2024
Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling
Mühlenbeck H, Tsutsui Y, Lemmon M, Bender K, Zipfel C. Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling. ELife 2024, 12: rp92110. PMID: 39028038, PMCID: PMC11259431, DOI: 10.7554/elife.92110.Peer-Reviewed Original ResearchConceptsKinase domainReceptor kinasePhosphorylation-dependent conformational changesActive conformationIntragenic suppressor mutationsCo-receptor BAK1Kinase-dead variantPlant receptor kinasesProtein kinase domainLeucine-rich repeatNon-catalytic functionsIntracellular kinase domainCo-receptorLRR-RKsSuppressor mutationsTrans-phosphorylationPseudokinase domainActivation loopActive kinaseAllosteric activationTransmembrane signalingBAK1Immune signalingRegulate signalingSignaling activityAllosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling
Mühlenbeck H, Tsutsui Y, Lemmon M, Bender K, Zipfel C. Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling. ELife 2024, 12 DOI: 10.7554/elife.92110.4.Peer-Reviewed Original ResearchKinase domainReceptor kinasePhosphorylation-dependent conformational changesActive conformationIntragenic suppressor mutationsCo-receptor BAK1Kinase-dead variantPlant receptor kinasesProtein kinase domainLeucine-rich repeatNon-catalytic functionsIntracellular kinase domainCo-receptorLRR-RKsSuppressor mutationsTrans-phosphorylationPseudokinase domainActivation loopActive kinaseAllosteric activationTransmembrane signalingBAK1Immune signalingRegulate signalingSignaling activity
2023
Distinct interactions stabilize EGFR dimers and higher-order oligomers in cell membranes
Mudumbi K, Burns E, Schodt D, Petrova Z, Kiyatkin A, Kim L, Mangiacapre E, Ortiz-Caraveo I, Rivera Ortiz H, Hu C, Ashtekar K, Lidke K, Lidke D, Lemmon M. Distinct interactions stabilize EGFR dimers and higher-order oligomers in cell membranes. Cell Reports 2023, 43: 113603. PMID: 38117650, PMCID: PMC10835193, DOI: 10.1016/j.celrep.2023.113603.Peer-Reviewed Original ResearchGlycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE
Chongsaritsinsuk J, Steigmeyer A, Mahoney K, Rosenfeld M, Lucas T, Smith C, Li A, Ince D, Kearns F, Battison A, Hollenhorst M, Judy Shon D, Tiemeyer K, Attah V, Kwon C, Bertozzi C, Ferracane M, Lemmon M, Amaro R, Malaker S. Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE. Nature Communications 2023, 14: 6169. PMID: 37794035, PMCID: PMC10550946, DOI: 10.1038/s41467-023-41756-y.Peer-Reviewed Original ResearchConceptsFamily of proteinsMucin domainO-glycosylationBiological functionsKey regulatorComplex glycansMass spectrometric analysisFunctional relevanceTIM familyDetailed molecular structureCritical roleGlycosylationProteinSpectrometric analysisStructural featuresUnique abilityStructural dynamicsMolecular dynamics simulationsTim-3 functionFamilyPowerful workflowRegulatorImmune cellsCheckpointGlycansAllosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling.
