2025
MAP kinase phosphatases in metabolic diseases
Hota A, Bennett A. MAP kinase phosphatases in metabolic diseases. Trends In Endocrinology And Metabolism 2025 PMID: 40555575, DOI: 10.1016/j.tem.2025.05.002.Peer-Reviewed Original ResearchMitogen-activated protein kinaseInactivate mitogen-activated protein kinasesMAP kinase phosphatasesRegulation of MAPK signaling pathwaysMetabolic diseasesMAPK signaling pathwayRegulatory residuesInsulin signalingProtein kinaseSignaling pathwayCellular responsesKey pathwaysLipid metabolismGlucose homeostasisTherapeutic targetPathwayMetabolismKinaseResiduesHomeostasisMKPRegulationPhosphataseA triple-action inhibitory mechanism of allosteric TYK2-specific inhibitors
Wang J, Lomakin I, Batista V, Bunick C. A triple-action inhibitory mechanism of allosteric TYK2-specific inhibitors. Journal Of Investigative Dermatology 2025 PMID: 40378946, DOI: 10.1016/j.jid.2025.04.025.Peer-Reviewed Original ResearchJak-signal transducer and activatorAutoinhibited statePseudokinase domainIFN-induced gene expressionAtomic resolution structuresPhosphorylation of downstream proteinsAdenosine triphosphate bindingTyk2 kinaseTriphosphate bindingKinase domainActive stateResolution structureKinase activityTyk2Gene expressionStructural basisDownstream proteinsAllosteric drugsSteric clashesAllosteric inhibitorsInhibition mechanismMechanistic hypothesesKinaseBindingProteinPantothenate kinase is an effective target for antifungal therapy
Regan J, DeJarnette C, Reitler P, Gihaz S, Srivastava A, Ge W, Tucker K, Peters T, Meibohm B, Ben Mamoun C, Fortwendel J, Hevener K, Palmer G. Pantothenate kinase is an effective target for antifungal therapy. Cell Chemical Biology 2025, 32: 710-721.e6. PMID: 40378822, DOI: 10.1016/j.chembiol.2025.04.007.Peer-Reviewed Original ResearchConceptsPantothenate kinasePathogenic yeast Candida albicansDisseminated C. albicans infectionYeast Candida albicansIn vivo antifungal efficacyChemical-genetic approachBroad-spectrum antifungalAntifungal therapeuticsCoA productionCandida albicansMammalian hostsAntifungal therapyCoenzyme ASmall molecule inhibitorsAntifungal efficacyPanKEssential cofactorChemical probesMolecule inhibitorsKinaseLiving organismsPantothenateMouse modelEffective targetVirulenceA 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
Ezrin drives adaptation of monocytes to the inflamed lung microenvironment
Gudneppanavar R, Di Pietro C, H Öz H, Zhang P, Cheng E, Huang P, Tebaldi T, Biancon G, Halene S, Hoppe A, Kim C, Gonzalez A, Krause D, Egan M, Gupta N, Murray T, Bruscia E. Ezrin drives adaptation of monocytes to the inflamed lung microenvironment. Cell Death & Disease 2024, 15: 864. PMID: 39613751, PMCID: PMC11607083, DOI: 10.1038/s41419-024-07255-8.Peer-Reviewed Original ResearchConceptsActivation of focal adhesion kinaseExtracellular matrixActin-binding proteinsFocal adhesion kinaseLung extracellular matrixKnock-out mouse modelProtein kinase signalingCortical cytoskeletonLoss of ezrinKinase signalingPlasma membraneCell migrationSignaling pathwayEzrinResponse to lipopolysaccharideTissue-resident macrophagesMouse modelLipopolysaccharideCytoskeletonEzrin expressionLung microenvironmentKinaseMonocyte recruitmentProteinAktRegulation and signaling of the LIM domain kinases
Casanova‐Sepúlveda G, Boggon T. Regulation and signaling of the LIM domain kinases. BioEssays 2024, 47: e2400184. PMID: 39361252, PMCID: PMC11663136, DOI: 10.1002/bies.202400184.Peer-Reviewed Original ResearchLIM domain kinaseDownstream of Rho GTPasesCofilin/actin depolymerizing factorActin cytoskeleton regulationIntra-molecular mechanismFilament severingDepolymerizing factorRho GTPasesActin depolymerizationCytoskeleton regulationRegulation mechanismKinaseLIMProteinRegulationGTPaseLIMK2LIMK1ActinEnzymeHuman healthSignalDepolymerizationCascadeMechanismPTMoreR-enabled cross-species PTM mapping and comparative phosphoproteomics across mammals
