2018
The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling
Kofler N, Corti F, Rivera-Molina F, Deng Y, Toomre D, Simons M. The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. Journal Of Biological Chemistry 2018, 293: 4805-4817. PMID: 29425100, PMCID: PMC5880142, DOI: 10.1074/jbc.m117.812172.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEndosomesEndothelial CellsMiceMice, Inbred BALB CProtein TransportProtein Tyrosine Phosphatase, Non-Receptor Type 1Rab GTP-Binding ProteinsRab4 GTP-Binding ProteinsRab7 GTP-Binding ProteinsSignal TransductionVascular Endothelial Growth Factor Receptor-2Vesicular Transport ProteinsConceptsEndosomal traffickingVascular endothelial growth factor receptor 2Phosphotyrosine phosphatase 1BVEGFR2 traffickingEndothelial growth factor receptor 2Small GTPase Rab4Rab effector proteinsEndothelial cell functionRab7-positive endosomesCell functionRab GTPaseSorting endosomesCell surface expressionMaster regulatorEndosomal compartmentsVEGFR2 degradationPhosphatase 1BRABEP2Dependent signalingVascular developmentVEGFR2 signalingHigh-resolution microscopyTraffickingEndosomesBiochemical assays
2017
Novel ecto-tagged integrins reveal their trafficking in live cells
Huet-Calderwood C, Rivera-Molina F, Iwamoto DV, Kromann EB, Toomre D, Calderwood DA. Novel ecto-tagged integrins reveal their trafficking in live cells. Nature Communications 2017, 8: 570. PMID: 28924207, PMCID: PMC5603536, DOI: 10.1038/s41467-017-00646-w.Peer-Reviewed Original ResearchConceptsIntegrin functionΒ1 integrinLive cellsCell surface adhesion receptorsHeterodimeric cell-surface adhesion receptorsIntegrin endocytosisMulticellular organismsNovel powerful toolFocal adhesionsKnockout fibroblastsIntegrin activationAdhesion receptorsExtracellular loopIntegrinsTraffickingMajor mysteriesCellsTagsAdhesionHaloTagEndocytosisPowerful toolExocytosisOrganismsVesiclesExcess cholesterol inhibits glucose‐stimulated fusion pore dynamics in insulin exocytosis
Xu Y, Toomre DK, Bogan JS, Hao M. Excess cholesterol inhibits glucose‐stimulated fusion pore dynamics in insulin exocytosis. Journal Of Cellular And Molecular Medicine 2017, 21: 2950-2962. PMID: 28544529, PMCID: PMC5661106, DOI: 10.1111/jcmm.13207.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell MembraneCholesterolDiabetes Mellitus, Type 2DynaminsExocytosisGene Expression RegulationGlucoseHumansInsulinInsulin-Secreting CellsMembrane FusionMiceMicroscopy, FluorescenceModels, BiologicalPhosphatidylinositol 4,5-DiphosphateSecretory VesiclesSignal TransductionConceptsFusion pore dynamicsInsulin exocytosisFusion eventsPore dynamicsGlucose-triggered insulin secretionΒ-cellsFull fusionSingle granule levelTotal internal reflection fluorescence microscopySingle exocytic eventsReflection fluorescence microscopyImpairs β-cell functionExcess cholesterolGTPase dynaminExocytic eventsRole of cholesterolPlasma membranePancreatic β-cellsMolecular mechanismsInsulin granulesCompound exocytosisFusion kineticsΒ-cell dysfunctionExocytosisType 2 diabetes
2016
Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation
