2019
Mapping connections in signaling networks with ambiguous modularity
Lill D, Rukhlenko O, Mc Elwee A, Kashdan E, Timmer J, Kholodenko B. Mapping connections in signaling networks with ambiguous modularity. Npj Systems Biology And Applications 2019, 5: 19. PMID: 31149348, PMCID: PMC6533310, DOI: 10.1038/s41540-019-0096-1.Peer-Reviewed Original ResearchConceptsModular Response AnalysisProtein abundanceProtein complexesNetwork reconstructionDownstream modulesRetroactive interactionsUpstream moduleComputational restorationNetwork modulesSuite of methodsAbundanceSuch complexesExperimental approachComplexesProteinEnzymePathwaySequestration effectNetwork responseDifferent modules
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
2008
Domain-oriented reduction of rule-based network models.
Borisov N, Chistopolsky A, Faeder J, Kholodenko B. Domain-oriented reduction of rule-based network models. IET Systems Biology 2008, 2: 342-51. PMID: 19045829, PMCID: PMC2628550, DOI: 10.1049/iet-syb:20070081.Peer-Reviewed Original ResearchConceptsMulti-domain proteinsAuxiliary proteinsMembrane-bound receptorsTranscriptional regulatorsProgenitor proteinsProtein interactionsComplex assemblyGrowth factor receptorProteinFactor receptorSpeciesCorrect mass balanceEffector functionsHeterodimerisationReceptorsSitesRegulatorAssemblyInteractionDomain
2005
Signaling through Receptors and Scaffolds: Independent Interactions Reduce Combinatorial Complexity
Borisov N, Markevich N, Hoek J, Kholodenko B. Signaling through Receptors and Scaffolds: Independent Interactions Reduce Combinatorial Complexity. Biophysical Journal 2005, 89: 951-966. PMID: 15923229, PMCID: PMC1366644, DOI: 10.1529/biophysj.105.060533.Peer-Reviewed Original ResearchConceptsProtein complexesComplex signaling networksDistinct physiological responsesSignaling networksAdaptor proteinDocking siteMolecular eventsTemporal dynamicsPhysiological responsesDistinct sitesIndependent interactionsBranched networkSeparate domainsMolecular speciesDomain-oriented approachCombinatorial increaseReceptorsIndividual sitesSitesComplexesScaffoldsSpeciesTens of thousandsProteinDifferent sites
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 ResearchInferring dynamic architecture of cellular networks using time series of gene expression, protein and metabolite data
Sontag E, Kiyatkin A, Kholodenko BN. Inferring dynamic architecture of cellular networks using time series of gene expression, protein and metabolite data. Bioinformatics 2004, 20: 1877-1886. PMID: 15037511, DOI: 10.1093/bioinformatics/bth173.Peer-Reviewed Original Research
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
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
Occurrence of paradoxical or sustained control by an enzyme when overexpressed: necessary conditions and experimental evidence with regard to hepatic glucokinase
DE ATAURI P, ACERENZA L, KHOLODENKO B, DE LA IGLESIA N, GUINOVART J, AGIUS L, CASCANTE M. Occurrence of paradoxical or sustained control by an enzyme when overexpressed: necessary conditions and experimental evidence with regard to hepatic glucokinase. Biochemical Journal 2001, 355: 787-793. PMID: 11311143, PMCID: PMC1221796, DOI: 10.1042/bj3550787.Peer-Reviewed Original ResearchConceptsRegulatory proteinsFlux control coefficientsParadoxical controlHigh flux control coefficientAllosteric enzymePathway fluxHepatic glucokinaseEnzymeEnzyme activitySigmoidal kineticsEnzyme kineticsControl coefficientsProteinEnzyme increasesGlucokinaseHill coefficientSubstrate concentrationEnzyme concentration
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 gradientsCytoplasmPathwayWhy cytoplasmic signalling proteins should be recruited to cell membranes
Kholodenko B, Hoek J, Westerhoff H, Kholodenko B, Hoek J, Westerhoff H. Why cytoplasmic signalling proteins should be recruited to cell membranes. Trends In Cell Biology 2000, 10: 173-178. PMID: 10754559, DOI: 10.1016/s0962-8924(00)01741-4.Peer-Reviewed Original ResearchConceptsSignal transduction proteinsSignal transduction chainTransduction proteinsCytoplasmic signaling proteinsMembrane localizationAdaptor proteinSignaling proteinsMembrane proteinsSignal transductionPlasma membraneRate of encounterImportant structural constraintsCell membraneProteinExtent of activationMembraneNumber of complexesDownstream processesActivationLocalizationTransductionReceptorsStructural constraintsLow concentrationsComplexes
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