2023
Heparin is essential for optimal cell signaling by FGF21 and for regulation of βKlotho cellular stability
An S, Mohanty J, Tome F, Suzuki Y, Lax I, Schlessinger J. Heparin is essential for optimal cell signaling by FGF21 and for regulation of βKlotho cellular stability. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2219128120. PMID: 36745784, PMCID: PMC9962926, DOI: 10.1073/pnas.2219128120.Peer-Reviewed Original ResearchConceptsHeparan sulfate proteoglycanCellular stabilityCell membraneSingle-molecule fluorescenceProtein kinase responsesChinese hamster ovary cellsFGF moleculesHamster ovary cellsFactor bindsReceptor assemblyReceptor dimerizationGrowth factor bindsHigh-affinity bindingFGF1 stimulationKinase responseCHO cellsOvary cellsSulfate proteoglycanIntracellular CaKlotho proteinFGFR1cPotential roleRegulationΒKlothoCells
2021
Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases
Sheetz J, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, Perttila R, Preuss F, Suresh K, Stayrook S, Tsutsui Y, Radhakrishnan R, Ungureanu D, Knapp S, Lemmon M. Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. The FASEB Journal 2021, 35 DOI: 10.1096/fasebj.2021.35.s1.02446.Peer-Reviewed Original ResearchReceptor tyrosine kinasesPseudokinase domainTyrosine kinaseTyrosine kinase-mediated signalingKey cellular processesKinase-mediated signalingExtracellular cuesViable drug targetTransduce signalsCellular processesEmbryonic developmentPseudokinasesTissue homeostasisFuture dissectionReceptor dimerizationStructural insightsKinase activityCancer hallmarksSignaling mechanismDrug targetsPutative routesKinaseOncogenic driversSmall moleculesPhosphotransfer
2017
Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF β receptor in an active dimeric conformation
Karabadzhak AG, Petti LM, Barrera FN, Edwards APB, Moya-Rodríguez A, Polikanov YS, Freites JA, Tobias DJ, Engelman DM, DiMaio D. Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF β receptor in an active dimeric conformation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e7262-e7271. PMID: 28808001, PMCID: PMC5584431, DOI: 10.1073/pnas.1705622114.Peer-Reviewed Original ResearchConceptsTransmembrane domainE5 proteinE5 dimerPlatelet-derived growth factor β receptorGrowth factor β receptorActive dimeric conformationPDGF β-receptorTransmembrane dimerProtein bindsMembrane environmentReceptor dimerizationDimeric conformationAtom molecular dynamics simulationsBiochemical experimentsMouse cellsMolecular mechanismsActive dimerΒ receptorBovine papillomavirusProteinSpecific interactionsMembrane modelingReceptor activationDimerizationComplexesDimerization of Tie2 mediated by its membrane-proximal FNIII domains
Moore JO, Lemmon MA, Ferguson KM. Dimerization of Tie2 mediated by its membrane-proximal FNIII domains. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 4382-4387. PMID: 28396397, PMCID: PMC5410832, DOI: 10.1073/pnas.1617800114.Peer-Reviewed Original ResearchConceptsExtracellular regionFNIII domainsResolution X-ray crystal structureMembrane-proximal fibronectin type III domainsDomain-mediated interactionsDifferent cellular contextsLigand-binding regionHigher-order oligomersTie2 activationFibronectin type III domainReceptor tyrosine kinasesTyrosine kinase familyEGF-homology domainThird FNIII domainType III domainPrevious structural studiesStructural studiesHomology domainCellular contextKinase familyDimer interfaceDimerization modeReceptor dimerizationTyrosine kinasePrimary activator
2015
Ligand regulation of a constitutively dimeric EGF receptor
Freed DM, Alvarado D, Lemmon MA. Ligand regulation of a constitutively dimeric EGF receptor. Nature Communications 2015, 6: 7380. PMID: 26060020, PMCID: PMC4465127, DOI: 10.1038/ncomms8380.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorLin-3Ligand-induced receptor dimerizationInsulin receptor family membersReceptor family membersLET-23Minor structural rearrangementsDomain compositionLigand regulationGrowth factor receptorDimerization armAllosteric changesExtracellular regionOligomerization stateReceptor dimerizationMutational analysisEGF receptorFactor receptorStructural rearrangementsKey eventsCovalent dimersStructural studiesFamily membersCaenorhabditisDimers
2014
Complex Relationship between Ligand Binding and Dimerization in the Epidermal Growth Factor Receptor
