2015
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
Jambrina P, Rauch N, Pilkington R, Rybakova K, Nguyen L, Kholodenko B, Buchete N, Kolch W, Rosta E. Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation. Angewandte Chemie 2015, 128: 995-998. DOI: 10.1002/ange.201509272.Peer-Reviewed Original ResearchRAF dimerizationStructure-based mechanismPhysiological activation mechanismKinase dimerΑC-helixAcidic motifRaf kinaseRAF dimersR-spineConformational changesTrp residuesRAF inhibitorsPhosphorylationActivation mechanismKey playersSalt bridgeMotifKinaseCooperative interactionsRafPersonalized cancer therapyActive siteImportant targetResiduesPathwayDrug 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
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 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
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 roleU0126AktRegulatorEmploying Systems Biology to Quantify Receptor Tyrosine Kinase Signaling in Time and Space
Kholodenko B. Employing Systems Biology to Quantify Receptor Tyrosine Kinase Signaling in Time and Space. 2007, 300-318. DOI: 10.1007/978-1-59745-531-2_16.Peer-Reviewed Original ResearchProtein phosphorylation networksReceptor tyrosine kinase signalingTrafficking of endosomesPivotal physiological processesTyrosine kinase signalingPlasma membrane receptorsPhosphorylation networksUltrasensitive switchPhosphorylated kinasesKinase signalingEnvironmental cuesCell motilitySystems biologyNegative feedback circuitPhysiological processesCellular responsesMembrane receptorsLiving cellsCellular architectureSpatiotemporal response patternsComputational approachIntricate relationshipEndosomesKinaseMitosis
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
2002
MAP 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
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 gradientsCytoplasmPathwayNegative 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 ResearchConceptsMitogen-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