Featured Publications
Untangling the wires: A strategy to trace functional interactions in signaling and gene networks
Kholodenko BN, Kiyatkin A, Bruggeman FJ, Sontag E, Westerhoff HV, Hoek JB. Untangling the wires: A strategy to trace functional interactions in signaling and gene networks. Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 12841-12846. PMID: 12242336, PMCID: PMC130547, DOI: 10.1073/pnas.192442699.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsMAP Kinase Signaling SystemModels, BiologicalModels, TheoreticalProtein BindingProtein KinasesSignal TransductionConceptsGene networksFunctional interactionMitogen-activated protein kinase cascadeProtein kinase cascadeProteomic data setsKinase cascadeCellular signalingLarge genomicsUnidentified elementsMechanistic levelCellular networkingSignalingCell systemGenomicsInteractionInteraction routesCascadeComputer-generated responsesNetwork responseCurrent methodologiesResponse
2024
Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells
Sevrin T, Imoto H, Robertson S, Rauch N, Dyn'ko U, Koubova K, Wynne K, Kolch W, Rukhlenko O, Kholodenko B. Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells. Cell Reports 2024, 43: 114710. PMID: 39240715, PMCID: PMC11474227, DOI: 10.1016/j.celrep.2024.114710.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Pancreatic DuctalCell Line, TumorDrug SynergismHumansMAP Kinase Signaling SystemPancreatic NeoplasmsProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)Raf KinasesConceptsPancreatic ductal adenocarcinomaResistance to RAFResistant PDAC cellsPancreatic cancer cellsPancreatic ductal adenocarcinoma cell linesProtein expression profilesTumor-specific variationsIsogenic pairsCell-specific modelsConformational specificityERK signalingInhibitor combinationsERK pathwayKRAS mutationsTargeted therapyExpression profilesMEK inhibitorsDuctal adenocarcinomaCancer cellsKRAS mutantPhospho-ERKCell linesPDAC cellsCell viabilityDifferential sensitivity
2020
Systems biology approaches to macromolecules: the role of dynamic protein assemblies in information processing
Rukhlenko O, Kholodenko B, Kolch W. Systems biology approaches to macromolecules: the role of dynamic protein assemblies in information processing. Current Opinion In Structural Biology 2020, 67: 61-68. PMID: 33126139, PMCID: PMC8062579, DOI: 10.1016/j.sbi.2020.09.007.Peer-Reviewed Original ResearchMeSH KeywordsHumansMacromolecular SubstancesMAP Kinase Signaling SystemNeoplasmsSignal TransductionSystems BiologyConceptsProtein assembliesProtein complex dynamicsDynamic protein assembliesMacromolecular protein assembliesSignal transduction networksSystems biology approachMEK-ERK pathwayProtein complexesTransduction networksCellular processesBiology approachMolecular machinesRAS-RAFOncogenic mutationsStructural studiesDrug resistanceTemporal dynamicsAssemblyRecent progressTumorigenesisMutationsPicture highlightsFine tuningPathwayDynamic process
2018
Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling
Rukhlenko OS, Khorsand F, Krstic A, Rozanc J, Alexopoulos LG, Rauch N, Erickson KE, Hlavacek WS, Posner RG, Gómez-Coca S, Rosta E, Fitzgibbon C, Matallanas D, Rauch J, Kolch W, Kholodenko BN. Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Cell Systems 2018, 7: 161-179.e14. PMID: 30007540, PMCID: PMC6149545, DOI: 10.1016/j.cels.2018.06.002.Peer-Reviewed Original ResearchConceptsOncogenic RASERK signalingRAS/ERK pathwayRAF inhibitorsOncogenic Ras signalingMEK/ERKStructure-based modelingRAF inhibitor resistanceRAS mutant tumorsRas signalingPosttranslational modificationsRaf kinaseERK activityRAF dimerizationDrug-protein interactionsERK pathwayMultiple inhibitorsColony formationSignalingMutant NRASCell proliferationDrug designParadoxical activationInhibitor resistanceMechanistic dynamic model
