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 roleDomainWntMotifROR1Residues
2017
Dimerization 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
2016
Overcoming resistance to HER2 inhibitors through state-specific kinase binding
Novotny CJ, Pollari S, Park JH, Lemmon MA, Shen W, Shokat KM. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nature Chemical Biology 2016, 12: 923-930. PMID: 27595329, PMCID: PMC5069157, DOI: 10.1038/nchembio.2171.Peer-Reviewed Original ResearchThe ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma
Infarinato NR, Park JH, Krytska K, Ryles HT, Sano R, Szigety KM, Li Y, Zou HY, Lee NV, Smeal T, Lemmon MA, Mossé YP. The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Cancer Discovery 2016, 6: 96-107. PMID: 26554404, PMCID: PMC4707106, DOI: 10.1158/2159-8290.cd-15-1056.Peer-Reviewed Original ResearchMeSH KeywordsAminopyridinesAnaplastic Lymphoma KinaseAnimalsCell Line, TumorCrizotinibDrug Resistance, NeoplasmHumansLactamsLactams, MacrocyclicMiceMutationNeuroblastomaPhosphorylationProtein Kinase InhibitorsPyrazolesPyridinesReceptor Protein-Tyrosine KinasesTreatment OutcomeXenograft Model Antitumor AssaysConceptsAnaplastic lymphoma kinaseCrizotinib resistancePF-06463922ALK variantsTreatment of patientsALK inhibitor crizotinibPatient-derived xenograftsXenograft mouse modelPreclinical rationaleClinical obstacleNeuroblastoma modelClinical trialsTumor regressionPrimary resistanceInhibitor crizotinibXenograft tumorsMouse modelXenograft modelLymphoma kinaseNeuroblastomaCrizotinibHigh potencyF1174LVivo dataImproved potency
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
2009
The 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 contacts
2006
The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity
Baumeister MA, Rossman KL, Sondek J, Lemmon MA. The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity. Biochemical Journal 2006, 400: 563-572. PMID: 17007612, PMCID: PMC1698603, DOI: 10.1042/bj20061020.Peer-Reviewed Original Research
2000
The Role of the Pleckstrin Homology Domain in Membrane Targeting and Activation of Phospholipase Cβ1 *
Razzini G, Brancaccio A, Lemmon M, Guarnieri S, Falasca M. The Role of the Pleckstrin Homology Domain in Membrane Targeting and Activation of Phospholipase Cβ1 *. Journal Of Biological Chemistry 2000, 275: 14873-14881. PMID: 10809731, DOI: 10.1074/jbc.275.20.14873.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAndrostadienesAnimalsCell MembraneChromonesCOS CellsCulture Media, Serum-FreeEnzyme ActivationEnzyme InhibitorsGlutathione TransferaseGreen Fluorescent ProteinsGrowth SubstancesGTP-Binding ProteinsHeLa CellsHumansIsoenzymesLuminescent ProteinsMiceMicroscopy, ConfocalMicroscopy, FluorescenceMorpholinesPhosphatidylinositolsPhospholipase C betaPolymerase Chain ReactionRatsRecombinant Fusion ProteinsSrc Homology DomainsTransfectionType C PhospholipasesWortmanninConceptsPlasma membrane localizationPleckstrin homology domainMembrane localizationSerum-starved cellsPlasma membraneMembrane targetingLysophosphatidic acidHomology domainGreen fluorescent protein fusion proteinFluorescent protein fusion proteinProtein fusion proteinIsolated PH domainActivation of PLCbetaStimulation of cellsPH domainPhospholipase Cβ1Gbetagamma subunitsBetagamma subunitsAmino terminusWortmannin pretreatmentFusion proteinG proteinsActivation of phospholipaseFluorescence microscopyPhosphoinositide
1998
Specificity and Promiscuity in Phosphoinositide Binding by Pleckstrin Homology Domains*
Kavran J, Klein D, Lee A, Falasca M, Isakoff S, Skolnik E, Lemmon M. Specificity and Promiscuity in Phosphoinositide Binding by Pleckstrin Homology Domains*. Journal Of Biological Chemistry 1998, 273: 30497-30508. PMID: 9804818, DOI: 10.1074/jbc.273.46.30497.Peer-Reviewed Original ResearchConceptsPleckstrin homology domainPH domainGrp1 PH domainD-myo-inositolParticular phosphoinositidesPhosphoinositide bindingHomology domainDependent membrane recruitmentDifferent PH domainsPH domain bindsSmall protein modulesSoluble inositol phosphatesMembrane recruitmentDomain bindsProtein modulesSpecific phosphoinositideMammalian cellsPlasma membraneSingle speciesAbundant speciesMultiple phosphoinositidesCellular membranesPhosphoinositidePI 3Clear specificity
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
1995
Scratching the surface with the PH domain
Ferguson K, Lemmon M, Sigler P, Schlessinger J. Scratching the surface with the PH domain. Nature Structural & Molecular Biology 1995, 2: 715-718. PMID: 7552736, DOI: 10.1038/nsb0995-715.Commentaries, Editorials and Letters