Mühlenbeck H, Tsutsui Y, Lemmon MA, Bender KW, Zipfel C. Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling. BioRxiv 2023 PMID: 37662281, DOI: 10.1101/2023.08.23.554490.Peer-Reviewed Original ResearchCirculating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma
Berko E, Witek G, Matkar S, Petrova Z, Wu M, Smith C, Daniels A, Kalna J, Kennedy A, Gostuski I, Casey C, Krytska K, Gerelus M, Pavlick D, Ghazarian S, Park J, Marachelian A, Maris J, Goldsmith K, Radhakrishnan R, Lemmon M, Mossé Y. Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma. Nature Communications 2023, 14: 2601. PMID: 37147298, PMCID: PMC10163008, DOI: 10.1038/s41467-023-38195-0.Peer-Reviewed Original ResearchConceptsAnaplastic lymphoma kinaseLorlatinib resistanceTumor DNAPhase 1 trialCirculating tumor DNAPre-clinical studiesResistance mechanismsTumor DNA samplesALK mutationsDisease progressionHeterogeneity of tumorsClinical utilityRAS-MAPK pathwayTherapeutic strategiesLymphoma kinasePatientsResistance mutationsNeuroblastomaProgressionTrialsMutationsBiochemical assaysDNA samplesPoint mutationsLorlatinibEfficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations
Grant M, Aredo J, Starrett J, Stockhammer P, van Rosenburgh I, Wurtz A, Piper-Valillo A, Piotrowska Z, Falcon C, Yu H, Aggarwal C, Scholes D, Patil T, Nguyen C, Phadke M, Li F, Neal J, Lemmon M, Walther Z, Politi K, Goldberg S. Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations. Clinical Cancer Research 2023, 29: of1-of8. PMID: 36913537, PMCID: PMC10493186, DOI: 10.1158/1078-0432.ccr-22-3497.Peer-Reviewed Original ResearchConceptsProgression-free survivalNon-small cell lung cancerInferior progression-free survivalMulticenter retrospective cohortEfficacy of osimertinibMulti-institutional cohortCell lung cancerExon 19 deletion mutationUncommon EGFRRetrospective cohortClinical outcomesClinical efficacyLung cancerOsimertinib efficacyEGFR mutationsPreclinical modelsEx19delPatientsAACR Genie databaseLater linesOsimertinibMutant cohortFirst lineCohortEfficacy
2022
Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
van Alderwerelt van Rosenburgh I, Lu D, Grant M, Stayrook S, Phadke M, Walther Z, Goldberg S, Politi K, Lemmon M, Ashtekar K, Tsutsui Y. Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations. Nature Communications 2022, 13: 6791. PMID: 36357385, PMCID: PMC9649653, DOI: 10.1038/s41467-022-34398-z.Peer-Reviewed Original ResearchLooking lively: emerging principles of pseudokinase signaling
Sheetz JB, Lemmon MA. Looking lively: emerging principles of pseudokinase signaling. Trends In Biochemical Sciences 2022, 47: 875-891. PMID: 35585008, PMCID: PMC9464697, DOI: 10.1016/j.tibs.2022.04.011.Peer-Reviewed Original ResearchGlioblastoma mutations alter EGFR dimer structure to prevent ligand bias
Hu C, Leche CA, Kiyatkin A, Yu Z, Stayrook SE, Ferguson KM, Lemmon MA. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. Nature 2022, 602: 518-522. PMID: 35140400, PMCID: PMC8857055, DOI: 10.1038/s41586-021-04393-3.Peer-Reviewed Original Research
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 PathwayPhosphatidylserine binding directly regulates TIM-3 function
Smith CM, Li A, Krishnamurthy N, Lemmon MA. Phosphatidylserine binding directly regulates TIM-3 function. Biochemical Journal 2021, 478: 3331-3349. PMID: 34435619, PMCID: PMC8454703, DOI: 10.1042/bcj20210425.Peer-Reviewed Original ResearchConceptsTim-3T cell receptorTherapeutic targetCo-signaling receptorsTim-3 functionTim-3 ligandTim-3 signalingCo-inhibitory receptorsCo-stimulatory receptorsImmune modulation approachesIL-2 secretionPotential therapeutic targetNF-κB signalingImportant therapeutic targetPD-1Jurkat cellsCultured Jurkat cellsT cellsCell receptorTCR stimulationReceptorsImportance of phosphatidylserineDifferent studiesCellsSignalingStructural 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 moleculesPhosphotransferComputational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation
Patil K, Jordan EJ, Park JH, Suresh K, Smith CM, Lemmon AA, Mossé YP, Lemmon MA, Radhakrishnan R. Computational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2019132118. PMID: 33674381, PMCID: PMC7958353, DOI: 10.1073/pnas.2019132118.Peer-Reviewed Original Research
2020
210 Regulation of TIM-3 by phosphatidylserine
Smith C, Li A, Krishnamurthy N, Lemmon M. 210 Regulation of TIM-3 by phosphatidylserine. Journal For ImmunoTherapy Of Cancer 2020, 8: a229-a229. DOI: 10.1136/jitc-2020-sitc2020.0210.Peer-Reviewed Original ResearchTim-3-expressing cellsTim-3 antibodyTim-3 functionTim-3Exhausted T cellsT cell signalingPD-1Receptor expressionT cellsTIM-1Tumor antigen-specific CD8Role of PST cell exhaustion phenotypeTim-3 receptorAntigen-specific CD8PD-1-mediated inhibitionPD-1 expressionImmune checkpoint blockadeMajority of patientsCheckpoint blockade therapyT cell dysfunctionImmune checkpoint receptorsAcute myelogenous leukemiaApoptotic cellsNew therapeutic targetsKinetics of receptor tyrosine kinase activation define ERK signaling dynamics
Kiyatkin A, van Alderwerelt van Rosenburgh IK, Klein DE, Lemmon MA. Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics. Science Signaling 2020, 13 PMID: 32817373, PMCID: PMC7521189, DOI: 10.1126/scisignal.aaz5267.Peer-Reviewed Original ResearchStructural 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 immunotherapiesDrug Sensitivity and Allele‐specificity of First‐line Osimertinib Resistance EGFR Mutations
Starrett J, Guernet A, Cuomo M, Poels K, van Rosenburgh I, Nagelberg A, Farnsworth D, Price K, Khan H, Ashtekar K, Gaefele M, Ayeni D, Stewart T, Kuhlmann A, Kaech S, Unni A, Homer R, Lockwood W, Michor F, Goldberg S, Lemmon M, Smith P, Cross D, Politi K. Drug Sensitivity and Allele‐specificity of First‐line Osimertinib Resistance EGFR Mutations. The FASEB Journal 2020, 34: 1-1. DOI: 10.1096/fasebj.2020.34.s1.00612.Peer-Reviewed Original ResearchFirst-line osimertinibEGFR-mutant lung cancerMutant lung cancerOsimertinib treatmentEGFR-TKILung cancerEGFR mutationsTotal tumorsPreferred first-line therapySecondary mutationsThird-generation EGFR-TKIFirst-line osimertinib treatmentMichael Smith FoundationResistance EGFR mutationsFirst-line therapySecondary EGFR mutationGeneration EGFR-TKISubsequent treatment approachesTransgenic mouse modelLung cancer researchTumor volume changesCoronal MR imagesTumor volume measurementsNew Investigator AwardResistance mechanisms
2019
Computational algorithms for in silico profiling of activating mutations in cancer
Jordan EJ, Patil K, Suresh K, Park JH, Mosse YP, Lemmon MA, Radhakrishnan R. Computational algorithms for in silico profiling of activating mutations in cancer. Cellular And Molecular Life Sciences 2019, 76: 2663-2679. PMID: 30982079, PMCID: PMC6589134, DOI: 10.1007/s00018-019-03097-2.Peer-Reviewed Original ResearchConceptsTarget proteinsSingle nucleotide polymorphismsB-RafSerine/threonine-protein kinase B-RafDifferent target proteinsEffects of mutationsStructure-based computational approachKinase domainStructure-based methodsStructure-based modelProtein structureProtein activationSilico profilingAnaplastic lymphoma kinaseInteraction of inhibitorsMutational landscapeHuman cancersPoint mutationsProteinMutationsMutational patternsDifferent mutationsActivation statusComputational approachLymphoma kinase