2016
Three-factor models versus time series models: quantifying time-dependencies of interactions between stimuli in cell biology and psychobiology for short longitudinal data
Frank TD, Kiyatkin A, Cheong A, Kholodenko BN. Three-factor models versus time series models: quantifying time-dependencies of interactions between stimuli in cell biology and psychobiology for short longitudinal data. Mathematical Medicine And Biology A Journal Of The IMA 2016, 34: 177-191. PMID: 27079221, DOI: 10.1093/imammb/dqw001.Peer-Reviewed Original ResearchConceptsBeta-adrenoceptor agonist clenbuterolGlucocorticoid receptor systemHuman embryonic kidney 293 cellsEmbryonic kidney 293 cellsAgonist clenbuterolTumor necrosisCritical time windowExtracellular signal-regulated kinases 1Mood disordersAntagonist drugsEpidermal growth factorAnimal studiesKidney 293 cellsCell responsesSignal-regulated kinases 1Behavioral levelGrowth factorCertain antagonistsLongitudinal dataERK activationHEK293 cellsKinase 1Cellular levelTime effectsTranscriptional activity
2015
Signalling mechanisms regulating phenotypic changes in breast cancer cells
Volinsky N, McCarthy CJ, von Kriegsheim A, Saban N, Okada-Hatakeyama M, Kolch W, Kholodenko BN. Signalling mechanisms regulating phenotypic changes in breast cancer cells. Bioscience Reports 2015, 35: e00178. PMID: 25643809, PMCID: PMC4370098, DOI: 10.1042/bsr20140172.Peer-Reviewed Original ResearchConceptsCell fate decisionsATP-citrate lyaseFate decisionsPhenotypic changesBreast cancer cellsEpidermal growth factorCell fate decision processesCancer cellsLipid accumulationIrreversible phenotypic changesPhosphoinositide-3 kinaseSimilar cellular responsesPI3K pathwayGrowth factorRapamycin complexKinase pathwayNegative regulatorMolecular mechanismsCellular responsesMetabolic pathwaysMammalian targetK pathwayCitrate lyaseLipogenic pathwayCell proliferation
2013
Pseudophosphatase STYX modulates cell-fate decisions and cell migration by spatiotemporal regulation of ERK1/2
Reiterer V, Fey D, Kolch W, Kholodenko BN, Farhan H. Pseudophosphatase STYX modulates cell-fate decisions and cell migration by spatiotemporal regulation of ERK1/2. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: e2934-e2943. PMID: 23847209, PMCID: PMC3732994, DOI: 10.1073/pnas.1301985110.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsCell DifferentiationCell MovementCell NucleusDual-Specificity PhosphatasesEnzyme ActivationGene Knockdown TechniquesGolgi ApparatusHumansIntracellular Signaling Peptides and ProteinsMAP Kinase Signaling SystemMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinase PhosphatasesNuclear ProteinsPC12 CellsRatsConceptsPC12 cell differentiationCell migrationCell differentiationDual-specificity phosphatase familyCell fate decisionsDirectional cell migrationNuclear anchorPhosphatase familySpatiotemporal regulationGolgi polarizationSpatial regulatorCellular signalingNuclear exportERK activityGolgi apparatusERK signalingERK1/2 activationImportant regulatorInactive membersSignalingRegulatorERK1/2StyxDifferentiationDUSPs
2009
Four‐dimensional dynamics of MAPK information‐processing systems
Kholodenko BN, Birtwistle MR. Four‐dimensional dynamics of MAPK information‐processing systems. WIREs Mechanisms Of Disease 2009, 1: 28-44. PMID: 20182652, PMCID: PMC2826817, DOI: 10.1002/wsbm.16.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsHumansMammalsMAP Kinase Signaling SystemReceptors, Cell SurfaceSystems BiologyYeastsConceptsMultiple target proteinsMyriad of stimuliCell surface receptorsMAPK cascadeActive kinasePhosphorylation signalsProtein phosphorylationCellular outcomesCytosolic localizationProtein kinaseEndocytotic traffickingPlasma membraneProtein activityTarget proteinsMembrane confinementXenopus eggsToggle switchKinaseMolecular motorsIntracellular gradientsSpatio-temporal guidanceLarge cellsFour-dimensional dynamicsPhosphorylationTrafficking