Zhou HJ, Qin L, Zhang H, Tang W, Ji W, He Y, Liang X, Wang Z, Yuan Q, Vortmeyer A, Toomre D, Fuh G, Yan M, Kluger MS, Wu D, Min W. Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation. Nature Medicine 2016, 22: 1033-1042. PMID: 27548575, PMCID: PMC5014607, DOI: 10.1038/nm.4169.Peer-Reviewed Original ResearchMeSH KeywordsAngiopoietin-1Angiopoietin-2AnimalsApoptosis Regulatory ProteinsBrainEndothelium, VascularEnzyme-Linked Immunosorbent AssayExocytosisFluorescent Antibody TechniqueGene Expression ProfilingHemangioma, Cavernous, Central Nervous SystemHumansIntracellular Signaling Peptides and ProteinsMembrane ProteinsMiceNerve Tissue ProteinsProto-Oncogene ProteinsReceptor, TIE-2Vesicle-Associated Membrane Protein 3Ultra-High Resolution 3D Imaging of Whole Cells
Huang F, Sirinakis G, Allgeyer ES, Schroeder LK, Duim WC, Kromann EB, Phan T, Rivera-Molina FE, Myers JR, Irnov I, Lessard M, Zhang Y, Handel MA, Jacobs-Wagner C, Lusk CP, Rothman JE, Toomre D, Booth MJ, Bewersdorf J. Ultra-High Resolution 3D Imaging of Whole Cells. Cell 2016, 166: 1028-1040. PMID: 27397506, PMCID: PMC5005454, DOI: 10.1016/j.cell.2016.06.016.Peer-Reviewed Original ResearchConceptsCell biological researchResolution 3D imagingHigh-resolution 3D imagingOptical nanoscopeSuper-resolution microscopyThree-dimensional structureMammalian cellsNuclear poresSynaptonemal complexFluorescence nanoscopyThick samplesThin samplesBiological researchNanoscopyInferior resolutionCellular volumeWhole cellsDepth directionMolecular architecturePractical biological applicationsBiological applicationsComplex molecular architecturesResolutionNanoscopeCellsOptogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action
Xu Y, Nan D, Fan J, Bogan JS, Toomre D. Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action. Journal Of Cell Science 2016, 129: 2085-2095. PMID: 27076519, PMCID: PMC4878990, DOI: 10.1242/jcs.174805.Peer-Reviewed Original ResearchConceptsPI3KGLUT4 translocationDistinct rolesAkt-independent pathwayNew optogenetic toolsGlucose transporter 4Drug-mediated inhibitionTranslocation responseIntracellular vesiclesOverall insulin actionPlasma membraneInsulin actionN-terminusOptogenetic toolsInsulin stimulationTransporter 4Biochemical assaysAktTranslocationAdipose cellsVesiclesPathwayCIB1PIP3Cells
2014
Reticulon 4 Is Necessary for Endoplasmic Reticulum Tubulation, STIM1-Orai1 Coupling, and Store-operated Calcium Entry
Jozsef L, Tashiro K, Kuo A, Park EJ, Skoura A, Albinsson S, Rivera-Molina F, Harrison KD, Iwakiri Y, Toomre D, Sessa WC. Reticulon 4 Is Necessary for Endoplasmic Reticulum Tubulation, STIM1-Orai1 Coupling, and Store-operated Calcium Entry. Journal Of Biological Chemistry 2014, 289: 9380-9395. PMID: 24558039, PMCID: PMC3969502, DOI: 10.1074/jbc.m114.548602.Peer-Reviewed Original ResearchConceptsSTIM1-Orai1 couplingER morphologyRedistribution of STIM1Store-operated calcium entryER tubulationER sheetsElevated cytoplasmicReticulon 4Functional consequencesRTN4SOCETubulationCalcium entryRecent advancesFundamental questionsSTIM1CytoplasmicHomeostasisApoptosisRegulationMechanisticallyFirst timeCellsMorphology
2013
A Network of Interactions Enables CCM3 and STK24 to Coordinate UNC13D-Driven Vesicle Exocytosis in Neutrophils
Zhang Y, Tang W, Zhang H, Niu X, Xu Y, Zhang J, Gao K, Pan W, Boggon TJ, Toomre D, Min W, Wu D. A Network of Interactions Enables CCM3 and STK24 to Coordinate UNC13D-Driven Vesicle Exocytosis in Neutrophils. Developmental Cell 2013, 27: 215-226. PMID: 24176643, PMCID: PMC3834565, DOI: 10.1016/j.devcel.2013.09.021.Peer-Reviewed Original ResearchConceptsNeutrophil degranulationAcute innate immune responseIschemia-reperfusion injuryInnate immune responseProtection of kidneyNeutrophil functionImmune responseInhibition of exocytosisTissue damageGranule poolGranule contentsDegranulationImportant regulatorImportant roleVesicle exocytosisExocytosisSTK24InjuryNeutrophilsKidneyUNC13DThe Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis
Lanahan A, Zhang X, Fantin A, Zhuang Z, Rivera-Molina F, Speichinger K, Prahst C, Zhang J, Wang Y, Davis G, Toomre D, Ruhrberg C, Simons M. The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis. Developmental Cell 2013, 25: 156-168. PMID: 23639442, PMCID: PMC3774154, DOI: 10.1016/j.devcel.2013.03.019.Peer-Reviewed Original ResearchAnimalsArteriesCells, CulturedCytoplasmEndocytosisEndosomesEndothelium, VascularMAP Kinase Signaling SystemMiceMorphogenesisNeovascularization, PathologicNeuropilin-1PhosphorylationSignal TransductionTransferrinVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Vesicular Transport Proteins
2012
Caveolae, Fenestrae and Transendothelial Channels Retain PV1 on the Surface of Endothelial Cells
Tkachenko E, Tse D, Sideleva O, Deharvengt SJ, Luciano MR, Xu Y, McGarry CL, Chidlow J, Pilch PF, Sessa WC, Toomre DK, Stan RV. Caveolae, Fenestrae and Transendothelial Channels Retain PV1 on the Surface of Endothelial Cells. PLOS ONE 2012, 7: e32655. PMID: 22403691, PMCID: PMC3293851, DOI: 10.1371/journal.pone.0032655.Peer-Reviewed Original ResearchConceptsFormation of diaphragmsRemoval of caveolaeDynamin-independent pathwayAbsence of caveolaeEndothelial cellsProtein levelsCellular rolesCavin-1Knockout phenotypesPlasma membraneCaveolin-1CaveolaeLung endothelial cellsCell surfaceRapid internalizationInternalization rateAbundance of structuresMice resultsTransendothelial channelsEssential componentOnly roleFenestral diaphragmsCellsClathrinTranscription
2011
Dual-mode of insulin action controls GLUT4 vesicle exocytosis
Xu Y, Rubin BR, Orme CM, Karpikov A, Yu C, Bogan JS, Toomre DK. Dual-mode of insulin action controls GLUT4 vesicle exocytosis. Journal Of Cell Biology 2011, 193: 643-653. PMID: 21555461, PMCID: PMC3166865, DOI: 10.1083/jcb.201008135.Peer-Reviewed Original ResearchMeSH Keywords3T3-L1 CellsAdipocytesAnimalsBiosensing TechniquesCarrier ProteinsExocytosisGlucose Transporter Type 4Green Fluorescent ProteinsInsulinIntracellular Signaling Peptides and ProteinsKineticsMembrane FusionMiceMicroscopy, FluorescenceMicroscopy, VideoPhospholipase DRecombinant Fusion ProteinsRNA InterferenceTransfectionTransport VesiclesVesicle-Associated Membrane Protein 2ConceptsGLUT4 storage vesiclesVesicle exocytosisInsulin-stimulated control cellsGLUT4 vesicle exocytosisPlasma membrane fusionNovel regulatory siteSingle vesicle exocytosisInsulin triggersVesicle trafficExocytic rateFusion poreSurface of adipocytesMembrane fusionRegulatory sitesPhospholipase DStorage vesiclesPore expansionExocytosisControl cellsAcute perturbationVesiclesInsulin actionVesicle characteristicsAdipocytesCells
2010
The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics
Nakatsu F, Perera RM, Lucast L, Zoncu R, Domin J, Gertler FB, Toomre D, De Camilli P. The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics. Journal Of Cell Biology 2010, 190: 307-315. PMID: 20679431, PMCID: PMC2922640, DOI: 10.1083/jcb.201005018.Peer-Reviewed Original ResearchConceptsClathrin-coated pitsNegative regulatorEndocytic clathrin-coated pitsClathrin-coated pit dynamicsPit maturationCCP lifetimeProduct phosphatidylinositolCoat assemblyCellular functionsMajor phosphoinositidePlasma membraneSHIP2SHIP2 expressionPit dynamicsDependent signalingReceptor signalingPhosphatidylinositolPhosphoinositide metabolismSignalingRegulatorInositolIntersectinPositive roleClathrinEndocytosis
