, Bender J. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circulation Research 1997, 81: 885-92. PMID: 9351464, DOI: 10.1161/01.res.81.5.885.Peer-Reviewed Original ResearchConceptsHuman umbilical vein endothelial cellsEstrogen receptorCytosolic Ca2ENOS activityBasal nitric oxide releaseEndothelial NO synthase activityCardiovascular protective roleNO synthase activityDevelopment of atherosclerosisFemale human umbilical vein endothelial cellsNitric oxide releaseCritical effector moleculeUmbilical vein endothelial cellsVein endothelial cellsCardiovascular protectionEstradiol exposureAnimal modelsCGMP formationProtective roleOxide releaseEndothelial cellsNO releaseE2Physiological concentrationsEffector molecules