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
Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas
Kummar S, Shen L, Hong D, McDermott R, Keedy V, Casanova M, Demetri G, Dowlati A, Melcón S, Lassen U, Leyvraz S, Liu T, Moreno V, Patel J, Patil T, Mallick A, Sousa N, Tahara M, Ziegler D, Norenberg R, Arvis P, Brega N, Drilon A, Tan D. Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas. Cancer 2023, 129: 3772-3782. PMID: 37769113, PMCID: PMC11265530, DOI: 10.1002/cncr.35036.Peer-Reviewed Original ResearchConceptsTropomyosin receptor kinaseNTRK gene fusionsAdult patientsFusion sarcomaAdverse eventsData cutoffGrade 3 treatment-emergent adverse eventsTropomyosin receptor kinase fusion cancerCohort of adult patientsClinical management of adult patientsExtended survival benefitSafety of larotrectinibManagement of adult patientsGastrointestinal stromal tumorsSoft tissue sarcomasTreatment of patientsFirst-in-classGene fusionsInvestigator-assessedNTRK genesReceptor kinaseStromal tumorsSurvival benefitPediatric patientsSolid tumors1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo
HUBBARD B, GASPAR R, ZHANG D, KAHN M, NASIRI A, SHULMAN G. 1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo. Diabetes 2023, 72 DOI: 10.2337/db23-1510-p.Peer-Reviewed Original ResearchInsulin receptor kinasePyruvate carboxylaseHyperinsulinemic-euglycemic clampMitochondrial pyruvate oxidationInsulin resistanceOxidative metabolismMitochondrial pyruvate carboxylaseReceptor kinaseInhibitory phosphorylationAktS473 phosphorylationKinase axisChow fed miceImpairs insulinPyruvate oxidationKnockin micePhosphorylationKey targetFortress BiotechFed micePKCεDiacylglycerolRenal cortexHFDMetabolismBasal conditions
2022
Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice
Gaspar R, Lyu K, Hubbard B, Leitner B, Luukkonen P, Hirabara S, Sakuma I, Nasiri A, Zhang D, Kahn M, Cline G, Pauli J, Perry R, Petersen K, Shulman G. Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice. Diabetologia 2022, 66: 567-578. PMID: 36456864, PMCID: PMC11194860, DOI: 10.1007/s00125-022-05838-8.Peer-Reviewed Original ResearchConceptsProtein kinase CsSubcellular compartmentsDistinct subcellular localisationMuscle insulin sensitivityMultiple subcellular compartmentsInsulin receptor kinaseNovel protein kinase CsActivation of PKCεSubcellular localisationPKCθ translocationReceptor kinasePlasma membraneSubcellular distributionTriacylglycerol contentCrucial pathwaysIntramuscular triacylglycerol contentRC miceDiacylglycerolConclusions/interpretationThese resultsPKCεPM compartmentPhosphorylationMuscle triacylglycerol contentSkeletal muscleRecent findings
2021
NTRK genomic alterations in Latin-American cancer patients.
Carvajal D, Salas C, Marcelain K, Perez F, Rivas S, Feliu E, Schalper K, Arminsen R. NTRK genomic alterations in Latin-American cancer patients. Journal Of Clinical Oncology 2021, 39: e15088-e15088. DOI: 10.1200/jco.2021.39.15_suppl.e15088.Peer-Reviewed Original ResearchReceptor kinaseIndependent patient seriesChimeric proteinLatin American patientsDownstream signalingOncomine Comprehensive AssayTropomyosin receptor kinaseNTRK1-3Patient seriesTertiary hospitalActionable alterationsFFPE tumor samplesTRK fusionsNGS panelFocus assayTumor samplesComprehensive assayAssaysKinaseGenesSignalingMultiple institutionsOncogeneProteinOverexpression
2020
A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance. Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.Peer-Reviewed Original ResearchConceptsPlasma membraneEndoplasmic reticulumHigh-fat diet-induced hepatic insulin resistanceSubcellular fractionation methodInsulin receptor kinaseKey lipid speciesHepatic insulin resistanceDiet-induced hepatic insulin resistanceReceptor kinaseDiacylglycerol acyltransferase 2Molecular mechanismsAcute knockdownPhosphorylationLipid dropletsLipid speciesAcyltransferase 2KnockdownLiver-specific overexpressionDAG accumulationPKCDAG contentMembraneFractionation methodKinaseMitochondriaStructural 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 roleDomainWntMotifROR1ResiduesIntegrin-mediated adhesions in regulation of cellular senescence
