2021
ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes
Shi F, Mendrola JM, Sheetz JB, Wu N, Sommer A, Speer KF, Noordermeer JN, Kan ZY, Perry K, Englander SW, Stayrook SE, Fradkin LG, Lemmon MA. ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes. Cell Reports 2021, 37: 109834. PMID: 34686333, PMCID: PMC8650758, DOI: 10.1016/j.celrep.2021.109834.Peer-Reviewed Original ResearchAnimalsDrosophila melanogasterDrosophila ProteinsModels, MolecularNerve Tissue ProteinsProtein BindingProtein ConformationProtein Interaction Domains and MotifsProtein-Tyrosine KinasesProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSf9 CellsStructure-Activity RelationshipWnt ProteinsWnt Signaling Pathway
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
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 activatorMolecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase.
Emptage RP, Lemmon MA, Ferguson KM. Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase. Biochemical Journal 2017, 474: 385-398. PMID: 27879374, PMCID: PMC5317272, DOI: 10.1042/bcj20160792.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsBinding SitesCloning, MolecularEnzyme AssaysEscherichia coliGene ExpressionHumansKineticsMitogen-Activated Protein Kinase 1Models, MolecularPeptidesPhospholipidsProtein BindingProtein Interaction Domains and MotifsProtein Structure, SecondaryRecombinant ProteinsScattering, Small AngleSubstrate SpecificityX-Ray DiffractionConceptsKA1 domainMAP/microtubule affinity-regulating kinasesMicrotubule affinity-regulating kinaseGroup of kinasesIntramolecular autoinhibitory interactionAnionic phospholipid bindingAnionic phospholipidsSite-directed mutagenesisAutoinhibitory interactionsRegulatory modulesAutoinhibitory roleProtein modulesMembrane-bound targetsRelated kinasesBind membranesFamily kinasesKinase domainProtein kinasePhospholipid activationC-terminusRegulatory mechanismsPhospholipid bindingMechanistic basisKinaseAutoinhibitory activity
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 Research
2015
Comparison of Saccharomyces cerevisiae F-BAR Domain Structures Reveals a Conserved Inositol Phosphate Binding Site
Moravcevic K, Alvarado D, Schmitz KR, Kenniston JA, Mendrola JM, Ferguson KM, Lemmon MA. Comparison of Saccharomyces cerevisiae F-BAR Domain Structures Reveals a Conserved Inositol Phosphate Binding Site. Structure 2015, 23: 352-363. PMID: 25620000, PMCID: PMC4319572, DOI: 10.1016/j.str.2014.12.009.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBinding SitesCrystallography, X-RayGreen Fluorescent ProteinsGTPase-Activating ProteinsHeLa CellsHumansInositol PhosphatesModels, MolecularMolecular Sequence DataProtein Structure, TertiarySaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSequence AlignmentSpecies SpecificityConceptsF-BAR domainLipid-binding specificityMembrane-binding propertiesNumerous functional studiesPhosphate binding siteUnappreciated determinantF-BARDomain bindsCell signalingCurved membranesMembrane interactionsFunctional studiesRgd1pBinding sitesX-ray crystal structureInositol phosphatesDomain structureDomainHof1pPhospholipidsRhoGAPCytokinesisEndocytosisPhosphoinositideSignaling
2014
ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma
Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K, Ryles H, Laudenslager M, Rappaport EF, Wood AC, McGrady PW, Hogarty MD, London WB, Radhakrishnan R, Lemmon MA, Mossé YP. ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma. Cancer Cell 2014, 26: 682-694. PMID: 25517749, PMCID: PMC4269829, DOI: 10.1016/j.ccell.2014.09.019.Peer-Reviewed Original ResearchMeSH KeywordsAnaplastic Lymphoma KinaseAntineoplastic AgentsCrizotinibDisease-Free SurvivalDrug Resistance, NeoplasmHumansHydrogen BondingInfantKaplan-Meier EstimateKineticsModels, MolecularMolecular Targeted TherapyMutation, MissenseNeuroblastomaOncogenesProtein BindingProtein Kinase InhibitorsPyrazolesPyridinesReceptor Protein-Tyrosine KinasesComplex 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 advancesReceptors
