2025
LRRK2, lysosome damage, and Parkinson's disease
Bentley-DeSousa A, Clegg D, Ferguson S. LRRK2, lysosome damage, and Parkinson's disease. Current Opinion In Cell Biology 2025, 93: 102482. PMID: 39983584, DOI: 10.1016/j.ceb.2025.102482.Peer-Reviewed Original ResearchConceptsLRRK2 kinase activityKinase activitySubstrate of LRRK2Rab familySmall GTPasesLysosomal biologyDamaged lysosomesEndolysosomal membranesRegulatory mechanismsNormal biologyPathogenesis of Parkinson's diseaseLRRK2Repair mechanismsLysosomal damageLysosomesBiologyGTPaseParkinson's diseaseRabGABARAPActivityA STING–CASM–GABARAP pathway activates LRRK2 at lysosomes
Bentley-DeSousa A, Roczniak-Ferguson A, Ferguson S. A STING–CASM–GABARAP pathway activates LRRK2 at lysosomes. Journal Of Cell Biology 2025, 224: e202310150. PMID: 39812709, PMCID: PMC11734622, DOI: 10.1083/jcb.202310150.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsApoptosis Regulatory ProteinsAutophagy-Related Protein 8 FamilyEnzyme ActivationHEK293 CellsHumansLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LysosomesMembrane ProteinsMiceMicrotubule-Associated ProteinsProtein Serine-Threonine KinasesSignal TransductionConceptsLRRK2 kinase activityKinase activityStimulator of interferon genesKinase activity of LRRK2Protein family membersLysosomal recruitmentLysosomal homeostasisEndogenous cellular mechanismsAberrant activationLRRK2Interferon genesLysosomesSingle membraneLysosomal damageMultiple chemical stimuliKinaseCellular mechanismsPathwayFamily membersChemical stimuliGABARAPMultiple stimuliGenesMutationsActivity
2024
Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation
Black E, Ramírez Parrado C, Trier I, Li W, Joo Y, Pichurin J, Liu Y, Kabeche L. Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation. Nature Communications 2024, 15: 10782. PMID: 39737931, PMCID: PMC11685634, DOI: 10.1038/s41467-024-54922-7.Peer-Reviewed Original ResearchConceptsPolo-like kinase 1Plk1 activityChromosome segregationMitotic polo-like kinase 1Mitotic chromosome segregationProtecting genome stabilitySensitivity to PLK1 inhibitorsMitotic cell divisionCheckpoint kinase 2Polo-like kinase 1 activityDNA damage repairGenome stabilityChromosome missegregationCytokinetic defectsCell divisionGenomic instabilityT-loopCell cycleKinase activityChromosome misalignmentMitotic errorsChk2Kinase 2Damage repairChromosomeA disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function
Ganga A, Sweeney L, Rubio Ramos A, Wrinn C, Bishop C, Hamel V, Guichard P, Breslow D. A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function. Current Biology 2024, 34: 4824-4834.e6. PMID: 39317195, PMCID: PMC11496028, DOI: 10.1016/j.cub.2024.08.058.Peer-Reviewed Original ResearchCentrosome functionKinase-phosphatase pairSystems genetics approachDisorders of gonadal developmentCentriolar localizationCentriole proteinsGrowth defectSystems geneticsPhosphatase subunitFunctional partnersCentrosomal proteinsGene functionMicrotubule organizationCentrosome regulationGenetic approachesPPP2R3CJNK signalingCell signalingKinase activityCentrosome biogenesisAcute overexpressionGonadal developmentRegulatory mechanismsMAP3K1Gonadal dysgenesisSignal integration and adaptive sensory diversity tuning in Escherichia coli chemotaxis
Moore J, Kamino K, Kottou R, Shimizu T, Emonet T. Signal integration and adaptive sensory diversity tuning in Escherichia coli chemotaxis. Cell Systems 2024, 15: 628-638.e8. PMID: 38981486, PMCID: PMC11307269, DOI: 10.1016/j.cels.2024.06.003.Peer-Reviewed Original ResearchEscherichia coli chemotaxisPopulation of E. coliMeasure kinase activityPhenotypic diversitySensory diversityDecreased diversityKinase activityDiverse phenotypesChemical signalsDiversitySingle cellsResponse to changesCellsSignalPhenotypePopulationChemotaxisSignal integrityLigandCompetitive ligandChemoattractantReduced kinase function in two ultra‐rare TNNI3K variants in families with congenital junctional ectopic tachycardia