Shin EY, Park JH, You ST, Lee CS, Won SY, Park JJ, Kim HB, Shim J, Soung NK, Lee OJ, Schwartz MA, Kim EG. Integrin-mediated adhesions in regulation of cellular senescence. Science Advances 2020, 6: eaay3909. PMID: 32494696, PMCID: PMC7202880, DOI: 10.1126/sciadv.aay3909.Peer-Reviewed Original ResearchConceptsClathrin-mediated endocytosisCellular senescenceG protein-coupled receptor kinasesProtein-coupled receptor kinasesElevated reactive oxygen species (ROS) productionIntegrin-mediated adhesionIntegrin endocytosisAmphiphysin 1Exchange factorReactive oxygen species productionReceptor kinaseOxygen species productionMolecular mechanismsCalpain cleavageSenescenceCell adhesionDirect competitionHuman fibroblastsGIT levelsSpecies productionΒPixNew therapeutic directionIntegrinsEndocytosisCentral role
2019
Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing
Klaver E, Zhao P, May M, Flanagan-Steet H, Freeze HH, Gilmore R, Wells L, Contessa J, Steet R. Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing. Disease Models & Mechanisms 2019, 12: dmm039602. PMID: 31101650, PMCID: PMC6602306, DOI: 10.1242/dmm.039602.Peer-Reviewed Original ResearchConceptsNull cellsReceptor processingEndoplasmic reticulum localizationGlycan site occupancyInsulin-like growth factor 1 receptorReceptor tyrosine kinasesGrowth factor 1 receptorFactor 1 receptorCell surface glycoproteinMutant cellsNGI-1Catalytic subunitReceptor kinaseGlycosylation statusReduced abundanceTyrosine kinaseGlycan occupancyTyrosine receptor kinaseSurface localizationInsulin receptorAbnormal glycosylationProteolytic processingFunctional consequencesCell surfaceGlycosylation
2018
Analysis of Cellular Tyrosine Phosphorylation via Chemical Rescue of Conditionally Active Abl Kinase
Wang Z, Kim MS, Martinez-Ferrando I, Koleske A, Pandey A, Cole P. Analysis of Cellular Tyrosine Phosphorylation via Chemical Rescue of Conditionally Active Abl Kinase. Biochemistry 2018, 57: 1390-1398. PMID: 29341593, PMCID: PMC5906802, DOI: 10.1021/acs.biochem.7b01158.Peer-Reviewed Original ResearchConceptsProtein kinaseNonreceptor tyrosine kinases AblMass spectrometry-based quantitative proteomicsNovel putative substratesTyrosine kinase AblCellular tyrosine phosphorylationExtracellular growth factorsChemical rescue approachIntracellular signal transductionQuantitative phosphoproteomicsUnanticipated functionCellular physiologyGrowth factorPhosphorylation sitesPutative substratesDirect substrateDownstream substratesSignal transductionReceptor kinaseQuantitative proteomicsTyrosine phosphorylationActive Abl kinasesAbl kinaseChemical rescueKinase
2016
Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase
Truong TH, Ung PM, Palde PB, Paulsen CE, Schlessinger A, Carroll KS. Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase. Cell Chemical Biology 2016, 23: 837-848. PMID: 27427230, PMCID: PMC4958504, DOI: 10.1016/j.chembiol.2016.05.017.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorEpidermal growth factor receptor kinaseGrowth factor receptor kinaseDetailed functional analysisNew electrostatic interactionsFirst detailed functional analysisKinase regulationS-sulfenylationRedox biologyReceptor kinaseCatalytic loopGrowth factor receptorMolecular basisChronic oxidative stressKinase activityFunctional analysisCatalytic importanceRedox activationFactor receptorMajor classesOxidative stressCatalytic efficiencyData highlightMolecular dynamics simulationsActivation
2012
Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression
Kickler K, Maltby K, Choileain S, Stephen J, Wright S, Hafler DA, Jabbour HN, Astier AL. Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression. The Journal Of Immunology 2012, 188: 5303-5310. PMID: 22544928, PMCID: PMC3758685, DOI: 10.4049/jimmunol.1103090.Peer-Reviewed Original ResearchConceptsG protein-coupled receptor kinasesCell functionProtein-coupled receptor kinasesT cell functionT cell activationG protein-coupled receptorsProtein-coupled receptorsCD46 expressionPrimary T cellsReceptor kinaseT cellsCD46 functionsCell activationRegulatory mechanismsDiverse rolesDifferentiation pathwayNovel roleCytokine productionProstanoid familyActivation signalsActivated T cellsT cell responsesChronic inflammatory diseaseSubtypes of receptorsCD46 activation