2004
Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades
Markevich N, Hoek J, Kholodenko B. Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. Journal Of Cell Biology 2004, 164: 353-359. PMID: 14744999, PMCID: PMC2172246, DOI: 10.1083/jcb.200308060.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEnzyme ActivationFeedback, PhysiologicalMAP Kinase Signaling SystemMitogen-Activated Protein KinasesModels, TheoreticalPhosphorylationConceptsExtracellular signal-regulated kinaseMultisite phosphorylationProtein kinase cascadeBistable switchSignal-regulated kinaseKinase cascadeMAPK cascadeWidespread mechanismDifferent kinasesSame phosphataseProtein kinasePositive feedback loopProtein activityDephosphorylation reactionsCovalent modificationKinaseMAPK phosphorylationFeedback regulationPhosphorylationKinetic propertiesPhosphataseFeedback loopCascade
2002
Modular Response Analysis of Cellular Regulatory Networks
BRUGGEMAN F, WESTERHOFF H, HOEK J, KHOLODENKO B. Modular Response Analysis of Cellular Regulatory Networks. Journal Of Theoretical Biology 2002, 218: 507-520. PMID: 12384053, DOI: 10.1006/jtbi.2002.3096.Peer-Reviewed Original ResearchConceptsRegulatory networksMitogen-activated protein kinase cascadeEpidermal growth factor receptor (EGFR) networkGrowth factor receptor networkProtein kinase cascadeIntermodular interactionsCellular regulatory networksModular Response AnalysisIntracellular regulatory networksAmmonium assimilationKinase cascadeMolecular biological analysisGenetic circuitsInteraction mapSignal transducingEscherichia coliReceptor networkModular organizationMolecular interactionsBiological analysisSignal transferColiTransducingRegulationInteractionMAP kinase cascade signaling and endocytic trafficking: a marriage of convenience?
Kholodenko BN. MAP kinase cascade signaling and endocytic trafficking: a marriage of convenience? Trends In Cell Biology 2002, 12: 173-177. PMID: 11978536, DOI: 10.1016/s0962-8924(02)02251-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell CompartmentationEndocytosisHumansMAP Kinase Signaling SystemMicrotubulesProtein TransportConceptsMitogen-activated protein kinase cascadeMembrane-bound kinaseSlow protein diffusionProtein kinase cascadeInhibitors of endocytosisTarget phosphoproteinsEffective signal transductionCytosolic phosphataseEndocytic traffickingKinase cascadePhosphorylation signalsSignal transductionEndocytic vesiclesRapid dephosphorylationMAP kinaseCascade signalingMAPK activationProtein diffusionMolecular motorsKinaseTraffickingProteinActive transportAdditional mechanismSuch gradients
2000
Negative feedback and ultrasensitivity can bring about oscillations in the mitogen‐activated protein kinase cascades
Kholodenko B. Negative feedback and ultrasensitivity can bring about oscillations in the mitogen‐activated protein kinase cascades. The FEBS Journal 2000, 267: 1583-1588. PMID: 10712587, DOI: 10.1046/j.1432-1327.2000.01197.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFeedbackMAP Kinase Signaling SystemModels, BiologicalPeriodicityPhosphorylationProtein Processing, Post-TranslationalConceptsMitogen-activated protein kinaseMAPK cascadeProtein kinaseProtein phosphorylation cascadeSlow protein diffusionNegative feedback loopPhosphorylation cascadeSignal transductionFeedback loopCellular targetsProtein diffusionMAPK phosphorylationPhosphorylation levelsCell typesIntracellular wavesKinasePhosphorylationCascadeFunctional organizationUltrasensitivityRecent kinetic dataExternal stimuliTransductionTotal proteinCytoplasm