Pham C, Koopmann T, Vinocur J, Blom N, Silbiger V, Mittal K, Bootsma M, Palm K, Clur S, Barge‐Schaapveld D, Hamilton R, Lodder E. Reduced kinase function in two ultra‐rare TNNI3K variants in families with congenital junctional ectopic tachycardia. Clinical Genetics 2024, 106: 37-46. PMID: 38424693, DOI: 10.1111/cge.14504.Peer-Reviewed Original ResearchCongenital junctional ectopic tachycardiaJunctional ectopic tachycardiaK variantEctopic tachycardiaDilated cardiomyopathySupraventricular tachycardiaReduction of kinase activityAssociated with dilated cardiomyopathyFour-generation familyAtrioventricular (AV) nodeInteracting kinasesMissense variantsKinase functionTroponin I-interacting kinaseKinase activityTNNI3KGenetic penetranceTNNI3Variant carriersMultigenerational familiesGenetic testingTroponin ICardiac arrhythmiasTachycardiaVariants
2023
Alternative glucose uptake mediated by β-catenin/RSK1 axis under stress stimuli in mammalian cells
Wang C, Lin R, Qi X, Xu Q, Sun X, Zhao Y, Jiang T, Jiang J, Sun Y, Deng Y, Wen J. Alternative glucose uptake mediated by β-catenin/RSK1 axis under stress stimuli in mammalian cells. Biochemical Pharmacology 2023, 214: 115645. PMID: 37321415, DOI: 10.1016/j.bcp.2023.115645.Peer-Reviewed Original ResearchConceptsPhosphorylation of TBC1D4Glucose uptakeGlucose transportActivation of RSK1Stress conditionsMechanism of glucose uptakeTranslocation of GLUT4Translocation of glucose transportersGlucose transporter translocationStress stimuliIncreased glucose uptakeB-cateninGlucose starvationEfficiency of glucose uptakeProtein complexesMammalian cellsScaffold proteinStress signalsCellular energy utilizationFamily 4TBC1D4Kinase activityRSK1Cellular adaptationCellular membranes169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation
Mekbib K, Zhao S, Nelson-Williams C, Prendergast A, Zeng X, Rolle M, Shohfi J, Smith H, Ocken J, Moyer Q, Piwowarczyk P, Allington G, Dong W, van der Ent M, Chen D, Li B, Duran D, Mane S, Walcott B, Stapleton C, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith E, Orbach D, Berenstein A, Bilguvar K, Zhao H, Erson-Omay Z, King P, Huttner A, Lifton R, Boggon T, Nicoli S, Jin S, Kahle K. 169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation. Neurosurgery 2023, 69: 22-22. DOI: 10.1227/neu.0000000000002375_169.Peer-Reviewed Original ResearchPathway analysisP120 Ras-GAPExome sequencingSevere vascular defectsGalen aneurysmal malformationReceptor tyrosine kinase activityTyrosine kinase activityDamaging de novoMutant embryosRas-GAPSignaling networksGenetic regulationRas activationAneurysmal malformationZebrafish modelDe novo mutationsKinase activityDisease genesAxon guidanceGenetic samplesWhole-exome sequencingHigh-output heart failureFunctional studiesCollected specimensSequencing
2022
Functional Analysis of MET Exon 14 Skipping Alteration in Cancer Invasion and Metastatic DisseminationMET Exon 14 Skipping Alteration Promotes Metastasis
Wang F, Liu Y, Qiu W, Shum E, Feng M, Zhao D, Zheng D, Borczuk A, Cheng H, Halmos B. Functional Analysis of MET Exon 14 Skipping Alteration in Cancer Invasion and Metastatic DisseminationMET Exon 14 Skipping Alteration Promotes Metastasis. Cancer Research 2022, 82: 1365-1379. PMID: 35078819, DOI: 10.1158/0008-5472.can-21-1327.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerMetastasis in vivoLung cancerInvasive capacity in vitroExtracellular matrix disassemblyReceptor kinase activityTumor progression of non-small cell lung cancerRNA sequencing analysisImpaired receptor internalizationTreatment of lung cancerMetastasis-related pathwaysCell lung cancerMolecular mechanisms of actionCytoskeleton remodelingEndocytic degradationSequence analysisCell scatteringEffective treatment of lung cancerPotential therapeutic optionCRISPR editingCell movementKinase activityMechanistic functionProgression of non-small cell lung cancerMatrix disassemblyThe P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor
Peng J, Ramatchandirin B, Wang Y, Pearah A, Namachivayam K, Wolf R, Steele K, MohanKumar K, Yu L, Guo S, White M, Maheshwari A, He L. The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor. Journal Of Biological Chemistry 2022, 298: 101621. PMID: 35074429, PMCID: PMC8850660, DOI: 10.1016/j.jbc.2022.101621.Peer-Reviewed Original ResearchConceptsAbsence of insulinP300 acetyltransferase activityTyrosine kinase activityAcetyltransferase activityInsulin receptorObese patientsTyrosine phosphorylationRole of acetylationInsulinNormal functionMembrane translocationSubsequent activationC646PatientsLiver hepatocytesProtein substratesInhibitionReceptorsMolecular mechanismsHepatocytesPhosphorylationBeta subunitKinase activityObesityUnique effects
2021
Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
Wu K, Wu H, Lyu W, Kim Y, Furdui CM, Anderson KS, Koleske AJ. Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation. Journal Of Biological Chemistry 2021, 297: 100883. PMID: 34144039, PMCID: PMC8259415, DOI: 10.1016/j.jbc.2021.100883.Peer-Reviewed Original ResearchConceptsAbl family kinasesFamily kinasesPlatelet-derived growth factor receptor betaGrowth factor receptor betaAbl familySrc homology 2 domainSrc homology 3 domainDiverse cellular stimuliPost-translational modificationsN-terminal halfNonreceptor tyrosine kinaseMultiple novel sitesAutoinhibited conformationSrc homologyCytoskeleton organizationCytoplasmic domainCellular stimuliKinase domainGrowth factor receptorReceptor betaKinase activityMolecular mechanismsTyrosine kinaseDirect bindingKinasePharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells
Chen S, Tjin C, Gao X, Xue Y, Jiao H, Zhang R, Wu M, He Z, Ellman J, Ha Y. Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2002486118. PMID: 34001596, PMCID: PMC8166193, DOI: 10.1073/pnas.2002486118.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein Kinase KinasesAnimalsEnergy MetabolismHumansInsulinInsulin Receptor Substrate ProteinsMechanistic Target of Rapamycin Complex 1MiceMuscle Fibers, SkeletalNeoplasmsPhosphorylationPhosphotransferases (Alcohol Group Acceptor)Ribosomal Protein S6 Kinases, 70-kDaSignal TransductionSmall Molecule LibrariesTumor Suppressor Protein p53ConceptsP53-null tumor cellsMost human cancer cellsCell energy homeostasisCell energy metabolismTumor suppressor genePI5P4KHuman cancer cellsGenetic experimentsDifferentiated myotubesAMPK activationStructural basisKinase activityEnergy stressMetabolic regulationSuppressor geneFunction mutationsLate-onset tumorsSubstrate loopP53 tumor suppressor geneChemical probesPI3KCell typesExquisite specificityEnergy metabolismTumor cellsStructural 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
Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines
Yi JS, Perla S, Enyenihi L, Bennett AM. Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines. JCI Insight 2020, 5 PMID: 32584792, PMCID: PMC7455087, DOI: 10.1172/jci.insight.137753.Peer-Reviewed Original ResearchConceptsProtein tyrosine phosphataseTyrosyl phosphorylationNSML micePhosphorylation-defective mutantPTPN11 mutationsS6 kinase activityPZR tyrosyl phosphorylationTyrosine phosphataseS6 kinasePathophysiological signalingKinase activityShp2 interactionMutant fibroblastsSHP2Transmembrane glycoproteinMultiple lentiginesNoonan syndromeCraniofacial defectsPTPN11 geneHeart lysatesPhosphorylationSHP2 bindingMutationsNF-κB pathwayProtein zeroMultivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane
Fang Z, Lee K, Huo K, Gasmi-Seabrook G, Zheng L, Moghal N, Tsao M, Ikura M, Marshall C. Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 12101-12108. PMID: 32414921, PMCID: PMC7275734, DOI: 10.1073/pnas.1914076117.Peer-Reviewed Original ResearchConceptsRas-binding domainCysteine-rich domainC-terminusΑ4-α5Transient electrostatic interactionsLipid-binding siteCancer-associated mutationsMembrane interfaceKRAS dimerizationMembrane anchoringMembrane associationKinase domainRaf kinaseMembrane complexPlasma membraneStructural insightsKinase activityMAPK signalingTerminusComplex formationMembraneDynamic interactionDynamic pictureComplexesDomainDefining the landscape of ATP-competitive inhibitor resistance residues in protein kinases
