Featured Publications
Control of cell state transitions
Rukhlenko O, Halasz M, Rauch N, Zhernovkov V, Prince T, Wynne K, Maher S, Kashdan E, MacLeod K, Carragher N, Kolch W, Kholodenko B. Control of cell state transitions. Nature 2022, 609: 975-985. PMID: 36104561, PMCID: PMC9644236, DOI: 10.1038/s41586-022-05194-y.Peer-Reviewed Original ResearchConceptsCell state transitionsCell fateCell statesCell fate transitionsCell fate decisionsSingle-cell dataNew biological insightsFate transitionsMovement of cellsFate decisionsWaddington landscapePhenotypic dataBiological insightsOmics datasetsOmics dataCellular modelMechanistic modelLandscape1FateCellsDevelopment pathwaysLandscapeBiologyState transitionsTherapeutic interventions
2024
Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets
Rukhlenko O, Imoto H, Tambde A, McGillycuddy A, Junk P, Tuliakova A, Kolch W, Kholodenko B. Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets. Cancers 2024, 16: 2354. PMID: 39001416, PMCID: PMC11240448, DOI: 10.3390/cancers16132354.Peer-Reviewed Original ResearchControl of cell movementCell linesCell statesLuminal BC cellsControl cell phenotypeWaddington landscapeTissue-derived cell linesCell movementOncogenic transformationSmall molecule inhibitorsSignaling nodeBC cell linesExpression profilesPerturbation datasetsNormal cell stateMolecule inhibitorsBC cellsCell phenotypeBasal BCBC subtypesBreast cancerOncogenic driversCellsCurrent biologicsBreast tissue cells
2020
Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D
Kennedy S, Jarboui M, Srihari S, Raso C, Bryan K, Dernayka L, Charitou T, Bernal-Llinares M, Herrera-Montavez C, Krstic A, Matallanas D, Kotlyar M, Jurisica I, Curak J, Wong V, Stagljar I, LeBihan T, Imrie L, Pillai P, Lynn M, Fasterius E, Al-Khalili Szigyarto C, Breen J, Kiel C, Serrano L, Rauch N, Rukhlenko O, Kholodenko B, Iglesias-Martinez L, Ryan C, Pilkington R, Cammareri P, Sansom O, Shave S, Auer M, Horn N, Klose F, Ueffing M, Boldt K, Lynn D, Kolch W. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D. Nature Communications 2020, 11: 499. PMID: 31980649, PMCID: PMC6981206, DOI: 10.1038/s41467-019-14224-9.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptor (EGFR) networkGrowth factor receptor networkFundamental biological processesColorectal cancer cellsCancer cellsEGFR networkTranscriptional regulationProtein complexesExtensive rewiringCellular phenotypesInteraction networksBiological processesOncogenic mutationsOncogenic KRAS mutationsReceptor networkGenetic alterationsProtein expressionPPInsMutationsCellsInteractorsPhosphorylationRewiringPoor patient outcomesSignal flow
2015
G 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 circuitryCellsConformationResponseCues
2012
Bimodal Protein Distributions in Heterogeneous Oscillating Systems
Dobrzyński M, Fey D, Nguyen L, Kholodenko B. Bimodal Protein Distributions in Heterogeneous Oscillating Systems. Lecture Notes In Computer Science 2012, 7605: 17-28. DOI: 10.1007/978-3-642-33636-2_3.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 Research
2000
Diffusion control of protein phosphorylation in signal transduction pathways
KHOLODENKO B, BROWN G, HOEK J. Diffusion control of protein phosphorylation in signal transduction pathways. Biochemical Journal 2000, 350: 901-907. PMID: 10970807, PMCID: PMC1221325, DOI: 10.1042/bj3500901.Peer-Reviewed Original ResearchConceptsProtein phosphorylationProtein kinasePhosphorylation fluxProtein diffusionSignal transduction pathwaysProtein phosphataseSpherical cellsTransduction pathwaysDifferent cellular geometriesCellular locationPlasma membranePlanar membranesKinaseCell membraneCellular geometryProtein diffusion coefficientsPhosphatasePhosphorylationCell centerProteinMembraneCellsSpatial gradientsCytoplasmPathwayCellular information transfer regarded from a stoichiometry and control analysis perspective
