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 ResearchConceptsGene networksFunctional interactionMitogen-activated protein kinase cascadeProtein kinase cascadeProteomic data setsKinase cascadeCellular signalingLarge genomicsUnidentified elementsMechanistic levelCellular networkingSignalingCell systemGenomicsInteractionInteraction routesCascadeComputer-generated responsesNetwork responseCurrent methodologiesResponse
2020
Inhaled multi-walled carbon nanotubes differently modulate global gene and protein expression in rat lungs
Seidel C, Zhernovkov V, Cassidy H, Kholodenko B, Matallanas D, Cosnier F, Gaté L. Inhaled multi-walled carbon nanotubes differently modulate global gene and protein expression in rat lungs. Nanotoxicology 2020, 15: 238-256. PMID: 33332178, DOI: 10.1080/17435390.2020.1851418.Peer-Reviewed Original ResearchConceptsNM-401Bronchoalveolar lavage fluidLong-term health effectsWeeks of inhalationDose-dependent increasePost-exposure timeLung inflammationLavage fluidWhole lungRat lungInhalationHealth effectsProtein expressionRecovery periodMechanisms of toxicityMWCNT exposureDifferent toxicological profilesLungToxicological profileDaysToxicological effectsPersistent effectsToxicityAnimalsToxicogenomic approach
2016
Rac1 and RhoA: Networks, loops and bistability
Nguyen LK, Kholodenko BN, von Kriegsheim A. Rac1 and RhoA: Networks, loops and bistability. Small GTPases 2016, 9: 316-321. PMID: 27533896, PMCID: PMC5997137, DOI: 10.1080/21541248.2016.1224399.Peer-Reviewed Original ResearchThree-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
Frequency modulation of ERK activation dynamics rewires cell fate
Ryu H, Chung M, Dobrzyński M, Fey D, Blum Y, Lee SS, Peter M, Kholodenko BN, Jeon NL, Pertz O. Frequency modulation of ERK activation dynamics rewires cell fate. Molecular Systems Biology 2015, 11: msb156458. PMID: 26613961, PMCID: PMC4670727, DOI: 10.15252/msb.20156458.Peer-Reviewed Original ResearchG Protein–Coupled Receptor Signaling Networks from a Systems Perspective
Roth S, Kholodenko B, Smit M, Bruggeman F. G Protein–Coupled Receptor Signaling Networks from a Systems Perspective. Molecular Pharmacology 2015, 88: 604-616. PMID: 26162865, DOI: 10.1124/mol.115.100057.Peer-Reviewed Original ResearchConceptsG protein-coupled receptorsRole of GPCRsSignal transduction networksProtein-protein interactionsSystems biology studiesSystems biology researchProtein-coupled receptorsCell surface receptorsSignaling networksExtracellular signalsMammalian cellsSignaling routeSingle proteinIntracellular proteinsExternal cuesAdaptive responseBiophysical conceptsProteinReceptorsFeedforward circuitryCellsConformationResponseCuesMitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation
Milewska M, Romano D, Herrero A, Guerriero ML, Birtwistle M, Quehenberger F, Hatzl S, Kholodenko BN, Segatto O, Kolch W, Zebisch A. Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation. PLOS ONE 2015, 10: e0129859. PMID: 26065894, PMCID: PMC4466796, DOI: 10.1371/journal.pone.0129859.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAdaptor Proteins, Signal TransducingAdultAnimalsCell Transformation, NeoplasticChlorocebus aethiopsCOS CellsErbB ReceptorsFeedback, PhysiologicalGene Expression Regulation, NeoplasticHEK293 CellsHumansMiceMiddle AgedMutation, MissenseProto-Oncogene Proteins B-rafThyroid NeoplasmsTumor Suppressor ProteinsConceptsMitogen-inducible gene 6Epidermal growth factor receptorOncogenic BRAFGrowth factor receptorGene 6Mig-6 expressionRAS-ERK pathwayRAS-ERK signalingFactor receptorNegative regulatory loopSignal-regulated kinaseInducible gene 6Focus formation assayBRAF kinase activityGenetic interactionsPI3K/AktCellular transformationTranscriptional levelBRAF functionCell line modelsKinase activityEGFR activationMethylation dataRegulatory loopNegative feedback circuit
2013
Systems biology‐embedded target validation: improving efficacy in drug discovery
Vandamme D, Minke BA, Fitzmaurice W, Kholodenko BN, Kolch W. Systems biology‐embedded target validation: improving efficacy in drug discovery. WIREs Mechanisms Of Disease 2013, 6: 1-11. PMID: 24214316, DOI: 10.1002/wsbm.1253.Peer-Reviewed Original ResearchConceptsSystems biology approachBiology approachDrug discoveryPotential drug targetsOmics technologiesMolecular mechanismsMultidrug treatmentDrug targetsMedical treatmentNovel targetDrug pipelineDrug developmentEfficacyAttrition ratesTreatmentDiscoveryGreater personalizationReductionist modelPatientsPseudophosphatase 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
Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle
Kaimachnikov NP, Kholodenko BN. Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle. The FEBS Journal 2009, 276: 4102-4118. PMID: 19627364, PMCID: PMC2924194, DOI: 10.1111/j.1742-4658.2009.07117.x.Peer-Reviewed Original ResearchFour‐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 ResearchConceptsMultiple 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
2008
Giving Space to Cell Signaling
Kholodenko BN, Kolch W. Giving Space to Cell Signaling. Cell 2008, 133: 566-567. PMID: 18485861, DOI: 10.1016/j.cell.2008.04.033.Peer-Reviewed Original Research
2005
Inference of signaling and gene regulatory networks by steady-state perturbation experiments: structure and accuracy
Andrec M, Kholodenko B, Levy R, Sontag E. Inference of signaling and gene regulatory networks by steady-state perturbation experiments: structure and accuracy. Journal Of Theoretical Biology 2005, 232: 427-441. PMID: 15572066, DOI: 10.1016/j.jtbi.2004.08.022.Peer-Reviewed Original Research
2004
Quantitative analysis of signaling networks
Sauro H, Kholodenko B. Quantitative analysis of signaling networks. Progress In Biophysics And Molecular Biology 2004, 86: 5-43. PMID: 15261524, DOI: 10.1016/j.pbiomolbio.2004.03.002.Peer-Reviewed Original ResearchSignal processing at the Ras circuit: what shapes Ras activation patterns?
Markevich NI, Moehren G, Demin OV, Kiyatkin A, Hoek JB, Kholodenko BN. Signal processing at the Ras circuit: what shapes Ras activation patterns? IET Systems Biology 2004, 1: 104-13. PMID: 17052120, DOI: 10.1049/sb:20045003.Peer-Reviewed Original ResearchConceptsP190 RhoGAPEpidermal growth factorActive GTP-bound stateGDP/GTP exchange factorGTP-bound stateSmall GTPase RasCellular signal transductionGTP exchange factorSystems biology approachSoluble tyrosine kinaseReceptor-mediated recruitmentSOS activationRasGAP activityRas proteinsCell fateExchange factorGTPase RasBiology approachRas mutantsSignal transductionInhibitory phosphorylationGTPase activityPlasma membraneRasGAPRegulatory mechanismsSignaling 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 ResearchConceptsExtracellular signal-regulated kinaseMultisite phosphorylationProtein kinase cascadeBistable switchSignal-regulated kinaseKinase cascadeMAPK cascadeWidespread mechanismDifferent kinasesSame phosphataseProtein kinasePositive feedback loopProtein activityDephosphorylation reactionsCovalent modificationKinaseMAPK phosphorylationFeedback regulationPhosphorylationKinetic propertiesPhosphataseFeedback loopCascade
2003
Control of spatially heterogeneous and time-varying cellular reaction networks: a new summation law
Peletier M, Westerhoff H, Kholodenko B. Control of spatially heterogeneous and time-varying cellular reaction networks: a new summation law. Journal Of Theoretical Biology 2003, 225: 477-487. PMID: 14615206, DOI: 10.1016/s0022-5193(03)00289-3.Peer-Reviewed Original ResearchConceptsMetabolic control analysisMembrane transportKinase/phosphatase systemCellular reaction networksIntracellular signaling pathwaysProtein networkIntracellular transportPhosphatase systemSignaling pathwaysControl coefficientsCell sizeSpherical cellsClassical metabolic control analysisActive mechanismProtein
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 ResearchConceptsMitogen-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
2001
Temperature Dependence of the Epidermal Growth Factor Receptor Signaling Network Can Be Accounted for by a Kinetic Model †
Moehren G, Markevich N, Demin O, Kiyatkin A, Goryanin I, Hoek JB, Kholodenko BN. Temperature Dependence of the Epidermal Growth Factor Receptor Signaling Network Can Be Accounted for by a Kinetic Model †. Biochemistry 2001, 41: 306-320. PMID: 11772030, DOI: 10.1021/bi011506c.Peer-Reviewed Original ResearchConceptsEpidermal growth factorEGF receptorEGFR kinaseDomain-mediated interactionsEGF receptor dimerizationProtein-protein interactionsRapid tyrosine phosphorylationMultiple signaling proteinsEGFR kinase activityReceptor phosphataseSignaling networksSignaling proteinsProtein interactionsPhosphorylation patternTyrosine phosphorylationReceptor dimerizationKinase activityTarget proteinsMembrane lipidsMolecular termsDephosphorylation reactionsEGFR pathwayPhosphataseKinasePhosphorylation