Persky NS, Hernandez D, Do Carmo M, Brenan L, Cohen O, Kitajima S, Nayar U, Walker A, Pantel S, Lee Y, Cordova J, Sathappa M, Zhu C, Hayes TK, Ram P, Pancholi P, Mikkelsen TS, Barbie DA, Yang X, Haq R, Piccioni F, Root DE, Johannessen CM. Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases. Nature Structural & Molecular Biology 2020, 27: 92-104. PMID: 31925410, DOI: 10.1038/s41594-019-0358-z.Peer-Reviewed Original ResearchConceptsMammalian kinasesDeep mutational scanning dataDrug discovery effortsProtein kinaseMutagenesis dataMutant kinasesKinase activityDrug resistanceKinomeKinaseDiscovery effortsRelevant inhibitorsResiduesDisease developmentResistance mutationsMutationsActivation siteERK2MEK1MutantsBroader interrogationInhibitorsCSNK2A1Valuable toolTBK1
2019
Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells
Kume K, Chen L, Lee J, Müschen M. Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells. Blood 2019, 134: 1253. DOI: 10.1182/blood-2019-130708.Peer-Reviewed Original ResearchBCR-ABL1Stromal interaction molecule 1Activation of NFATc1B cell receptorOncogenic kinase activityAutonomous Ca2Oncogenic signalingB cellsOscillatory Ca2Deletion of Stim1Poor clinical outcomeBCR-ABL1 kinase activityRole of SOCENormal B cellsCre-mediated deletionStrong cytotoxic responseStore-operated Ca2B cell survivalOncogenic kinasesClinical outcomesHodgkin's lymphomaB-ALLPump inhibitorsMouse modelKinase activityDNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma
Vyas M, Hechtman J, Zhang Y, Benayed R, Yavas A, Askan G, Shia J, Klimstra D, Basturk O. DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma. Modern Pathology 2019, 33: 648-656. PMID: 31676785, PMCID: PMC7125037, DOI: 10.1038/s41379-019-0398-2.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBiliary Tract NeoplasmsBiomarkers, TumorCarcinoma, HepatocellularCyclic AMP-Dependent Protein Kinase Catalytic SubunitsFemaleGene FusionGenetic Predisposition to DiseaseHSP40 Heat-Shock ProteinsHumansLiver NeoplasmsMaleMiddle AgedOxyphil CellsPancreatic NeoplasmsPhenotypePrognosisSodium-Potassium-Exchanging ATPaseConceptsDNAJB1-PRKACA fusionProtein kinase activityKinase activityAnchored multiplex PCR technologyIdentification of sequence mutationsMultiplex PCR technologyFibrolamellar hepatocellular carcinomaDetect gene fusionsCopy number alterationsNext-generation sequencingNext-generation sequencing assayHybridization capture-based next-generation sequencing assaySequence mutationsHepatocellular carcinomaGene fusionsSequencing assayFISH analysisPancreatobiliary neoplasmsPCR technologyProtein kinase inhibitionStructural rearrangementsArginase-1MRNA in situ hybridizationAlbumin mRNA in situ hybridizationGenesAcylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8+ T Cells
Hu Z, Qu G, Yu X, Jiang H, Teng XL, Ding L, Hu Q, Guo X, Zhou Y, Wang F, Li HB, Chen L, Jiang J, Su B, Liu J, Zou Q. Acylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8+ T Cells. Cell Metabolism 2019, 30: 290-302.e5. PMID: 31204281, DOI: 10.1016/j.cmet.2019.05.016.Peer-Reviewed Original ResearchConceptsAcylglycerol kinasePhosphatidylinositol-3-OH kinasePTEN phosphatase activityRecruitment of PTENCell glycolytic metabolismCell antigen receptorPTEN activityPlasma membranePTEN phosphorylationKinase activityRapamycin (mTOR) signalingMammalian targetPhosphatase activityCell glycolysisCell expansionGlycolytic metabolismCell proliferationMetabolic programmingMetabolic stateAntigen receptorKinaseCritical roleGlycolysisCellsFunctional stateHIPK2 is necessary for type I interferon–mediated antiviral immunity
Cao L, Yang G, Gao S, Jing C, Montgomery RR, Yin Y, Wang P, Fikrig E, You F. HIPK2 is necessary for type I interferon–mediated antiviral immunity. Science Signaling 2019, 12 PMID: 30890658, PMCID: PMC6893850, DOI: 10.1126/scisignal.aau4604.Peer-Reviewed Original ResearchConceptsHomeodomain-interacting protein kinase 2Type I interferonProtein kinase 2I interferonRNA virus infectionAntiviral immunityN-terminal fragmentVesicular stomatitis virus infectionNuclear localizationActive caspasesKinase activityB transcriptionHIPK2 deficiencyKinase 2Virus infectionStomatitis virus infectionAntiviral responseWild-type miceVSV infection
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