Featured Publications
Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops*
Kiyatkin A, Aksamitiene E, Markevich NI, Borisov NM, Hoek JB, Kholodenko BN. Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops*. Journal Of Biological Chemistry 2006, 281: 19925-19938. PMID: 16687399, PMCID: PMC2312093, DOI: 10.1074/jbc.m600482200.Peer-Reviewed Original ResearchConceptsEpidermal growth factorRas/MAPK signalingGab1 tyrosine phosphorylationGrowth factorRole of Gab1PI3K/Akt activationMultiple positive feedback loopsProtein Grb2Mutant proteinsScaffold proteinTyrosine phosphorylationBinder 1Positive feedback loopMitogenic pathwaysMAPK signalingEssential functionsSurvival signalingDiverse perturbationsCellular responsesAkt activationCytokine receptorsPharmacological inhibitorsGab1EGF dosesGrb2
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
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
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
2002
Modular Response Analysis of Cellular Regulatory Networks
BRUGGEMAN F, WESTERHOFF H, HOEK J, KHOLODENKO B. Modular Response Analysis of Cellular Regulatory Networks. Journal Of Theoretical Biology 2002, 218: 507-520. PMID: 12384053, DOI: 10.1006/jtbi.2002.3096.Peer-Reviewed Original ResearchConceptsRegulatory networksMitogen-activated protein kinase cascadeEpidermal growth factor receptor (EGFR) networkGrowth factor receptor networkProtein kinase cascadeIntermodular interactionsCellular regulatory networksModular Response AnalysisIntracellular regulatory networksAmmonium assimilationKinase cascadeMolecular biological analysisGenetic circuitsInteraction mapSignal transducingEscherichia coliReceptor networkModular organizationMolecular interactionsBiological analysisSignal transferColiTransducingRegulationInteraction