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 agonism
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 membersCaenorhabditisDimersEGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features
Ganetzky R, Finn E, Bagchi A, Zollo O, Conlin L, Deardorff M, Harr M, Simpson MA, McGrath JA, Zackai E, Lemmon MA, Sondheimer N. EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features. Molecular Genetics & Genomic Medicine 2015, 3: 452-458. PMID: 26436111, PMCID: PMC4585453, DOI: 10.1002/mgg3.156.Peer-Reviewed Original ResearchEpidermal growth factor receptorExtracellular domainEpidermal growth factor signalingGrowth factor signalingPatient-derived fibroblastsBinding of EGFExtracellular signalsGrowth factor receptorEarly senescenceFactor signalingDownstream targetsOncogenic transformationTissue developmentTyrosine kinaseConstitutive activationReceptor phosphorylationLarge familyFactor receptorProgeroid featuresAccelerated expressionMutationsΒ-galactosidaseEGFEGFR genotypeActivation
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
2013
Mechanism for activation of mutated epidermal growth factor receptors in lung cancer
Brewer M, Yun CH, Lai D, Lemmon MA, Eck MJ, Pao W. Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: e3595-e3604. PMID: 24019492, PMCID: PMC3780914, DOI: 10.1073/pnas.1220050110.Peer-Reviewed Original ResearchConceptsWT epidermal growth factor receptorEpidermal growth factor receptorTyrosine kinase domainGrowth factor receptorConformational changesAsymmetric dimer interfaceMutant epidermal growth factor receptorAllosteric conformational changeAsymmetric dimer formationFactor receptorIntermolecular regulationKinase domainEGFR tyrosine kinase domainDimer interfaceMutantsM mutantActive conformation
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
ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor
Alvarado D, Klein DE, Lemmon MA. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature 2009, 461: 287-291. PMID: 19718021, PMCID: PMC2762480, DOI: 10.1038/nature08297.Peer-Reviewed Original ResearchThe Juxtamembrane Region of the EGF Receptor Functions as an Activation Domain
Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G. The Juxtamembrane Region of the EGF Receptor Functions as an Activation Domain. Molecular Cell 2009, 34: 641-651. PMID: 19560417, PMCID: PMC2719887, DOI: 10.1016/j.molcel.2009.04.034.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCarcinoma, Non-Small-Cell LungCell LineCell Transformation, NeoplasticChlorocebus aethiopsCOS CellsCrystallography, X-RayDimerizationErbB ReceptorsHumansMiceModels, MolecularMutagenesis, Site-DirectedMutationNIH 3T3 CellsPhosphorylationProtein Structure, TertiaryTyrosineConceptsEpidermal growth factor receptorActivation domainJuxtamembrane regionJM regionGrowth factor receptorIntracellular juxtamembrane regionEGF receptor functionAlanine-scanning mutagenesisFactor receptorTyrosine kinase activationAsymmetric dimerTyrosine kinase domainAutoinhibitory interactionsKinase domainCellular transformationScanning mutagenesisKinase activationEGFR activationC-lobeXenograft assayCancer mutationsC-terminal 19 residuesCrystallographic approachReceptor functionExtensive contactsStructural basis for EGFR ligand sequestration by Argos
Klein D, Stayrook S, Shi F, Narayan K, Lemmon M. Structural basis for EGFR ligand sequestration by Argos. The FASEB Journal 2009, 23: 883.7-883.7. DOI: 10.1096/fasebj.23.1_supplement.883.7.Peer-Reviewed Original ResearchEpidermal growth factor receptorHuman urokinase-type plasminogen activator receptorDiverse developmental processesClamp-like structureEGF-like domainGrowth factor ligandsArgos functionMammalian counterpartsLigand sequestrationEGF-like modulesUrokinase-type plasminogen activator receptorEGF domainsEGF ligandGrowth factor receptorEssential regulatorStructural basisDevelopmental processesStructural homologuesEGFR ligandsFactor ligandHuman cancersPlasminogen activator receptorFactor receptorErbB/Inappropriate activation
2008
Structural basis for EGFR ligand sequestration by Argos
Klein DE, Stayrook SE, Shi F, Narayan K, Lemmon MA. Structural basis for EGFR ligand sequestration by Argos. Nature 2008, 453: 1271-1275. PMID: 18500331, PMCID: PMC2526102, DOI: 10.1038/nature06978.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCell LineCrystallography, X-RayDrosophila melanogasterDrosophila ProteinsEpidermal Growth FactorErbB ReceptorsEye ProteinsHumansLigandsMembrane ProteinsModels, MolecularNerve Tissue ProteinsProtein Structure, TertiaryReceptors, Transforming Growth Factor betaSpodopteraConceptsEpidermal growth factor receptorLigand sequestrationEGFR ligand SpitzLigand SpitzMammalian counterpartsGrowth factor receptorStructural basisUrokinase plasminogen activatorStructural homologuesEGFR ligandsFactor receptorAnticancer therapeuticsStructural resemblanceHomologuesPlasminogen activatorReceptorsSequestrationProteinActivatorLigandsSpitzTGFTherapeuticsDomain