2011
Protein Phosphatase 2A Interacts with the Na+,K+-ATPase and Modulates Its Trafficking by Inhibition of Its Association with Arrestin
Kimura T, Han W, Pagel P, Nairn AC, Caplan MJ. Protein Phosphatase 2A Interacts with the Na+,K+-ATPase and Modulates Its Trafficking by Inhibition of Its Association with Arrestin. PLOS ONE 2011, 6: e29269. PMID: 22242112, PMCID: PMC3248462, DOI: 10.1371/journal.pone.0029269.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArrestinBinding, CompetitiveChlorocebus aethiopsCOS CellsGene DeletionG-Protein-Coupled Receptor KinasesHumansImmunoprecipitationKidneyMicePhosphorylationProtein BindingProtein BiosynthesisProtein Phosphatase 2Protein Structure, SecondaryProtein SubunitsProtein TransportRatsSodium-Potassium-Exchanging ATPaseConceptsC subunitATPase traffickingCatalytic subunitP-type ATPase familyG proteinsCatalytic C subunitTwo-hybrid systemIon transport proteinsEffect of arrestinNative rat kidneyATPase interactsProtein phosphataseATPase familyReceptor kinaseHomologous sequencesTransport proteinsFunctional domainsTrafficking propertiesImportant regulatorArrestinReceptor signalingIon pumpsTraffickingDirect interactionPP2A
2010
Spatial control of EGF receptor activation by reversible dimerization on living cells
Chung I, Akita R, Vandlen R, Toomre D, Schlessinger J, Mellman I. Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature 2010, 464: 783-787. PMID: 20208517, DOI: 10.1038/nature08827.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell Line, TumorCell PolarityCell SurvivalCHO CellsCricetinaeCricetulusDiffusionEnzyme ActivationEnzyme StabilityEpidermal Growth FactorErbB ReceptorsGene Expression RegulationGRB2 Adaptor ProteinHumansKineticsLigandsProtein MultimerizationProtein TransportSignal TransductionThermodynamicsConceptsLigand bindingEpidermal growth factor receptor moleculeType I receptor kinaseEGF receptor activationDimer formationReceptor kinaseReceptor dimerizationDimerization dynamicsReceptor dimersLiving cellsReceptor moleculesCell marginsDimer populationSpatial controlHuman carcinomasConformation changeDimerizationCell centerReceptor activationRate of dissociationCellsBindingActivationKinaseReversible dimerization
2008
Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2
Wu J, Tseng Y, Xu C, Neubert T, White M, Hubbard S. Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nature Structural & Molecular Biology 2008, 15: 251-258. PMID: 18278056, DOI: 10.1038/nsmb.1388.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCHO CellsCricetinaeCricetulusCrystallography, X-RayHumansInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMiceModels, MolecularMolecular Sequence DataMutationPhosphoproteinsPhosphorylationPhosphotyrosineProtein BindingProtein Structure, TertiaryProtein-Tyrosine KinasesReceptor, IGF Type 1Structure-Activity RelationshipSubstrate SpecificityConceptsInsulin receptorPleckstrin homology domainCrucial adaptor proteinTwo-hybrid studiesInsulin receptor kinaseKinase active siteInsulin receptor substrate 2C-terminal regionTyrosine kinase domainPrevious yeastThreonine phosphorylationHomology domainAdaptor proteinReceptor kinaseKinase domainTyrosine phosphorylationBiochemical characterizationRegion functionsSubstrate 2Binding regionsPhosphorylationKinase inhibitionFactor 1IRS2Insulin-like growth factor-1
2007
Multiple mechanisms modulate brassinosteroid signaling
Gendron JM, Wang ZY. Multiple mechanisms modulate brassinosteroid signaling. Current Opinion In Plant Biology 2007, 10: 436-441. PMID: 17904409, PMCID: PMC2093957, DOI: 10.1016/j.pbi.2007.08.015.Peer-Reviewed Original ResearchConceptsTranscription factorsCell surface receptor kinaseSubsequent biochemical studiesBR perceptionNuclear transcription factorPlant growthMultiple mechanismsReceptor kinaseGene expressionIntracellular kinasesGenetic studiesBiochemical studiesCell surfaceEssential hormoneKinasePathwayRecent studiesBRI1BAK1BrassinosteroidsEndosomesMajor gapsPhosphorylationKey componentProtein
2005
