Featured Publications
Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance
Aksamitiene E, Kiyatkin A, Kholodenko BN. Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochemical Society Transactions 2012, 40: 139-146. PMID: 22260680, DOI: 10.1042/bst20110609.Peer-Reviewed Original ResearchUntangling 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 ResearchMeSH KeywordsAnimalsMAP Kinase Signaling SystemModels, BiologicalModels, TheoreticalProtein BindingProtein KinasesSignal TransductionConceptsGene networksFunctional interactionMitogen-activated protein kinase cascadeProtein kinase cascadeProteomic data setsKinase cascadeCellular signalingLarge genomicsUnidentified elementsMechanistic levelCellular networkingSignalingCell systemGenomicsInteractionInteraction routesCascadeComputer-generated responsesNetwork responseCurrent methodologiesResponse
2020
Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB.
Artim SC, Kiyatkin A, Lemmon MA. Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB. Biochemical Journal 2020, 477: 4053-4070. PMID: 33043964, PMCID: PMC7606831, DOI: 10.1042/bcj20200695.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain-Derived Neurotrophic FactorCatalytic DomainCell DifferentiationCell ProliferationGene Knockdown TechniquesKineticsMutationNerve Growth FactorsNerve Tissue ProteinsNeuroblastomaPC12 CellsPhosphorylationProtein DomainsRatsReceptor, trkAReceptor, trkBReceptors, Growth FactorRecombinant ProteinsRNA, Small InterferingSignal Transduction
2017
Modeling of Receptor Tyrosine Kinase Signaling: Computational and Experimental Protocols
Fey D, Aksamitiene E, Kiyatkin A, Kholodenko BN. Modeling of Receptor Tyrosine Kinase Signaling: Computational and Experimental Protocols. Methods In Molecular Biology 2017, 1636: 417-453. PMID: 28730495, DOI: 10.1007/978-1-4939-7154-1_27.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesReceptor tyrosine kinase signalingMultiple cellular processesTyrosine kinase signalingCellular processesProtein phosphorylationKinase signalingNetwork biologySystems biologyTyrosine kinaseCell survivalIntegration of experimentsPowerful approachIntegrative approachBiologyComputational protocolQuantitative datasetsKinasePhosphorylationSignalingIdentification of salientApoptosisDifferentiationGlucose metabolismRegulation
2016
Three-factor models versus time series models: quantifying time-dependencies of interactions between stimuli in cell biology and psychobiology for short longitudinal data
Frank TD, Kiyatkin A, Cheong A, Kholodenko BN. Three-factor models versus time series models: quantifying time-dependencies of interactions between stimuli in cell biology and psychobiology for short longitudinal data. Mathematical Medicine And Biology A Journal Of The IMA 2016, 34: 177-191. PMID: 27079221, DOI: 10.1093/imammb/dqw001.Peer-Reviewed Original ResearchConceptsBeta-adrenoceptor agonist clenbuterolGlucocorticoid receptor systemHuman embryonic kidney 293 cellsEmbryonic kidney 293 cellsAgonist clenbuterolTumor necrosisCritical time windowExtracellular signal-regulated kinases 1Mood disordersAntagonist drugsEpidermal growth factorAnimal studiesKidney 293 cellsCell responsesSignal-regulated kinases 1Behavioral levelGrowth factorCertain antagonistsLongitudinal dataERK activationHEK293 cellsKinase 1Cellular levelTime effectsTranscriptional activityThe Dark Side of Cell Signaling: Positive Roles for Negative Regulators
Lemmon MA, Freed DM, Schlessinger J, Kiyatkin A. The Dark Side of Cell Signaling: Positive Roles for Negative Regulators. Cell 2016, 164: 1172-1184. PMID: 26967284, PMCID: PMC4830124, DOI: 10.1016/j.cell.2016.02.047.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFeedback, PhysiologicalHumansPhosphorylationReceptor Protein-Tyrosine KinasesReceptors, G-Protein-CoupledSignal TransductionConceptsCell signalingNegative regulatorGTP/GDP cycleNew cellular statesKinase/phosphataseCell surface receptorsCellular statesSignal terminationSwitch-like transitionsSuch regulatorsReceptor internalizationGDP cycleReceptor signalingSignal activationKinetic proofreadingSignalingRegulatorOnly negative effectNegative signalsPositive roleImportant roleNegative effectsProofreadingPhosphataseInternalizationBistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches
Byrne KM, Monsefi N, Dawson JC, Degasperi A, Bukowski-Wills JC, Volinsky N, Dobrzyński M, Birtwistle MR, Tsyganov MA, Kiyatkin A, Kida K, Finch AJ, Carragher NO, Kolch W, Nguyen LK, von Kriegsheim A, Kholodenko BN. Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches. Cell Systems 2016, 2: 38-48. PMID: 27136688, PMCID: PMC4802415, DOI: 10.1016/j.cels.2016.01.003.Peer-Reviewed Original ResearchConceptsPAK inhibitionMesenchymal breast cancer cellsCell migrationActin cytoskeleton dynamicsRho small GTPase familyRac1 activation levelsSmall GTPase familySwitch-like responsePAK family kinasesSmall chemical inhibitorsCytoskeleton dynamicsActin dynamicsGTPase familyFamily kinasesGTPase activityBistable fashionInhibitory crosstalkChemical inhibitorsBreast cancer cellsMass spectrometry-based quantitationRac1RhoACell morphologyCancer cellsPAK
2012
Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise
Birtwistle MR, Rauch J, Kiyatkin A, Aksamitiene E, Dobrzyński M, Hoek JB, Kolch W, Ogunnaike BA, Kholodenko BN. Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise. BMC Systems Biology 2012, 6: 109. PMID: 22920937, PMCID: PMC3484110, DOI: 10.1186/1752-0509-6-109.Peer-Reviewed Original ResearchConceptsProtein expression noiseSingle-cell signalingExtracellular signal-regulated kinaseExpression noiseCell variabilityEpidermal growth factor stimulationProtein abundance variationCell fate decisionsPopulation responsesGrowth factor stimulationSingle cellsSignal-regulated kinaseCell population levelProtein expressionSingle-cell levelERK pathway activationFate decisionsPopulation levelFactor stimulationCell signalingCell population responseERK responseBiological outcomesPathway activationCell level
2011
Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells
Aksamitiene E, Achanta S, Kolch W, Kholodenko BN, Hoek JB, Kiyatkin A. Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells. Cellular Signalling 2011, 23: 1794-1805. PMID: 21726627, PMCID: PMC3156300, DOI: 10.1016/j.cellsig.2011.06.014.Peer-Reviewed Original ResearchMeSH KeywordsBreastBreast NeoplasmsCell Line, TumorFemaleGene Expression Regulation, NeoplasticGene SilencingHumansImmunoprecipitationMitogen-Activated Protein KinasesP21-Activated KinasesPhosphatidylinositol 3-KinasesPhosphorylationProlactinProtein BindingProto-Oncogene Proteins c-aktReal-Time Polymerase Chain ReactionRNA, Small InterferingSignal TransductionTransfectionConceptsBreast cancer cellsExtracellular signal-regulated kinases ERK1PI3-kinase/Akt pathwayDistinct signal transduction pathwaysERK1/2 mitogen-activated protein kinasesRac/PAK pathwayCancer cellsMitogen-activated protein kinaseSignal transduction pathwaysKinase/AktPDK1/AktJAK/STATSiRNA-mediated suppressionMAPK/ERKJAK2/STAT5MAPK signaling pathwaysRegulatory circuitsFAK activityKinases ERK1PAK pathwaySrc familyProtein interactionsProtein kinaseTransduction pathwaysPhosphoinositide 3
2009
Systems‐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
2004
Signal processing at the Ras circuit: what shapes Ras activation patterns?
Markevich NI, Moehren G, Demin OV, Kiyatkin A, Hoek JB, Kholodenko BN. Signal processing at the Ras circuit: what shapes Ras activation patterns? IET Systems Biology 2004, 1: 104-13. PMID: 17052120, DOI: 10.1049/sb:20045003.Peer-Reviewed Original ResearchConceptsP190 RhoGAPEpidermal growth factorActive GTP-bound stateGDP/GTP exchange factorGTP-bound stateSmall GTPase RasCellular signal transductionGTP exchange factorSystems biology approachSoluble tyrosine kinaseReceptor-mediated recruitmentSOS activationRasGAP activityRas proteinsCell fateExchange factorGTPase RasBiology approachRas mutantsSignal transductionInhibitory phosphorylationGTPase activityPlasma membraneRasGAPRegulatory mechanismsInferring 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
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