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
2020
Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases
Sheetz JB, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, Perttilä R, Preuss F, Suresh K, Stayrook SE, Tsutsui Y, Radhakrishnan R, Ungureanu D, Knapp S, Lemmon MA. Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. Molecular Cell 2020, 79: 390-405.e7. PMID: 32619402, PMCID: PMC7543951, DOI: 10.1016/j.molcel.2020.06.018.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBaculoviridaeBinding SitesCell Adhesion MoleculesCell LineCloning, MolecularCrystallography, X-RayGene ExpressionHumansMiceModels, MolecularPrecursor Cells, B-LymphoidProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsProtein Kinase InhibitorsReceptor Protein-Tyrosine KinasesReceptor Tyrosine Kinase-like Orphan ReceptorsReceptors, Eph FamilyRecombinant ProteinsSf9 CellsSmall Molecule LibrariesSpodopteraStructural Homology, ProteinSubstrate SpecificityConceptsInsulin receptor kinasePseudokinase domainReceptor tyrosine kinasesTyrosine kinaseNon-catalytic functionsATP-binding pocketType II inhibitorsDomain plasticityActivation loopReceptor kinaseInactive conformationStructural insightsPseudokinasesATP siteStructural comparisonAromatic residuesKinaseAlternative interactionsApparent lackImportant roleDomainWntMotifROR1Residues4558 Investigating the functional consequences of anaplastic lymphoma kinase (ALK) mutations arising upon Lorlatinib treatment
Witek G, Miller W, Slochower D, Berko E, Mossé Y, Lemmon M, Radhakrishnan R. 4558 Investigating the functional consequences of anaplastic lymphoma kinase (ALK) mutations arising upon Lorlatinib treatment. Journal Of Clinical And Translational Science 2020, 4: 9-10. PMCID: PMC8823389, DOI: 10.1017/cts.2020.74.Peer-Reviewed Original ResearchAnaplastic lymphoma kinaseNB patientsALK mutationsMechanisms of resistanceCompound mutationsALK inhibitorsNon-small cell lung cancerLimited anti-tumor activityAnaplastic lymphoma kinase (ALK) mutationsDiverse clinical responsesSympathetic nervous systemCell lung cancerRecent clinical trialsSignificant side effectsDe novo resistanceALK tyrosine kinaseAnti-tumor activityActivation stateNew ALK inhibitorsHereditary neuroblastomaLorlatinib treatmentClinical responseTyrosine kinaseRelapsed neuroblastomaNew immunotherapies
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
EGFR 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
2013
Receptor tyrosine kinases with intracellular pseudokinase domains
Mendrola JM, Shi F, Park JH, Lemmon MA. Receptor tyrosine kinases with intracellular pseudokinase domains. Biochemical Society Transactions 2013, 41: 1029-1036. PMID: 23863174, PMCID: PMC3777422, DOI: 10.1042/bst20130104.Peer-Reviewed Original ResearchConceptsWeak kinase activityKinase activitySignificant kinase activityReceptor tyrosine kinasesPseudokinase domainHuman proteomeProtein kinaseImportant residuesWnt receptorsTyrosine kinaseEGFR familyKinaseFunctional studiesRTKPseudokinasesPseudokinaseProteomeReceptorsWntNew lightErbB3MutationsResiduesActivityRecent work
2012
Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma
Carpenter EL, Haglund EA, Mace EM, Deng D, Martinez D, Wood AC, Chow AK, Weiser DA, Belcastro LT, Winter C, Bresler SC, Asgharzadeh S, Seeger R, Zhao H, Guo R, Christensen J, Orange J, Pawel B, Lemmon M, Mossé Y. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene 2012, 31: 4859-4867. PMID: 22266870, PMCID: PMC3730824, DOI: 10.1038/onc.2011.647.Peer-Reviewed Original ResearchMeSH KeywordsAnaplastic Lymphoma KinaseAntibodies, MonoclonalAntigens, NeoplasmCell DeathCell Line, TumorCell ProliferationCrizotinibHumansMutationNeuroblastomaPhosphorylationProtein Kinase InhibitorsProtein-Tyrosine KinasesProto-Oncogene Proteins c-metPyrazolesPyridinesReceptor Protein-Tyrosine KinasesSignal TransductionConceptsAnaplastic lymphoma kinaseLymphoma kinaseHuman neuroblastomaSmall molecule tyrosine kinase inhibitorsAntibody-dependent cellular cytotoxicityReceptor tyrosine kinasesDevastating pediatric cancerSympathetic nervous systemALK inhibitor crizotinibComplementary therapeutic approachALK-positive tumorsPromising therapeutic strategyTyrosine kinase inhibitorsAntibody-induced growth inhibitionCell linesTractable therapeutic targetWild-type ALKTyrosine kinaseALK aberrationsNeuroblastoma patientsLung cancerALK mutationsInhibitor crizotinibCellular cytotoxicityALK antibody
2011
Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases
Shih AJ, Telesco SE, Choi SH, Lemmon MA, Radhakrishnan R. Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases. Biochemical Journal 2011, 436: 241-251. PMID: 21426301, PMCID: PMC3138537, DOI: 10.1042/bj20101791.Peer-Reviewed Original ResearchConceptsErbB familyDifferent molecular contextsIntracellular kinase domainImportant regulatory elementsSrc kinase HckReceptor tyrosine kinasesHomologous receptor tyrosine kinasesSequence similarityKinase domainRegulatory elementsDimer interfaceSubdomain motionsInactive conformationKey residuesEGFR activationMolecular contextTyrosine kinasePresent molecular dynamics studyBond networkActive conformationConformational statesKinaseErbB kinasesMolecular dynamics analysisSalt bridge
2010
Cell Signaling by Receptor Tyrosine Kinases
Lemmon MA, Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell 2010, 141: 1117-1134. PMID: 20602996, PMCID: PMC2914105, DOI: 10.1016/j.cell.2010.06.011.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesTyrosine kinaseIntracellular tyrosine kinase domainRecent structural studiesGrowth factor ligandsTyrosine kinase domainUnexpected diversityKinase domainCell signalingLigand bindingCellular responsesFactor ligandRTK mutationsKinaseStructural studiesActivationSignalingDiversityMutationsDimerizationMechanismBindingDomain
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
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 insightsDimerizationReceptorsHomodimerizationKinaseMechanism of Activation and Inhibition of the HER4/ErbB4 Kinase
Qiu C, Tarrant MK, Choi SH, Sathyamurthy A, Bose R, Banjade S, Pal A, Bornmann WG, Lemmon MA, Cole PA, Leahy DJ. Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase. Structure 2008, 16: 460-467. PMID: 18334220, PMCID: PMC2858219, DOI: 10.1016/j.str.2007.12.016.Peer-Reviewed Original ResearchConceptsErbB4 kinaseEGF receptorBa/F3 cellsReceptor tyrosine kinasesMechanism of activationHER4/ErbB4ErbB family membersKinase domainHER2/ErbB2Kinase activationMutagenesis studiesTyrosine kinaseF3 cellsKinaseDimer conformationErbB familyNormal developmentInactive formAsymmetric dimerMammary glandErbB4ActivationFamily members
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
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
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 1DimerizationDimerization 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