2007
Activation 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
2006
EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer
Choi SH, Mendrola JM, Lemmon MA. EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer. Oncogene 2006, 26: 1567-1576. PMID: 16953218, DOI: 10.1038/sj.onc.1209957.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorTyrosine kinase domainKinase domainEGF receptorRecent structural studiesSomatic mutationsCell surface EGF receptorsTyrosine kinase activityAbsence of EGFAutoinhibitory interactionsActivation loopErbB family membersGrowth factor receptorTyrosine phosphorylationEGFR tyrosine kinase domainKinase activityNull backgroundMechanistic basisOncogenic mutationsBiochemical propertiesCell surfaceCell lung carcinoma patientsFactor receptorMutationsLung carcinoma patientsPalmitoylation of the EGFR Ligand Spitz by Rasp Increases Spitz Activity by Restricting Its Diffusion
Miura GI, Buglino J, Alvarado D, Lemmon MA, Resh MD, Treisman JE. Palmitoylation of the EGFR Ligand Spitz by Rasp Increases Spitz Activity by Restricting Its Diffusion. Developmental Cell 2006, 10: 167-176. PMID: 16459296, DOI: 10.1016/j.devcel.2005.11.017.Peer-Reviewed Original ResearchMeSH KeywordsAcyltransferasesAnimalsBase SequenceBiological Transport, ActiveCell LineCell MembraneCysteineDNADrosophilaDrosophila ProteinsEpidermal Growth FactorErbB ReceptorsFemaleGenes, InsectIn Vitro TechniquesLigandsMaleMembrane ProteinsModels, BiologicalMutagenesis, Site-DirectedMutationOvaryPalmitic AcidRecombinant ProteinsTransfectionWings, AnimalConceptsEpidermal growth factor receptorDrosophila epidermal growth factor receptorEGFR ligand SpitzPlasma membrane associationN-terminal cysteine residueLigand SpitzMembrane associationWnt familyDevelopmental functionsGrowth factor receptorCysteine residuesBiological functionsLipid modificationPalmitoylationIntracellular proteinsCultured cellsCell membraneFactor receptorSpitzReduced activityVivoTransmembraneHedgehogProteinActivity
2001
The Single Transmembrane Domains of ErbB Receptors Self-associate in Cell Membranes*
Mendrola JM, Berger MB, King MC, Lemmon MA. The Single Transmembrane Domains of ErbB Receptors Self-associate in Cell Membranes*. Journal Of Biological Chemistry 2001, 277: 4704-4712. PMID: 11741943, DOI: 10.1074/jbc.m108681200.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceCell MembraneChloramphenicol O-AcetyltransferaseDimerizationDNA Mutational AnalysisErbB ReceptorsEscherichia coliGenetic VectorsGlutamic AcidHumansLigandsMaltoseModels, MolecularMolecular Sequence DataMutagenesis, Site-DirectedMutationProtein Structure, TertiaryReceptor Protein-Tyrosine KinasesReceptor, ErbB-2Receptor, ErbB-3Receptor, ErbB-4Recombinant Fusion ProteinsSequence Homology, Amino AcidValineConceptsTM domain interactionsTM domainReceptor tyrosine kinasesEpidermal growth factor receptorGrowth factor receptorDomain interactionsSingle transmembrane alpha-helixReceptor dimersTyrosine kinaseExtracellular domainErbB receptor functionEscherichia coli cell membraneSingle transmembrane domainTransmembrane alpha-helixErbB receptorsCell membraneLimited mutational analysisFactor receptorGlutamic acid mutationTransmembrane domainGxxxG motifDomain dimerMutational analysisAlpha-helixErythropoietin receptorDevelopment of Strategies to Manipulate ErbB Receptor Heterodimerization from a Quantitative Analysis of Receptor/Ligand Relationships
Lemmon M. Development of Strategies to Manipulate ErbB Receptor Heterodimerization from a Quantitative Analysis of Receptor/Ligand Relationships. 2001 DOI: 10.21236/ada398353.Peer-Reviewed Original ResearchBreast cancerErbB-1Growth factorHuman breast cancer casesBreast cancer casesInappropriate receptor activationEpidermal growth factor receptorGrowth factor receptorSame growth factorsCancer casesReceptor activationExtracellular domainReceptor heterodimerizationReceptor tyrosine kinasesFactor receptorErbB receptorsReceptorsErbB2ErbB familyErbB2 activationReceptor transmodulationDevelopment of strategiesCancerTyrosine kinaseReceptor homo
1997
Dimerization of the p185neu transmembrane domain is necessary but not sufficient for transformation
Burke C, Lemmon M, Coren B, Engelman D, Stern D. Dimerization of the p185neu transmembrane domain is necessary but not sufficient for transformation. Oncogene 1997, 14: 687-696. PMID: 9038376, DOI: 10.1038/sj.onc.1200873.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesTransmembrane domainEpidermal growth factor receptorSignal transductionWild-type domainSecond-site mutationsPosition 664Dimerization domainGrowth factor receptorTyrosine kinaseGlycophorin AFactor receptorValine substitutionDimerizationMutationsTransductionGlutamic acidDomainWeak dimerizationMutantsKinaseSignalingProteinEGFChimeras