2009
Exocyst is involved in polarized cell migration and cerebral cortical development
Letinic K, Sebastian R, Toomre D, Rakic P. Exocyst is involved in polarized cell migration and cerebral cortical development. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 11342-11347. PMID: 19549839, PMCID: PMC2708724, DOI: 10.1073/pnas.0904244106.Peer-Reviewed Original ResearchConceptsCell migrationDelivery of vesiclesNeuronal migrationVesicle tetheringExocyst complexMembrane trafficExocytic pathwayProtein complexesExocytic processExocystSpatial regulationEmbryonic developmentVesicle exocytosisSecretory vesiclesPlasma membraneTIRF microscopyPostmitotic cellsCortical neuronal migrationProper developmentCerebral cortical developmentWound assaysExocytosisVesiclesMembraneCells
2008
Automatic Detection of Large Dense-Core Vesicles in Secretory Cells and Statistical Analysis of Their Intracellular Distribution
Díaz E, Ayala G, Díaz ME, Gong LW, Toomre D. Automatic Detection of Large Dense-Core Vesicles in Secretory Cells and Statistical Analysis of Their Intracellular Distribution. IEEE/ACM Transactions On Computational Biology And Bioinformatics 2008, 7: 2-11. PMID: 20150664, DOI: 10.1109/tcbb.2008.30.Peer-Reviewed Original ResearchMeSH KeywordsAlgorithmsAnimalsAnimals, NewbornArtificial IntelligenceCells, CulturedChromaffin CellsChromaffin GranulesComputer SimulationData Interpretation, StatisticalImage EnhancementImage Interpretation, Computer-AssistedInformation Storage and RetrievalMiceMicroscopy, ElectronModels, BiologicalModels, StatisticalPattern Recognition, AutomatedReproducibility of ResultsSecretory VesiclesSensitivity and SpecificityConceptsPlasma membraneLarge dense-core vesiclesDense-core vesiclesDifferent spatial point processesRegulated exocytosisLocation of granulesStudy of secretionIntracellular distributionCell cytoplasmSecretory cellsDysfunctional secretionDifferent cellsFunctional descriptorsDifferent cell groupsAnalysis of diseasesVesiclesCellsMembraneNovel toolCell groupsDensity of granulesGranulesExocytosisCytoplasmMorphological appearance
2007
Internalization, Intracellular Trafficking, Biodistribution of Monoclonal Antibody 806: A Novel Anti-Epidermal Growth Factor Receptor Antibody
Perera RM, Zoncu R, Johns TG, Pypaert M, Lee FT, Mellman I, Old LJ, Toomre DK, Scott AM. Internalization, Intracellular Trafficking, Biodistribution of Monoclonal Antibody 806: A Novel Anti-Epidermal Growth Factor Receptor Antibody. Neoplasia 2007, 9: 1099-1110. PMID: 18084617, PMCID: PMC2134906, DOI: 10.1593/neo.07721.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorMonoclonal antibody 806EGFR antibodyAnti-epidermal growth factor receptor (EGFR) antibodiesGrowth factor receptor antibodyHuman tumor xenograftsSynergistic antitumor activityNude mouse modelXenografted nude mouse modelSignificant therapeutic efficacyGrowth factor receptorPoor prognosisReceptor antibodiesEGFR therapeuticsEpithelial tumorsMouse modelTumor xenograftsNude miceSingle agentToxin conjugatesTherapeutic efficacyTherapeutic useTumor modelBiodistribution analysisTumor cellsThe Tyrosine Kinase Activity of c-Src Regulates Actin Dynamics and Organization of Podosomes in Osteoclasts