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 conformationReceptor 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
Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family
Artim SC, Mendrola JM, Lemmon MA. Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family. Biochemical Journal 2012, 448: 213-220. PMID: 22992069, PMCID: PMC3492919, DOI: 10.1042/bj20121365.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceAntigens, CDCatalytic DomainCrystallography, X-RayEnzyme ActivationHumansIn Vitro TechniquesModels, MolecularMutationNeoplasmsProtein Structure, QuaternaryReceptor Tyrosine Kinase-like Orphan ReceptorsReceptor, InsulinReceptor, trkARecombinant Proteins
2011
Conditional Peripheral Membrane Proteins: Facing up to Limited Specificity
Moravcevic K, Oxley CL, Lemmon MA. Conditional Peripheral Membrane Proteins: Facing up to Limited Specificity. Structure 2011, 20: 15-27. PMID: 22193136, PMCID: PMC3265387, DOI: 10.1016/j.str.2011.11.012.Peer-Reviewed Original ResearchDifferential Inhibitor Sensitivity of Anaplastic Lymphoma Kinase Variants Found in Neuroblastoma
Bresler SC, Wood AC, Haglund EA, Courtright J, Belcastro LT, Plegaria JS, Cole K, Toporovskaya Y, Zhao H, Carpenter EL, Christensen JG, Maris JM, Lemmon MA, Mossé YP. Differential Inhibitor Sensitivity of Anaplastic Lymphoma Kinase Variants Found in Neuroblastoma. Science Translational Medicine 2011, 3: 108ra114. PMID: 22072639, PMCID: PMC3319004, DOI: 10.1126/scitranslmed.3002950.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnaplastic Lymphoma KinaseCell Line, TumorCrizotinibDrug Resistance, NeoplasmGenome, HumanHumansKineticsModels, MolecularMutant ProteinsMutationNeuroblastomaPhosphorylationProtein Kinase InhibitorsProtein Structure, TertiaryPyrazolesPyridinesReceptor Protein-Tyrosine Kinases
2010
Kinase Associated-1 Domains Drive MARK/PAR1 Kinases to Membrane Targets by Binding Acidic Phospholipids
Moravcevic K, Mendrola JM, Schmitz KR, Wang YH, Slochower D, Janmey PA, Lemmon MA. Kinase Associated-1 Domains Drive MARK/PAR1 Kinases to Membrane Targets by Binding Acidic Phospholipids. Cell 2010, 143: 966-977. PMID: 21145462, PMCID: PMC3031122, DOI: 10.1016/j.cell.2010.11.028.Peer-Reviewed Original ResearchConceptsKA1 domainBud neck localizationMembrane association domainAcidic phospholipidsImportance of phosphatidylserineAssociation domainMembrane associationMembrane localizationProtein kinaseC2 domainC-terminusMembrane targetsKinaseIntact proteinAnionic phospholipidsX-ray crystallographyNeck localizationPhosphatidylserinePhospholipidsCrucial roleDomainMembrane surfaceLocalizationTerminusRegulatorStructural 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 sitesErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation
Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 7692-7697. PMID: 20351256, PMCID: PMC2867849, DOI: 10.1073/pnas.1002753107.Peer-Reviewed Original Research
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 ResearchA possible effector role for the pleckstrin homology (PH) domain of dynamin
Bethoney KA, King MC, Hinshaw JE, Ostap EM, Lemmon MA. A possible effector role for the pleckstrin homology (PH) domain of dynamin. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 13359-13364. PMID: 19666604, PMCID: PMC2720410, DOI: 10.1073/pnas.0906945106.Peer-Reviewed Original ResearchConceptsPleckstrin homology domainHomology domainPH domainAbility of dynaminLarge GTPase dynaminPH domain mutationsPhosphoinositide-containing membranesGTPase dynaminDynamin functionVesicle scissionMembrane scissionDynamin helixDynamin assemblyTargeting roleDynamin oligomersDynamin 1Possible effector roleAnimal cellsBisphosphate moleculesActin polymerizationDynaminClathrinDomain mutationsPhosphoinositideEndocytosisThe 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