Bessman NJ, Bagchi A, Ferguson KM, Lemmon MA. Complex Relationship between Ligand Binding and Dimerization in the Epidermal Growth Factor Receptor. Cell Reports 2014, 9: 1306-1317. PMID: 25453753, PMCID: PMC4254573, DOI: 10.1016/j.celrep.2014.10.010.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorLigand bindingExtracellular regionGrowth factor receptorIntact epidermal growth factor receptorEGFR extracellular regionComplex allosteric regulationExtracellular epidermal growth factor receptorFactor receptorLigand-binding affinityAllosteric regulationReceptor dimerizationEGFR dimerizationAllosteric linkagePathological mutationsOncogenic mutationsNegative cooperativityMutationsDimerizationUnexpected relationshipBindingSpecific ligandsPivotal roleRecent advancesReceptorsSmall transmembrane protein inhibitors of the platelet‐derived growth factor β receptor (LB215)
Petti L, Talbert‐Slagle K, Chacon K, Hochstrasser M, DiMaio D. Small transmembrane protein inhibitors of the platelet‐derived growth factor β receptor (LB215). The FASEB Journal 2014, 28 DOI: 10.1096/fasebj.28.1_supplement.lb215.Peer-Reviewed Original ResearchTransmembrane domainTransmembrane proteinPlatelet-derived growth factor β receptorProtein inhibitorGrowth factor receptor signalingSingle conservative amino acid substitutionSmall transmembrane proteinConservative amino acid substitutionsGrowth factor β receptorParticular tyrosine residueReceptor tyrosine kinasesAmino acid substitutionsSequence similarityGrowth factor receptorTraptamersReceptor dimerizationEffects of PDGFSmall proteinsTyrosine residuesExtracellular domainTyrosine kinaseAcid substitutionsReceptor signalingRetroviral libraryPDGFβRTemporal resolution of protein signaling (473.1)
Anderson K, Sohl C, Luo B, Mo S, Kim Y, Apetri M, Lew E, Furdui C, Schlessinger J. Temporal resolution of protein signaling (473.1). The FASEB Journal 2014, 28 DOI: 10.1096/fasebj.28.1_supplement.473.1.Peer-Reviewed Original ResearchReceptor tyrosine kinasesProtein signalingMultiple signal transduction pathwaysSpecific tyrosine residuesSignal transduction pathwaysSingle receptor tyrosine kinaseCellular processesTyrosine autophosphorylationOncogenic formsTransduction pathwaysRTK activityPhosphorylation modificationMutant formsReceptor dimerizationTyrosine residuesLigand bindingMolecular mechanismsTyrosine kinaseFunctional understandingOncogenic behaviorMolecular signaturesMultiple developmental disordersEarly dynamic eventsCell proliferationEssential role
2010
Spatial control of EGF receptor activation by reversible dimerization on living cells
Chung I, Akita R, Vandlen R, Toomre D, Schlessinger J, Mellman I. Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature 2010, 464: 783-787. PMID: 20208517, DOI: 10.1038/nature08827.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell Line, TumorCell PolarityCell SurvivalCHO CellsCricetinaeCricetulusDiffusionEnzyme ActivationEnzyme StabilityEpidermal Growth FactorErbB ReceptorsGene Expression RegulationGRB2 Adaptor ProteinHumansKineticsLigandsProtein MultimerizationProtein TransportSignal TransductionThermodynamicsConceptsLigand bindingEpidermal growth factor receptor moleculeType I receptor kinaseEGF receptor activationDimer formationReceptor kinaseReceptor dimerizationDimerization dynamicsReceptor dimersLiving cellsReceptor moleculesCell marginsDimer populationSpatial controlHuman carcinomasConformation changeDimerizationCell centerReceptor activationRate of dissociationCellsBindingActivationKinaseReversible dimerization
2009
Regulation of the epidermal growth factor receptor intracellular domain
Choi S, Lemmon M. Regulation of the epidermal growth factor receptor intracellular domain. The FASEB Journal 2009, 23: 883.2-883.2. DOI: 10.1096/fasebj.23.1_supplement.883.2.Peer-Reviewed Original ResearchC-terminal tailTyrosine kinase domainIntracellular domainJuxtamembrane regionJM regionEGFR intracellular domainEpidermal growth factor receptorC-tailEGFR extracellular regionC-tail regionReceptor intracellular domainEffects of mutationsReceptor tyrosine kinasesReceptor-receptor interactionsSmall-angle X-ray scatteringKinase assaysKinase domainGrowth factor receptorExtracellular regionReceptor dimerizationEGFR activationBaculovirus systemIntracellular dimerTyrosine kinaseDeletion mutations
2008
The bovine papillomavirus E5 protein and the PDGF β receptor: It takes two to tango
