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
2016
The Dark Side of Cell Signaling: Positive Roles for Negative Regulators
Lemmon MA, Freed DM, Schlessinger J, Kiyatkin A. The Dark Side of Cell Signaling: Positive Roles for Negative Regulators. Cell 2016, 164: 1172-1184. PMID: 26967284, PMCID: PMC4830124, DOI: 10.1016/j.cell.2016.02.047.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFeedback, PhysiologicalHumansPhosphorylationReceptor Protein-Tyrosine KinasesReceptors, G-Protein-CoupledSignal TransductionConceptsCell signalingNegative regulatorGTP/GDP cycleNew cellular statesKinase/phosphataseCell surface receptorsCellular statesSignal terminationSwitch-like transitionsSuch regulatorsReceptor internalizationGDP cycleReceptor signalingSignal activationKinetic proofreadingSignalingRegulatorOnly negative effectNegative signalsPositive roleImportant roleNegative effectsProofreadingPhosphataseInternalizationThe 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
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 Kinases
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 ResearchMeSH KeywordsAmino Acid SequenceCatalysisGlycineHumansModels, MolecularMolecular Sequence DataReceptor Protein-Tyrosine KinasesSequence Homology, Amino AcidSignal TransductionWnt ProteinsConceptsWeak 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
Differential 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
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 ResearchMeSH KeywordsAnimalsEnzyme ActivationHumansNeoplasmsReceptor Protein-Tyrosine KinasesSignal TransductionConceptsReceptor tyrosine kinasesTyrosine kinaseIntracellular tyrosine kinase domainRecent structural studiesGrowth factor ligandsTyrosine kinase domainUnexpected diversityKinase domainCell signalingLigand bindingCellular responsesFactor ligandRTK mutationsKinaseStructural studiesActivationSignalingDiversityMutationsDimerizationMechanismBindingDomain
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 receptor
1994
Regulation of signal transduction and signal diversity by receptor oligomerization
Lemmon M, Schlessinger J. Regulation of signal transduction and signal diversity by receptor oligomerization. Trends In Biochemical Sciences 1994, 19: 459-463. PMID: 7855887, DOI: 10.1016/0968-0004(94)90130-9.Peer-Reviewed Original ResearchConceptsReceptor oligomerizationProtein tyrosine kinase activityTyrosine kinase activityDiversity of ligandsGrowth factorCytoplasmic domainSignal transductionEpidermal growth factorKinase activityExtracellular domainDifferent complementsSame receptor familySignal diversityReceptor familyIndividual receptorsOligomerizationHeterodimerizationDiversityAccessory moleculesReceptorsImportant roleSH2TransmembraneTransductionDomain