2017
EGFR 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 agonismDimerization 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 advancesReceptorsPutting together structures of epidermal growth factor receptors
Bessman NJ, Freed DM, Lemmon MA. Putting together structures of epidermal growth factor receptors. Current Opinion In Structural Biology 2014, 29: 95-101. PMID: 25460273, PMCID: PMC4268130, DOI: 10.1016/j.sbi.2014.10.002.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorGrowth factor receptorIntact epidermal growth factor receptorChemical biology methodsNumerous crystal structuresFactor receptorTyrosine kinase domainVariety of inhibitorsKinase domainExtracellular regionMembrane environmentIntracellular regionBiology methodsIntact receptorReceptorsCancer therapyNext challengeCrystal structureMembraneActivationRegionInhibitorsDomain
2010
Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor
Alvarado D, Klein DE, Lemmon MA. Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor. Cell 2010, 142: 568-579. PMID: 20723758, PMCID: PMC2925043, DOI: 10.1016/j.cell.2010.07.015.Peer-Reviewed Original ResearchConceptsEGFR extracellular regionEpidermal growth factor receptorExtracellular regionEGF receptorDifferent signaling propertiesLigand-binding eventsLigand-induced dimerizationIntracellular tyrosine kinase domainNegative cooperativityCooperative ligand bindingTyrosine kinase domainAllosteric regulationEGF-binding sitesKinase domainFactor bindingGrowth factor receptorGrowth factor bindingStructural basisLigand bindingEGFR ligandsSignaling propertiesFactor receptorReduced affinityAsymmetric dimerUnoccupied sites
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 mutationsErbB2/HER2/Neu resembles an autoinhibited invertebrate EGF receptor
Alvarado D, Klein D, Lemmon M. ErbB2/HER2/Neu resembles an autoinhibited invertebrate EGF receptor. The FASEB Journal 2009, 23: 884.3-884.3. DOI: 10.1096/fasebj.23.1_supplement.884.3.Peer-Reviewed Original ResearchReceptor tyrosine kinase ErbB2Human cancersAutoinhibitory interactionsExtracellular regionInterdomain interactionsEGF receptorErbB2 signalingOrphan receptorOncogenic propertiesHuman EGFRErbB receptorsImportant therapeutic targetErbB2Structural studiesTherapeutic targetNovel aspectsReceptorsAutoinhibitoryAutoinhibitionSignalingOverexpressionImportant implicationsRegulationTherapeutic approachesEGFR
2008
Ligand-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
Ligand-Induced Structural Transitions in ErbB Receptor Extracellular Domains
Dawson JP, Bu Z, Lemmon MA. Ligand-Induced Structural Transitions in ErbB Receptor Extracellular Domains. Structure 2007, 15: 942-954. PMID: 17697999, DOI: 10.1016/j.str.2007.06.013.Peer-Reviewed Original ResearchConceptsExtracellular regionDimerization siteLow-resolution molecular envelopeEpidermal growth factor receptor (EGFR) activationGrowth factor receptor activationAutoinhibitory intramolecular interactionMajor domain rearrangementsSmall-angle X-ray scatteringReceptor extracellular domainDomain rearrangementsEGF receptorExtracellular domainLigand bindingEGFR mutantsReceptor conformationMutantsMolecular envelopeExtended conformationNew insightsReceptor activationCrystallographic studiesConformationIntramolecular interactionsReceptorsX-ray scatteringActivation and Inhibition of the EGF Receptor
Lemmon M. Activation and Inhibition of the EGF Receptor. The FASEB Journal 2007, 21: a46-a46. DOI: 10.1096/fasebj.21.5.a46-b.Peer-Reviewed Original ResearchReceptor tyrosine kinasesEGFR extracellular regionEGF-induced dimerizationActivation of EGFRErbB family receptor tyrosine kinasesKekkon-1D. melanogasterEpidermal growth factor receptorC. elegansLigand sinkMembrane proteinsGrowth factor receptorExtracellular regionEGF receptorExtracellular domainTyrosine kinaseCurrent mechanistic viewsCell surfaceHuman cancersCell growthOrthologsFactor receptorMechanistic viewNovel EGFRDimerization