Featured Publications
Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias
Hu C, Leche CA, Kiyatkin A, Yu Z, Stayrook SE, Ferguson KM, Lemmon MA. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. Nature 2022, 602: 518-522. PMID: 35140400, PMCID: PMC8857055, DOI: 10.1038/s41586-021-04393-3.Peer-Reviewed Original ResearchKinetics of receptor tyrosine kinase activation define ERK signaling dynamics
Kiyatkin A, van Alderwerelt van Rosenburgh IK, Klein DE, Lemmon MA. Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics. Science Signaling 2020, 13 PMID: 32817373, PMCID: PMC7521189, DOI: 10.1126/scisignal.aaz5267.Peer-Reviewed Original ResearchEGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics
Freed DM, Bessman NJ, Kiyatkin A, Salazar-Cavazos E, Byrne PO, Moore JO, Valley CC, Ferguson KM, Leahy DJ, Lidke DS, Lemmon MA. EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 2017, 171: 683-695.e18. PMID: 28988771, PMCID: PMC5650921, DOI: 10.1016/j.cell.2017.09.017.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesEpidermal growth factor receptorEGFR ligandsEGFR extracellular regionG protein-coupled receptorsDifferent EGFR ligandsCellular programsDifferent activating ligandsEGFR dimersCell signalingGrowth factor receptorExtracellular regionDimeric conformationEGFR dimerizationNew therapeutic opportunitiesReceptor dimersTyrosine kinaseBreast cancer cellsDimerization strengthActivating ligandsFactor receptorCancer cellsEpigenTherapeutic opportunitiesBiased agonismCross-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 Research
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 ResearchConceptsCell 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
2013
Kinetochore kinesin CENP-E is a processive bi-directional tracker of dynamic microtubule tips
Gudimchuk N, Vitre B, Kim Y, Kiyatkin A, Cleveland DW, Ataullakhanov FI, Grishchuk EL. Kinetochore kinesin CENP-E is a processive bi-directional tracker of dynamic microtubule tips. Nature Cell Biology 2013, 15: 1079-1088. PMID: 23955301, PMCID: PMC3919686, DOI: 10.1038/ncb2831.Peer-Reviewed Original ResearchConceptsDynamic microtubule endsMicrotubule endsMicrotubule tipsKinetochore kinesin CENPCENP-E motorDynamic microtubule tipsSingle-molecule approachVertebrate mitosisSpindle microtubulesTail domainCENPStable associationKinetochoresPlus endsChromosomesMolecular frameworkCentromeresMitosisMicrotubulesTransportersMotor mechanismsStability of attachmentVitroActive roleComputational modellingRefinement of a DNA based Alzheimer disease epitope vaccine in rabbits
Ghochikyan A, Davtyan H, Petrushina I, Hovakimyan A, Movsesyan N, Davtyan A, Kiyatkin A, Cribbs D, Agadjanyan M. Refinement of a DNA based Alzheimer disease epitope vaccine in rabbits. Human Vaccines & Immunotherapeutics 2013, 9: 1002-1010. PMID: 23399748, PMCID: PMC3899134, DOI: 10.4161/hv.23875.Peer-Reviewed Original ResearchConceptsDNA epitope vaccineEpitope vaccineTh epitopesAlzheimer's diseaseStrong humoral immune responseHumoral immune responseB-cell epitopesΒ-amyloid peptideN-terminal aspartic acidDNA vaccinePoor immunogenicityAD therapyHuman β-amyloid peptideImmune responseAD casesBrain sectionsCell epitopesEfficacy studiesVaccineEx vivoRhesus monkeysImmunogenicityShort amyloidEpitopesRabbitsImmunogenicity, Efficacy, Safety, and Mechanism of Action of Epitope Vaccine (Lu AF20513) for Alzheimer's Disease: Prelude to a Clinical Trial
Davtyan H, Ghochikyan A, Petrushina I, Hovakimyan A, Davtyan A, Poghosyan A, Marleau AM, Movsesyan N, Kiyatkin A, Rasool S, Larsen AK, Madsen PJ, Wegener KM, Ditlevsen DK, Cribbs DH, Pedersen LO, Agadjanyan MG. Immunogenicity, Efficacy, Safety, and Mechanism of Action of Epitope Vaccine (Lu AF20513) for Alzheimer's Disease: Prelude to a Clinical Trial. Journal Of Neuroscience 2013, 33: 4923-4934. PMID: 23486963, PMCID: PMC3634356, DOI: 10.1523/jneurosci.4672-12.2013.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnalysis of VarianceAnimalsAntibodies, Anti-IdiotypicAntibody FormationBrainCells, CulturedCytokinesDisease Models, AnimalDose-Response Relationship, ImmunologicEnzyme-Linked Immunosorbent AssayEpitopes, B-LymphocyteEpitopes, T-LymphocyteFemaleGuinea PigsHumansImmunologic MemoryMacaca fascicularisMaleMiceMice, TransgenicMutationNeurogliaPeptide FragmentsPlaque, AmyloidProtein BindingSurface Plasmon ResonanceT-LymphocytesVaccinationVaccinesConceptsAnti-Aβ antibodiesMemory T helper cellsT cell responsesT helper cellsClinical trialsMild ADDisease processAutoreactive T cell responsesAD mouse modelAD-like pathologyCerebral amyloid angiopathyRecent clinical trialsTetanus toxoid vaccineStrong humoral immunityStrong humoral responseAlzheimer's disease processNeurotoxic Aβ peptidesMechanism of actionMicroglial activationAmyloid angiopathyImmunotherapeutic approachesSingle immunizationHumoral immunityHumoral responseToxoid vaccine