Schuster S, Kholodenko B, Westerhoff H. Cellular information transfer regarded from a stoichiometry and control analysis perspective. Biosystems 2000, 55: 73-81. PMID: 10745111, DOI: 10.1016/s0303-2647(99)00085-4.Peer-Reviewed Original ResearchEngineering a Living Cell to Desired Metabolite Concentrations and Fluxes: Pathways with Multifunctional Enzymes
Kholodenko B, Westerhoff H, Schwaber J, Cascante M. Engineering a Living Cell to Desired Metabolite Concentrations and Fluxes: Pathways with Multifunctional Enzymes. Metabolic Engineering 2000, 2: 1-13. PMID: 10935931, DOI: 10.1006/mben.1999.0132.Peer-Reviewed Original ResearchConceptsMultifunctional enzymeRest of metabolismMetabolic engineeringMetabolic control analysisCellular pathwaysCellular metabolismMolecular geneticsCellular enzymesLiving cellsEnzymeMetabolismPathwayGeneticsMachineryMetabolic patternsEnzyme concentrationSingle intermediateModulationCellsMetabolite concentrationsPatterns
1999
Spatial gradients of cellular phospho‐proteins
Brown G, Kholodenko B. Spatial gradients of cellular phospho‐proteins. FEBS Letters 1999, 457: 452-454. PMID: 10471827, DOI: 10.1016/s0014-5793(99)01058-3.Peer-Reviewed Original ResearchConceptsCellular signalingProtein kinaseDifferent cellular geometriesCellular locationPlasma membranePhosphorylated formPlanar membranesProtein diffusionPhosphatase activityKinaseCellular geometryProtein diffusion coefficientsSpatial gradientsSpherical cellsProteinMembraneSuch gradientsCellsSignalingCytoplasmPhosphataseImportant implicationsGradientPotential size
1996
Direct Transfer of Control and Multidrug Resistance
Westerhoff H, Rohwer J, Heijn M, Mülder S, Ghauharali R, Wielinga P, Kholodenko B, Spoelstra E, Lankelma J. Direct Transfer of Control and Multidrug Resistance. NATO Science Series A: 1996, 283-292. DOI: 10.1007/978-1-4615-5845-3_29.Peer-Reviewed Original ResearchPhosphotransferase systemIntact cellsBacterial phosphotransferase systemPlasma membrane vesiclesCellular processesPTS enzymesSignal transductionPlasma membraneKinetic propertiesMultidrug pumpMembrane vesiclesIntracellular daunorubicin concentrationMultidrug resistanceIntricate organizationP-glycoproteinModel systemIntact systemDrug effluxDrug pumpCellsPassive permeabilityDirect transferTransductionDistribution of controlDNA
1995
Energy, control and DNA structure in the living cell
Wijker J, Jensen P, Snoep J, Gomes A, Guiral M, Jongsma A, de Waal A, Hoving S, van Dooren S, van der Weijden C, van Workum M, van Heeswijk W, Molenaar O, Wielinga P, Richard P, Diderich J, Bakker B, Teusink B, Hemker M, Rohwer J, van der Gugten A, Kholodenko B, Westerhoff H. Energy, control and DNA structure in the living cell. Biophysical Chemistry 1995, 55: 153-165. PMID: 7632875, DOI: 10.1016/0301-4622(94)00148-d.Peer-Reviewed Original ResearchConceptsHigh ATP/ADP ratiosATP/ADP ratioCell physiologyADP ratioCertain cell typesCellular functionsIntracellular ATP levelsTransduction pathwaysDNA structureLiving cellsCell typesIon gradientsHomeostatic control mechanismsATP levelsCell functionElaborate controlPhysiologyCellsControl mechanismsMaintenanceHIERARCHIES IN CONTROL
JENSEN P, VAN DER GUGTEN A, BIER M, VAN HEESWIJK W, ROHWER J, MOLENAAR D, VAN WORKUM M, RICHARD P, TEUSINK B, BAKKER B, KHOLODENKO B, WESTERHOFF H. HIERARCHIES IN CONTROL. Journal Of Biological System 1995, 3: 139-144. DOI: 10.1142/s0218339095000137.Peer-Reviewed Original ResearchThe macroworld versus the microworld of biochemical regulation and control
Kholodenko B, Westerhoff H. The macroworld versus the microworld of biochemical regulation and control. Trends In Biochemical Sciences 1995, 20: 52-54. PMID: 7701560, DOI: 10.1016/s0968-0004(00)88955-0.Peer-Reviewed Original Research
1993
Multiplicity of Control
Westerhoff H, Jensen P, van der Gugten A, Kahn D, Kholodenko B, Schuster S, Oldenburg N, van Dam K, van Heeswijk W. Multiplicity of Control. 1993, 263-268. DOI: 10.1007/978-1-4615-2962-0_41.Peer-Reviewed Original Research