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
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
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
2007
Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses
Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, Kholodenko BN. Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analyses. Molecular Systems Biology 2007, 3: msb4100188. PMID: 18004277, PMCID: PMC2132449, DOI: 10.1038/msb4100188.Peer-Reviewed Original ResearchMeSH KeywordsAndrostadienesButadienesCell Line, TumorCell MembraneDimerizationEnzyme ActivationEpidermal Growth FactorExtracellular Signal-Regulated MAP KinasesFeedback, PhysiologicalHumansLigandsModels, BiologicalNeuregulin-1NitrilesPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein Structure, TertiaryProto-Oncogene Proteins c-aktReceptor Protein-Tyrosine KinasesReproducibility of ResultsSignal TransductionWortmanninConceptsEpidermal growth factorERK activityEGF-induced signalingMultiple human cancersPhosphoinositol-3 kinaseLigand-dependent responsesSustained signalingERK activationDownstream proteinsAkt activationInhibitor U0126Major regulatorHuman cancersErbB receptorsLigand dosesHeregulinErbBKinaseSignalingGrowth factorActivationKey roleU0126AktRegulator
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