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 ResearchMeSH KeywordsAnimalsFeedback, PhysiologicalHumansReceptors, G-Protein-CoupledSignal TransductionSystems BiologyConceptsG 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 circuitryCellsConformationResponseCuesMitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation
Milewska M, Romano D, Herrero A, Guerriero ML, Birtwistle M, Quehenberger F, Hatzl S, Kholodenko BN, Segatto O, Kolch W, Zebisch A. Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation. PLOS ONE 2015, 10: e0129859. PMID: 26065894, PMCID: PMC4466796, DOI: 10.1371/journal.pone.0129859.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAdaptor Proteins, Signal TransducingAdultAnimalsCell Transformation, NeoplasticChlorocebus aethiopsCOS CellsErbB ReceptorsFeedback, PhysiologicalGene Expression Regulation, NeoplasticHEK293 CellsHumansMiceMiddle AgedMutation, MissenseProto-Oncogene Proteins B-rafThyroid NeoplasmsTumor Suppressor ProteinsConceptsMitogen-inducible gene 6Epidermal growth factor receptorOncogenic BRAFGrowth factor receptorGene 6Mig-6 expressionRAS-ERK pathwayRAS-ERK signalingFactor receptorNegative regulatory loopSignal-regulated kinaseInducible gene 6Focus formation assayBRAF kinase activityGenetic interactionsPI3K/AktCellular transformationTranscriptional levelBRAF functionCell line modelsKinase activityEGFR activationMethylation dataRegulatory loopNegative feedback circuit
2013
Complexity of Receptor Tyrosine Kinase Signal Processing
Volinsky N, Kholodenko BN. Complexity of Receptor Tyrosine Kinase Signal Processing. Cold Spring Harbor Perspectives In Biology 2013, 5: a009043. PMID: 23906711, PMCID: PMC3721286, DOI: 10.1101/cshperspect.a009043.Peer-Reviewed Original ResearchConceptsCombinatorial varietySignal processingMathematical modelingSpecific system propertiesSpecific cell fate decisionsSystem propertiesNetwork behaviorReceptor tyrosine kinasesMultiple feedsSpatiotemporal dynamicsComputational approachExcitable responseIntricate landscapeCell fate decisionsSpecific cellular outcomesPathway cross talkOscillationsBistabilityNetwork circuitryDynamicsModelingTranscriptional controlAdapts cellsCellular outcomes
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
2008
Giving Space to Cell Signaling
Kholodenko BN, Kolch W. Giving Space to Cell Signaling. Cell 2008, 133: 566-567. PMID: 18485861, DOI: 10.1016/j.cell.2008.04.033.Peer-Reviewed Original ResearchAnimalsCell ShapeFeedback, PhysiologicalHippocampusNeuronsReceptors, Adrenergic, beta-2Signal Transduction
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 ResearchMeSH KeywordsAnimalsEnzyme ActivationFeedback, PhysiologicalMAP Kinase Signaling SystemMitogen-Activated Protein KinasesModels, TheoreticalPhosphorylationConceptsExtracellular signal-regulated kinaseMultisite phosphorylationProtein kinase cascadeBistable switchSignal-regulated kinaseKinase cascadeMAPK cascadeWidespread mechanismDifferent kinasesSame phosphataseProtein kinasePositive feedback loopProtein activityDephosphorylation reactionsCovalent modificationKinaseMAPK phosphorylationFeedback regulationPhosphorylationKinetic propertiesPhosphataseFeedback loopCascade