Destaing O, Sanjay A, Itzstein C, Horne WC, Toomre D, De Camilli P, Baron R. The Tyrosine Kinase Activity of c-Src Regulates Actin Dynamics and Organization of Podosomes in Osteoclasts. Molecular Biology Of The Cell 2007, 19: 394-404. PMID: 17978100, PMCID: PMC2174183, DOI: 10.1091/mbc.e07-03-0227.Peer-Reviewed Original ResearchConceptsKinase activityActin cloudDynamic actin-rich structuresSrc family kinase activityDynamics of podosomesActin-rich structuresF-actin coresTyrosine kinase activityAbsence of SrcSrc mutantActin fluxActin dynamicsPodosome numbersEssential regulatorLife spanPodosomesActin polymerizationPodosome organizationF-actinPodosome structuresSrc inhibitorSrcFluorescence recoveryPodosome beltSpecific functions
2006
The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor
Murata T, Delprato A, Ingmundson A, Toomre DK, Lambright DG, Roy CR. The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nature Cell Biology 2006, 8: 971-977. PMID: 16906144, DOI: 10.1038/ncb1463.Peer-Reviewed Original ResearchConceptsGuanine nucleotide exchange factorsNucleotide exchange factorsType IV secretion apparatusIntracellular pathogen Legionella pneumophilaHost cellsEndoplasmic reticulum-derived vesiclesDot/IcmPathogen Legionella pneumophilaL. pneumophila mutantsRab1 recruitmentSubstrate proteinsRab familyExchange factorGTPase Rab1Secretion apparatusVesicular transportBacterial proteinsGolgi apparatusVisual screenEndoplasmic reticulumRab1Membrane transportSpecific membersDrrAIntracellular pathogens
2005
Phosphatidylinositol phosphate kinase type Iγ regulates dynamics of large dense-core vesicle fusion
Gong LW, Di Paolo G, Diaz E, Cestra G, Diaz ME, Lindau M, De Camilli P, Toomre D. Phosphatidylinositol phosphate kinase type Iγ regulates dynamics of large dense-core vesicle fusion. Proceedings Of The National Academy Of Sciences Of The United States Of America 2005, 102: 5204-5209. PMID: 15793002, PMCID: PMC555604, DOI: 10.1073/pnas.0501412102.Peer-Reviewed Original ResearchConceptsDense-core vesicle fusionLarge dense-core vesicle fusionLarge dense-core vesicle (LDCV) exocytosisDense-core vesicle exocytosisFusion pore expansionDirect genetic evidenceReleasable vesicle poolType IγVesicle exocytosisGenetic evidenceVesicle primingBisphosphate synthesisVesicle fusionKinetics of secretionImportant regulatorVesicle poolPore expansionNeuroendocrine tissuesPhosphatidylinositolFusion dynamicsChromaffin cellsI gammaKey role
2002
Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane
Chow A, Toomre D, Garrett W, Mellman I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 2002, 418: 988-994. PMID: 12198549, DOI: 10.1038/nature01006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationAntigens, CDCell DifferentiationCell MembraneCells, CulturedDendritic CellsEndocytosisEndosomesHistocompatibility Antigens Class IILysosome-Associated Membrane GlycoproteinsLysosomesMembrane GlycoproteinsMiceMice, Inbred C57BLMicroscopy, VideoProtein TransportStem CellsConceptsDendritic cellsMajor histocompatibility complex (MHC) class II moleculesLive dendritic cellsImmature dendritic cellsCo-stimulatory moleculesMHC II moleculesClass II moleculesInternalized antigensInflammatory mediatorsII-peptide complexesMHC-IIT lymphocytesImmune responseMHC class II transportPeptide antigensMaturation triggerClass II transportAntigenGreen fluorescent proteinCellsLysosomal compartmentPlasma membraneLysosomesTerminal degradative compartmentMicrobial products