Talbert-Slagle K, DiMaio D. The bovine papillomavirus E5 protein and the PDGF β receptor: It takes two to tango. Virology 2008, 384: 345-351. PMID: 18990418, PMCID: PMC2661243, DOI: 10.1016/j.virol.2008.09.033.Peer-Reviewed Original ResearchConceptsBovine papillomavirus E5 proteinE5 proteinTransmembrane domainTransmembrane proteinTarget proteinsPlatelet-derived growth factor beta receptorArtificial transmembrane proteinsMembrane-spanning segmentsHuman erythropoietin receptorBPV E5 proteinGrowth factor beta receptorCellular receptor tyrosine kinasesLigand-independent activationReceptor tyrosine kinasesGenetic screenPDGF β-receptorNovel proteinTransmembrane sequenceCellular proteinsMitogenic signalingHydrophobic proteinsReceptor dimerizationLarger target proteinsErythropoietin receptorSmall proteinsLigand-induced ErbB receptor dimerization
Lemmon MA. Ligand-induced ErbB receptor dimerization. Experimental Cell Research 2008, 315: 638-648. PMID: 19038249, PMCID: PMC2667204, DOI: 10.1016/j.yexcr.2008.10.024.Peer-Reviewed Original ResearchConceptsReceptor dimerizationEGF receptorCell surfaceStructural studiesReceptor tyrosine kinasesReceptor extracellular regionExtracellular regionSimple overexpressionImportant new insightsTyrosine kinaseIntact receptorCell transformationStructural predictionsWhole receptorErbB familyErbB receptorsEGF bindingNegative cooperativityMechanistic componentsKey mechanistic componentNew insightsDimerizationReceptorsHomodimerizationKinase
2007
Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor
Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J. Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor. Cell 2007, 130: 323-334. PMID: 17662946, DOI: 10.1016/j.cell.2007.05.055.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBinding SitesCrystallography, X-RayDimerizationDiseaseEnzyme ActivationHumansLigandsModels, MolecularMolecular Sequence DataMutationProtein BindingProtein Structure, SecondaryProtein Structure, TertiaryProto-Oncogene Proteins c-kitStem Cell FactorStructure-Activity RelationshipConceptsStem cell factorReceptor dimerizationLigand-induced receptor dimerizationCell factorMultiple cellular responsesTyrosine kinase activationReceptor tyrosine kinase KITKIT dimerizationTyrosine kinase KITDomain D4Structural basisCritical residuesKinase activationSCF stimulationCellular responsesConformational changesOncogenic mutationsCultured cellsAmino acidsPoint mutationsKIT activationEntire ectodomainKinase KITKey hallmarksSole role
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 pathwayPhosphataseKinasePhosphorylationMechanisms of cell transformation by papillomavirus E5 proteins
DiMaio D, Mattoon D. Mechanisms of cell transformation by papillomavirus E5 proteins. Oncogene 2001, 20: 7866-7873. PMID: 11753669, DOI: 10.1038/sj.onc.1204915.Peer-Reviewed Original ResearchConceptsE5 proteinBovine papillomavirus E5 proteinCellular signal transduction pathwaysSignal transduction pathwaysLigand-independent fashionGrowth factor receptor activityReceptor tyrosine kinasesTransforming proteinTransduction pathwaysGrowth factor receptorVacuolar ATPaseReceptor dimerizationTyrosine kinaseCell transformationProteinViral transformationBovine papillomavirusFactor receptorUnique mechanismStable complexesNew insightsReceptor activityPathwayReceptorsKinase
2000
The platelet-derived growth factor ß receptor as a target of the bovine papillomavirus E5 protein
DiMaio D, Lai C, Mattoon D. The platelet-derived growth factor ß receptor as a target of the bovine papillomavirus E5 protein. Cytokine & Growth Factor Reviews 2000, 11: 283-293. PMID: 10959076, DOI: 10.1016/s1359-6101(00)00012-5.Peer-Reviewed Original ResearchConceptsE5 proteinBovine papillomavirus E5 proteinSH2 domain-containing proteinsCellular signal transduction pathwaysDomain-containing proteinsSignal transduction complexSignal transduction pathwaysLigand-independent fashionGrowth factor receptor activitySpecific transmembraneTransduction complexCytoplasmic domainTransmembrane proteinTransduction pathwaysReceptor dimerizationTyrosine residuesAmino acidsProteinViral transformationDirect interactionBovine papillomavirusUnique mechanismStable complexesComplex formationNew insights
1999
Distinct Glucocorticoid Receptor Transcriptional Regulatory Surfaces Mediate the Cytotoxic and Cytostatic Effects of Glucocorticoids