Wang S, Di Y, Yang Y, Salovska B, Li W, Hu L, Yin J, Shao W, Zhou D, Cheng J, Liu D, Yang H, Liu Y. PTMoreR-enabled cross-species PTM mapping and comparative phosphoproteomics across mammals. Cell Reports Methods 2024, 4: 100859. PMID: 39255793, PMCID: PMC11440062, DOI: 10.1016/j.crmeth.2024.100859.Peer-Reviewed Original ResearchConceptsP-siteSurrounding amino acid sequenceKinase-substrate networkQuantitative phosphoproteomic analysisFunctional enrichment analysisPhosphoproteomic resultsKinase motifsComparative phosphoproteomicsPTM sitesPhosphorylation eventsPhosphoproteomic analysisProteomic analysisEnrichment analysisMammalian speciesSpeciesEvolutionary anglePhosphoproteomeMotifEnvironmental factorsNon-human speciesPTMProteomicsKinaseMammalsProteinThe intrinsic substrate specificity of the human tyrosine kinome
Yaron-Barir T, Joughin B, Huntsman E, Kerelsky A, Cizin D, Cohen B, Regev A, Song J, Vasan N, Lin T, Orozco J, Schoenherr C, Sagum C, Bedford M, Wynn R, Tso S, Chuang D, Li L, Li S, Creixell P, Krismer K, Takegami M, Lee H, Zhang B, Lu J, Cossentino I, Landry S, Uduman M, Blenis J, Elemento O, Frame M, Hornbeck P, Cantley L, Turk B, Yaffe M, Johnson J. The intrinsic substrate specificity of the human tyrosine kinome. Nature 2024, 629: 1174-1181. PMID: 38720073, PMCID: PMC11136658, DOI: 10.1038/s41586-024-07407-y.Peer-Reviewed Original ResearchIntrinsic substrate specificityTyr kinasesTyr sitesSequence specificityProtein Tyr kinasesSubstrate sequence specificitySites of phosphorylationPhosphorylation of proteinsMulticellular eukaryotesMetazoan organismsMotif preferencesPhosphoproteomic datasetsSubstrate sequenceTyrosine (Tyr) residuesKinase specificityPattern of residuesSubstrate specificitySignaling networksYears of evolutionPeptide arraysTyrosine kinomeAnti-cancer drugsOncogenic variantsTyr residuesKinaseDistinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Sexton J, Potchernikov T, Bibeau J, Casanova-Sepúlveda G, Cao W, Lou H, Boggon T, De La Cruz E, Turk B. Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail. Nature Communications 2024, 15: 1426. PMID: 38365893, PMCID: PMC10873347, DOI: 10.1038/s41467-024-45878-9.Peer-Reviewed Original ResearchConceptsN-terminal regionActin bindingSequence requirementsLIM kinaseAnalysis of individual variantsInactivates cofilinS. cerevisiaeRegulatory tailFamily proteinsActin depolymerizationPhosphorylation sitesKinase recognitionSequence variantsInhibitory phosphorylationCofilinN-terminusIndividual variantsFunctional constraintsActinDisordered sequencesPhosphorylationSequenceBiochemical analysisSequence constraintsKinase
2023
Discovery of the first unconventional myosin: Acanthamoeba myosin-I
Pollard T, Korn E. Discovery of the first unconventional myosin: Acanthamoeba myosin-I. Frontiers In Physiology 2023, 14: 1324623. PMID: 38046947, PMCID: PMC10693453, DOI: 10.3389/fphys.2023.1324623.Peer-Reviewed Original ResearchUnconventional myosinActin filamentsMyosin heavy chain kinaseFirst unconventional myosinsEvolution of eukaryotesClass I MyosinHeavy chain kinaseNovel unconventional myosinPhylogenetic analysisSlime moldMembrane lipidsChain kinaseProteolytic fragmentsHeavy chainMuscle myosinMyosinCofactorEnzymeMg-ATPaseMg-ATPase activityEukaryotesFilamentsCrude enzymeKinaseActinHigh-frequency variants in PKA signaling-related genes within a large pediatric cohort with obesity or metabolic abnormalities
