2022
Looking 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 Research
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 roleDomainWntMotifROR1Residues
2018
Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23
Liu L, Thaker TM, Freed DM, Frazier N, Malhotra K, Lemmon MA, Jura N. Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23. Structure 2018, 26: 270-281.e4. PMID: 29358026, PMCID: PMC5803352, DOI: 10.1016/j.str.2017.12.012.Peer-Reviewed Original ResearchConceptsLET-23Allosteric activatorEGF receptorAllosteric activation mechanismFull-length receptorCaenorhabditis elegansActive kinaseKinase domainAllosteric activationKinase activityReceptor dimersEGFR kinaseKinaseHuman EGFRDistinct rolesHuman counterpartActivation mechanismActivatorReceptorsElegansHeterodimerizationMutationsCrystal structureRegulationEGFR
2017
Molecular 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
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
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
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 surfaceLocalizationTerminusRegulatorCell 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
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
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