Rogatsky I, Hittelman A, Pearce D, Garabedian M. Distinct Glucocorticoid Receptor Transcriptional Regulatory Surfaces Mediate the Cytotoxic and Cytostatic Effects of Glucocorticoids. Molecular And Cellular Biology 1999, 19: 5036-5049. PMID: 10373553, PMCID: PMC84339, DOI: 10.1128/mcb.19.7.5036.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsApoptosisCell CycleCell Cycle ProteinsCyclin-Dependent Kinase Inhibitor p21Cyclin-Dependent Kinase Inhibitor p27CyclinsCytotoxicity, ImmunologicDimerizationGlucocorticoidsHumansMicrotubule-Associated ProteinsMifepristoneMutagenesisProto-Oncogene Proteins c-bcl-2Receptors, GlucocorticoidTranscriptional ActivationTumor Cells, CulturedTumor Suppressor ProteinsConceptsTranscriptional repression functionRepression of Bcl2Saos2 cellsTranscriptional regulatory mechanismsAF-1Transcriptional activation functionTransactivation-deficient mutantAF-2Cyclin-dependent kinase inhibitorRepression functionTranscriptional activatorGlucocorticoid receptorRegulatory surfaceTarget genesCell contextReceptor dimerizationRegulatory mechanismsCytostatic actionHuman osteosarcoma cellsVariety of cellsGR mutantsCytostatic effectMolecular mechanismsCytotoxic effectsU20S cells
1998
Bovine papillomavirus E5 protein induces oligomerization and trans-phosphorylation of the platelet-derived growth factor β receptor
Lai C, Henningson C, DiMaio D. Bovine papillomavirus E5 protein induces oligomerization and trans-phosphorylation of the platelet-derived growth factor β receptor. Proceedings Of The National Academy Of Sciences Of The United States Of America 1998, 95: 15241-15246. PMID: 9860953, PMCID: PMC28027, DOI: 10.1073/pnas.95.26.15241.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAnimalsBovine papillomavirus 1CattleCell LineCell Line, TransformedCross-Linking ReagentsDimerizationHumansKineticsMacromolecular SubstancesMiceOncogene Proteins, ViralPhosphorylationProtein-Tyrosine KinasesReceptor, Platelet-Derived Growth Factor betaReceptors, Platelet-Derived Growth FactorRecombinant ProteinsSequence DeletionTransfectionConceptsBovine papillomavirus E5 proteinE5 proteinPDGF beta receptorCellular platelet-derived growth factor (PDGF) beta receptorKinase-negative mutant receptorPlatelet-derived growth factor beta receptorPlatelet-derived growth factor β receptorChemical cross-linking experimentsGrowth factor β receptorConstitutive tyrosine phosphorylationGrowth factor beta receptorLigand-independent fashionCross-linking experimentsReceptor tyrosine kinasesStable complexesExtracts of cellsPDGF beta-receptor activationIntramolecular autophosphorylationBeta receptorsCoimmunoprecipitation experimentsTransmembrane proteinReceptor activationTyrosine phosphorylationReceptor dimerizationMutant receptors
1997
Kit Receptor Dimerization Is Driven by Bivalent Binding of Stem Cell Factor*
Lemmon M, Pinchasi D, Zhou M, Lax I, Schlessinger J. Kit Receptor Dimerization Is Driven by Bivalent Binding of Stem Cell Factor*. Journal Of Biological Chemistry 1997, 272: 6311-6317. PMID: 9045650, DOI: 10.1074/jbc.272.10.6311.Peer-Reviewed Original ResearchConceptsStem cell factorKIT dimerizationReceptor dimerizationExtracellular domainCell factorFourth Ig-like domainColony-stimulating factor-1Receptor tyrosine kinasesIg-like domainsCytokine stem cell factorDomain bindsPlatelet-derived growth factorGrowth factorLike domainDimer bindsMost growth factorsTyrosine kinaseDimerization siteConformational changesReceptor KITAnalytical ultracentrifugationForms of KITBivalent bindingFactor 1DimerizationTwo EGF molecules contribute additively to stabilization of the EGFR dimer
Lemmon M, Bu Z, Ladbury J, Zhou M, Pinchasi D, Lax I, Engelman D, Schlessinger J. Two EGF molecules contribute additively to stabilization of the EGFR dimer. The EMBO Journal 1997, 16: 281-294. PMID: 9029149, PMCID: PMC1169635, DOI: 10.1093/emboj/16.2.281.Peer-Reviewed Original ResearchConceptsEpidermal growth factorReceptor dimerizationEGF moleculesPrecise molecular detailsHuman growth hormone receptorReceptor-receptor interactionsGrowth factorInterferon-gamma receptorEGFR dimersSignaling eventsMolecular detailsReceptor oligomerizationGrowth hormone receptorExtracellular domainEGFR familyCell surfaceMonomer bindsSubsequent associationDimerizationHormone receptorsTitration calorimetrySmall-angle X-ray scatteringBindingReceptorsMultivalent binding
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