Bloyd M, Sinaii N, Faucz F, Iben J, Coon S, Caprio S, Santoro N, Stratakis C, London E. High-frequency variants in PKA signaling-related genes within a large pediatric cohort with obesity or metabolic abnormalities. Frontiers In Endocrinology 2023, 14: 1272939. PMID: 38027204, PMCID: PMC10679389, DOI: 10.3389/fendo.2023.1272939.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesSignaling-related genesProtein kinaseHigh-frequency variantsCAMP-dependent protein kinaseLarge-scale genome-wide association studiesNew genetic associationsPDE11A geneGenomic DNAAssociation studiesMonogenic obesityTargeted exome sequencingGenesGenetic variantsEnergy metabolismGenetic associationExome sequencingNovel variantsVariant searchMetabolic characteristicsVariantsKinaseType II diabetesLociSequencingChromophobe renal cell carcinoma
Henske E, Cheng L, Hakimi A, Choueiri T, Braun D. Chromophobe renal cell carcinoma. Cancer Cell 2023, 41: 1383-1388. PMID: 37541245, DOI: 10.1016/j.ccell.2023.07.006.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsChromophobe renal cell carcinomaClear cell RCCRenal cell carcinomaCell carcinomaCell/ILTerms of geneticsCell of originImmune therapyCell RCCTargetable pathwaysMTOR inhibitorsMitochondrial dysfunctionPathway mutationsOxidative stressPotential mechanismsChRCCCarcinomaCurrent dataRCCGenomicsKinaseImmunotherapyResponseDysfunctionGeneticsPhosphatases maintain low catalytic activity of SGK1: DNA damage resets the balance in favor of phosphorylation
Gu W, Zheng H, Canessa C. Phosphatases maintain low catalytic activity of SGK1: DNA damage resets the balance in favor of phosphorylation. Journal Of Biological Chemistry 2023, 299: 104941. PMID: 37343701, PMCID: PMC10372406, DOI: 10.1016/j.jbc.2023.104941.Peer-Reviewed Original ResearchConceptsDNA-dependent protein kinaseCell survivalHsp90 chaperone complexDNA damage responseGlucocorticoid-induced kinase 1Inhibitor of phosphatasesChaperone complexGenotoxic stressDamage responseCatalytic subunitProtein kinaseNovel cancer therapiesKinase 1Stress conditionsDNA damageMolecular pathwaysSGK1 activityPP2ASGK1Cancer cellsDephosphorylationEndogenous inhibitorKinasePP5PhosphorylationCroquemort elicits activation of the immune deficiency pathway in ticks
O’Neal A, Singh N, Rolandelli A, Laukaitis H, Wang X, Shaw D, Young B, Narasimhan S, Dutta S, Snyder G, Samaddar S, Marnin L, Butler L, Mendes M, Paz F, Valencia L, Sundberg E, Fikrig E, Pal U, Weber D, Pedra J. Croquemort elicits activation of the immune deficiency pathway in ticks. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2208673120. PMID: 37155900, PMCID: PMC10193931, DOI: 10.1073/pnas.2208673120.Peer-Reviewed Original ResearchConceptsImmune deficiency (IMD) pathwayIMD pathwayNon-insect arthropodsPeptidoglycan recognition proteinsJun N-terminal kinaseN-terminal kinaseArthropod immunityMembrane localizationRecognition proteinsLyme disease spirocheteEcdysteroid synthesisMicrobial moietiesDistinct mechanismsProteinArthropodsPathwayHost defenseElicit activationCroquemortPancrustaceaHomologInsectsActivationCrustaceansKinaseGeneration of ventralized human thalamic organoids with thalamic reticular nucleus
Kiral F, Cakir B, Tanaka Y, Kim J, Yang W, Wehbe F, Kang Y, Zhong M, Sancer G, Lee S, Xiang Y, Park I. Generation of ventralized human thalamic organoids with thalamic reticular nucleus. Cell Stem Cell 2023, 30: 677-688.e5. PMID: 37019105, PMCID: PMC10329908, DOI: 10.1016/j.stem.2023.03.007.Peer-Reviewed Original ResearchConceptsHuman embryonic stem cellsSingle-cell RNA sequencingReceptor tyrosine protein kinaseTyrosine protein kinaseEmbryonic stem cellsDisease-associated genesLineage developmentRNA sequencingHuman brain developmentOrganoid systemsStem cellsHuman brain organoidsNeuronal functionBrain organoidsOrganoidsBrain organoid systemsDistinct nucleiBrain developmentThalamic developmentPTCHD1NucleusKinaseGenesSequencingMitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?