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
2010
PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells
Aksamitiene E, Kholodenko BN, Kolch W, Hoek JB, Kiyatkin A. PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells. Cellular Signalling 2010, 22: 1369-1378. PMID: 20471474, PMCID: PMC2893265, DOI: 10.1016/j.cellsig.2010.05.006.Peer-Reviewed Original ResearchMeSH KeywordsBreast NeoplasmsCarcinoma, Ductal, BreastCell Line, TumorEpidermal Growth FactorExtracellular Signal-Regulated MAP KinasesFemaleHumansIntercellular Signaling Peptides and ProteinsMAP Kinase Signaling SystemMitogen-Activated Protein Kinase KinasesMutationPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktReceptors, EstrogenConceptsERK activationERK phosphorylationEpidermal growth factorRas/mitogen-activated protein kinase cascadeMitogen-activated protein kinase cascadeEGF-induced ERK phosphorylationT47D breast cancer cellsBreast cancer cellsProtein kinase cascadeErbB-family ligandsClass I PI3KMCF7 cellsCancer cellsErbB receptor ligandsSmall molecule inhibitorsPI3K/AktKinase cascadeProtein kinasePI3K inhibitionCandidate proteinsPD 098059Cellular growthCell survivalFamily ligandsMolecule inhibitors
2009
Molecular Dynamics Simulations Reveal that Tyr-317 Phosphorylation Reduces Shc Binding Affinity for Phosphotyrosyl Residues of Epidermal Growth Factor Receptor
Suenaga A, Hatakeyama M, Kiyatkin AB, Radhakrishnan R, Taiji M, Kholodenko BN. Molecular Dynamics Simulations Reveal that Tyr-317 Phosphorylation Reduces Shc Binding Affinity for Phosphotyrosyl Residues of Epidermal Growth Factor Receptor. Biophysical Journal 2009, 96: 2278-2288. PMID: 19289054, PMCID: PMC2717265, DOI: 10.1016/j.bpj.2008.11.018.Peer-Reviewed Original ResearchConceptsSrc homology 2Epidermal growth factor receptorGrowth factor receptorPhospho-tyrosine binding (PTB) domainsLinker regionFull-length ShcPhospho-tyrosine residuesKey conformational changesFactor receptorShc interactionTyr-317Protein ShcTyrosine kinase receptorsPhosphorylated ShcPTB domainRas-mitogenHomology 2Phosphorylation resultsPhosphotyrosyl peptidesProtein kinaseTyrosine phosphorylationBinding domainsSubsequent phosphorylationPhosphotyrosyl residuesShcSystems‐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
2008
Detection of the active components of calf thymus nuclear proteins (TNP), histones that are binding with high affinity to HIV-1 envelope proteins and CD4 molecules.
Mamikonyan G, Kiyatkin A, Movsesyan N, Mkrtichyan M, Ghochikyan A, Petrushina I, Hwang J, Ichim T, Keledjian H, Agadjanyan M. Detection of the active components of calf thymus nuclear proteins (TNP), histones that are binding with high affinity to HIV-1 envelope proteins and CD4 molecules. Current HIV Research 2008, 6: 318-26. PMID: 18691030, DOI: 10.2174/157016208785132545.Peer-Reviewed Original ResearchConceptsCD4 moleculeHIV-1 receptors CD4HIV-1 envelope proteinHIV-1 patientsHIV-1 proteinsAnti-viral activityAIDS patientsClinical trialsImmune functionReceptor CD4CD4Viral entryHigh affinityEnvelope proteinPatientsViral moleculesGp120Active componentsMolecular mechanismsGel electrophoresisPossible mechanismImmunoaffinity chromatographyNuclear proteinsTandem mass spectrometryPlacebo
2007
Multistrip Western blotting to increase quantitative data output
Aksamitiene E, Hoek JB, Kholodenko B, Kiyatkin A. Multistrip Western blotting to increase quantitative data output. Electrophoresis 2007, 28: 3163-3173. PMID: 17722184, PMCID: PMC2410211, DOI: 10.1002/elps.200700002.Peer-Reviewed Original ResearchAnti-Aβ1–11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers*
Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan A, Petrushina I, Movsesyan N, Mina E, Kiyatkin A, Glabe C, Cribbs D, Agadjanyan M. Anti-Aβ1–11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers*. Journal Of Biological Chemistry 2007, 282: 22376-22386. PMID: 17545160, PMCID: PMC2435219, DOI: 10.1074/jbc.m700088200.Peer-Reviewed Original Research
2006
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