2021
Reengineering protein-phosphorylation switches
Kholodenko B, Okada M. Reengineering protein-phosphorylation switches. Science 2021, 373: 25-26. PMID: 34210865, PMCID: PMC8327301, DOI: 10.1126/science.abj5028.Peer-Reviewed Original Research
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
Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects
Kholodenko BN. Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects. Cell Reports 2015, 12: 1939-1949. PMID: 26344764, DOI: 10.1016/j.celrep.2015.08.014.Peer-Reviewed Original Research
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 ResearchMolecular Dynamics Simulations Reveal that Tyr-317 Phosphorylation Reduces Shc Binding Affinity for Phosphotyrosyl Residues of Epidermal Growth Factor Receptor
Suenaga A, Hatakeyama M, Kiyatkin AB, Radhakrishnan R, Taiji M, Kholodenko BN. Molecular Dynamics Simulations Reveal that Tyr-317 Phosphorylation Reduces Shc Binding Affinity for Phosphotyrosyl Residues of Epidermal Growth Factor Receptor. Biophysical Journal 2009, 96: 2278-2288. PMID: 19289054, PMCID: PMC2717265, DOI: 10.1016/j.bpj.2008.11.018.Peer-Reviewed Original ResearchConceptsSrc homology 2Epidermal growth factor receptorGrowth factor receptorPhospho-tyrosine binding (PTB) domainsLinker regionFull-length ShcPhospho-tyrosine residuesKey conformational changesFactor receptorShc interactionTyr-317Protein ShcTyrosine kinase receptorsPhosphorylated ShcPTB domainRas-mitogenHomology 2Phosphorylation resultsPhosphotyrosyl peptidesProtein kinaseTyrosine phosphorylationBinding domainsSubsequent phosphorylationPhosphotyrosyl residuesShcSystems‐level interactions between insulin–EGF networks amplify mitogenic signaling
Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, Kholodenko BN. Systems‐level interactions between insulin–EGF networks amplify mitogenic signaling. Molecular Systems Biology 2009, 5: msb200919. PMID: 19357636, PMCID: PMC2683723, DOI: 10.1038/msb.2009.19.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingCell LineDose-Response Relationship, DrugDrug SynergismEnzyme ActivationEpidermal Growth FactorGRB2 Adaptor ProteinHumansImmunoprecipitationInsulinMitogen-Activated Protein KinasesMitogensModels, BiologicalPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein Kinase InhibitorsProtein Tyrosine Phosphatase, Non-Receptor Type 11Ras ProteinsReproducibility of ResultsSignal TransductionSrc-Family KinasesSystems BiologyConceptsInsulin receptor substrateEpidermal growth factorRas/ERK cascadeCrosstalk mechanismsComplex cellular responsesPhosphatase SHP2Mitogenic signalingERK cascadeSrc kinaseReceptor substrateERK activityRaf levelsInsulin-induced increaseERK activationCellular responsesGab1HEK293 cellsExternal cuesEGF dosesPoor activatorGrowth factorMitogenicMitogenic responseComputational approachSHP2
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
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 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
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 ResearchMeSH KeywordsCell MembraneCytosolPhosphoprotein PhosphatasesPhosphoproteinsPhosphorylationProtein KinasesSignal TransductionConceptsProtein phosphorylationProtein kinasePhosphorylation fluxProtein diffusionSignal transduction pathwaysProtein phosphataseSpherical cellsTransduction pathwaysDifferent cellular geometriesCellular locationPlasma membranePlanar membranesKinaseCell membraneCellular geometryProtein diffusion coefficientsPhosphatasePhosphorylationCell centerProteinMembraneCellsSpatial gradientsCytoplasmPathwayKinetics and control of oxidative phosphorylation in rat liver mitochondria after chronic ethanol feeding.
Marcinkeviciute A, Mildaziene V, Crumm S, Demin O, Hoek J, Kholodenko B. Kinetics and control of oxidative phosphorylation in rat liver mitochondria after chronic ethanol feeding. Biochemical Journal 2000, 349: 519-26. PMID: 10880351, PMCID: PMC1221175, DOI: 10.1042/0264-6021:3490519.Peer-Reviewed Original ResearchConceptsOxidative phosphorylationRespiratory fluxMitochondrial proton leakRat liver mitochondriaMitochondrial oxidative phosphorylationCytochrome c oxidaseMitochondrial energy metabolismATP synthaseLiver mitochondriaProton leakC oxidaseProtonmotive forceState 3Blocks of reactionsPhosphorylationEnergy metabolismMitochondriaMitochondrial malfunctioningRespiration rateRespiratory activityRespiratory subsystemIndividual functional unitsFunctional unitsNegative 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
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
1998
Subtleties in control by metabolic channelling and enzyme organization
Kholodenko B, Rohwer J, Cascante M, Westerhoff H. Subtleties in control by metabolic channelling and enzyme organization. Molecular And Cellular Biochemistry 1998, 184: 311-320. PMID: 9746327, DOI: 10.1023/a:1006809028612.Peer-Reviewed Original ResearchConceptsPhosphotransferase systemMetabolic control analysisBacterial phosphotransferase systemEnzyme-enzyme associationsDirect metabolite transferEnzyme organizationConcomitant phosphorylationTernary complex formationPTS pathwayMetabolite transferEnzyme sequestrationMetabolic channellingLiving cellsMacromolecular crowdingPhosphoryl groupEnzyme controlTernary complexCell functionPathwayEnzymeComplex formationIdeal systemEnzyme control coefficientsMetabolic systemsControl coefficients