Shillingford S, Bennett A. Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable? The Annual Review Of Pharmacology And Toxicology 2023, 63: 617-636. PMID: 36662585, PMCID: PMC10127142, DOI: 10.1146/annurev-pharmtox-051921-121923.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseSmall molecule inhibitionProtein kinaseCritical cellular functionsInhibition of PTPsProtein tyrosineCellular functionsProtein substratesPhosphorylated proteinsCell signalingTyrosine residuesAttractive therapeutic targetCellular effectsKinaseNumerous diseasesPTPDiscovery toolTherapeutic developmentTherapeutic targetMetabolic diseasesInhibitionDephosphorylationSignalingMKPProteinAn atlas of substrate specificities for the human serine/threonine kinome
Johnson J, Yaron T, Huntsman E, Kerelsky A, Song J, Regev A, Lin T, Liberatore K, Cizin D, Cohen B, Vasan N, Ma Y, Krismer K, Robles J, van de Kooij B, van Vlimmeren A, Andrée-Busch N, Käufer N, Dorovkov M, Ryazanov A, Takagi Y, Kastenhuber E, Goncalves M, Hopkins B, Elemento O, Taatjes D, Maucuer A, Yamashita A, Degterev A, Uduman M, Lu J, Landry S, Zhang B, Cossentino I, Linding R, Blenis J, Hornbeck P, Turk B, Yaffe M, Cantley L. An atlas of substrate specificities for the human serine/threonine kinome. Nature 2023, 613: 759-766. PMID: 36631611, PMCID: PMC9876800, DOI: 10.1038/s41586-022-05575-3.Peer-Reviewed Original ResearchConceptsSer/ThrHuman Ser/ThrSubstrate specificityPhosphorylation eventsProtein serine/threonine kinaseWidespread post-translational modificationSerine/threonine kinasePutative protein kinaseSubstrate sequence specificityIntrinsic substrate specificityPost-translational modificationsThreonine phosphorylationGenetic perturbationsThreonine kinasePhosphorylation sitesHuman genomeProtein phosphorylationProtein kinaseSequence specificityBiological pathwaysHuman diseasesNegative selectivityKinaseUnexpected insightsKinome
2022
Targeting ferroptosis to treat colorectal cancer
Yan H, Talty R, Johnson C. Targeting ferroptosis to treat colorectal cancer. Trends In Cell Biology 2022, 33: 185-188. PMID: 36473802, DOI: 10.1016/j.tcb.2022.11.003.Peer-Reviewed Original ResearchConceptsProtein kinase BArachidonic acidColorectal cancer treatmentProtein kinaseKinase BMammalian targetKey pathwaysGlutathione metabolismFerroptosis inductionEnergy metabolismCRC treatmentColorectal cancerCRC pathogenesisFerroptosisCancer treatmentPromising targetNew conceptual avenuesMetabolismTreatmentHippoKinasePrimary strategyRapamycinTargetConceptual avenuesEnhanced access to the human phosphoproteome with genetically encoded phosphothreonine
Moen J, Mohler K, Rogulina S, Shi X, Shen H, Rinehart J. Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine. Nature Communications 2022, 13: 7226. PMID: 36433969, PMCID: PMC9700786, DOI: 10.1038/s41467-022-34980-5.Peer-Reviewed Original ResearchConceptsUbiquitous post-translational modificationCo-translational insertionKinase activation mechanismProtein interaction platformOrthogonal translation systemProtein-protein interactionsPost-translational modificationsPhospho-amino acidsAminoacyl-tRNA synthetaseHuman phosphoproteomePhosphorylation eventsTRNA pairsFunctional assignmentCellular processesProtein phosphorylationUpstream kinasePhysiological functionsActivation mechanismTranslation systemKinasePhosphorylationInteraction platformPhosphoproteomePhosphothreoninePhosphoRho family GTPase signaling through type II p21-activated kinases
Chetty A, Ha B, Boggon T. Rho family GTPase signaling through type II p21-activated kinases. Cellular And Molecular Life Sciences 2022, 79: 598. PMID: 36401658, PMCID: PMC10105373, DOI: 10.1007/s00018-022-04618-2.Peer-Reviewed Original ResearchConceptsRho family small GTPasesP21-activated kinaseRho GTPasesSmall GTPasesPAK family membersRho family GTPaseSignal transduction pathwaysMechanism of regulationPAK familySignal transductionTransduction pathwaysGTPasesMolecular basisDownstream effectorsDomain recognitionPAKsCross talkKinasePAK groupDistinct structuresRegulationPAKFamily membersGTPaseTransduction
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