Caenorhabditus elegans Arrestin Regulates Neural G Protein Signaling and Olfactory Adaptation and Recovery*
Palmitessa A, Hess HA, Bany IA, Kim YM, Koelle MR, Benovic JL. Caenorhabditus elegans Arrestin Regulates Neural G Protein Signaling and Olfactory Adaptation and Recovery*. Journal Of Biological Chemistry 2005, 280: 24649-24662. PMID: 15878875, DOI: 10.1074/jbc.m502637200.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAmino Acid SequenceAnimalsAnimals, Genetically ModifiedArrestinBenzaldehydesBlotting, NorthernCaenorhabditis elegansCell LineCells, CulturedChemotaxisClathrinCOS CellsDiacetylEndocytosisExonsGreen Fluorescent ProteinsGTP-Binding ProteinsHumansImmunohistochemistryModels, GeneticMolecular Sequence DataMutationNeuronsOdorantsOlfactory PathwaysPentanolsPhenotypePhylogenyProtein BindingProtein Structure, TertiarySequence Analysis, DNASignal TransductionTime FactorsConceptsARR-1Receptor endocytosisG protein signalingG protein-coupled receptorsOlfactory adaptationVolatile odorantsProtein-coupled receptorsPotential mechanistic basisEndocytic machineryCaenorhabditis elegansNull mutantsHSN neuronsProtein signalingReceptor kinaseAdaptation defectRecovery defectArrestin functionChemosensory neuronsEnvironmental cuesBind proteinsMechanistic basisVivo linkTransgenic expressionArrestinNormal chemotaxisBZR1 Is a Transcriptional Repressor with Dual Roles in Brassinosteroid Homeostasis and Growth Responses
He JX, Gendron JM, Sun Y, Gampala SS, Gendron N, Sun CQ, Wang ZY. BZR1 Is a Transcriptional Repressor with Dual Roles in Brassinosteroid Homeostasis and Growth Responses. Science 2005, 307: 1634-1638. PMID: 15681342, PMCID: PMC2925132, DOI: 10.1126/science.1107580.Peer-Reviewed Original ResearchMeSH KeywordsArabidopsisArabidopsis ProteinsBase SequenceBinding SitesChromatin ImmunoprecipitationDNA-Binding ProteinsFeedback, PhysiologicalGene Expression Regulation, PlantGenes, PlantGenes, ReporterHomeostasisLightMutationNuclear ProteinsOligonucleotide Array Sequence AnalysisPhenotypePlant Growth RegulatorsPlants, Genetically ModifiedPromoter Regions, GeneticRecombinant Fusion ProteinsRepressor ProteinsSignal TransductionSteroidsTranscription, GeneticConceptsBrassinosteroid homeostasisTranscriptional repressorCell surface receptor kinaseBR biosynthetic genesDevelopment of plantsGrowth responseBR homeostasisBR biosynthesisBiosynthetic genesBZR1Dual roleReceptor kinaseAdditional potential targetsGene expressionMicroarray analysisUnknown DNARepressorNormal growthHomeostasisPotential targetPhysiological studiesDephosphorylationBiosynthesisKinaseGenes
2003
The tyrphostin AG1024 accelerates the degradation of phosphorylated forms of retinoblastoma protein (pRb) and restores pRb tumor suppressive function in melanoma cells.
von Willebrand M, Zacksenhaus E, Cheng E, Glazer P, Halaban R. The tyrphostin AG1024 accelerates the degradation of phosphorylated forms of retinoblastoma protein (pRb) and restores pRb tumor suppressive function in melanoma cells. Cancer Research 2003, 63: 1420-9. PMID: 12649208.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Cycle ProteinsCell DivisionCyclin-Dependent KinasesDNA-Binding ProteinsE2F Transcription FactorsE2F1 Transcription FactorE2F3 Transcription FactorHumansMAP Kinase Signaling SystemMelanocytesMelanomaMiceMitogen-Activated Protein Kinase 1PhosphorylationRetinoblastoma ProteinTranscription FactorsTyrphostinsUbiquitinConceptsTumor suppressive functionPhosphorylated formCell surface receptor kinaseMitogen-activated protein kinase/extracellular signal-regulated kinase pathwayProtein kinase/extracellular signal-regulated kinase pathwayExtracellular signal-regulated kinase (ERK) pathwaySignal-regulated kinase pathwayMelanoma cellsPhosphorylation/inactivationCyclin-dependent kinase 2Insulin-like growth factor 1 receptorActivation of pRbReceptor kinase activitySpecific chemical inhibitorsGrowth factor 1 receptorFactor 1 receptorPocket proteinsRetinoblastoma familyMelanoma cell proliferationReceptor kinaseProtein degradationKinase pathwayRetinoblastoma proteinKinase activityMelanoma cell growth
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