2025
Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation
Mendiratta G, Abbott K, Li Y, Yu J, Carlip P, Tong M, Huang J, Shokhirev M, McFall T, Wahl G, Stites E. Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation. PLOS Computational Biology 2025, 21: e1013297. PMID: 40749078, PMCID: PMC12407542, DOI: 10.1371/journal.pcbi.1013297.Peer-Reviewed Original ResearchA 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
2023
Metformin inhibits digestive proteases and impairs protein digestion in mice
Kelly C, Verdegaal A, Anderson B, Shaw W, Bencivenga-Barry N, Folta-Stogniew E, Goodman A. Metformin inhibits digestive proteases and impairs protein digestion in mice. Journal Of Biological Chemistry 2023, 299: 105363. PMID: 37863262, PMCID: PMC10663847, DOI: 10.1016/j.jbc.2023.105363.Peer-Reviewed Original ResearchConceptsGastrointestinal side effectsSide effectsDrug concentrationsDaily metformin doseFirst-line therapyType 2 diabetesEnteropeptidase activityPrescribed medicationsMetformin doseIntestinal lumenGastrointestinal tissuesMice exhibitMetforminProtein maldigestionHuman duodenumProtein digestionTrypsin activityDigestive enzymesMedicationsDiabetesMaldigestionDuodenumTherapyActivityMicePhosphatases 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 ResearchMeSH KeywordsCell Line, TumorCell SurvivalDNA DamageEnzyme ActivationHumansPhosphoprotein PhosphatasesPhosphorylationProtein Serine-Threonine KinasesConceptsDNA-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 inhibitorKinasePP5Phosphorylation
2021
Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs)
Chen PH, Hu Z, An E, Okeke I, Zheng S, Luo X, Gong A, Jaime-Figueroa S, Crews CM. Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs). ACS Chemical Biology 2021, 16: 2808-2815. PMID: 34780684, PMCID: PMC10437008, DOI: 10.1021/acschembio.1c00693.Peer-Reviewed Original ResearchConceptsSer/Thr phosphataseChemical biology approachPP2A holoenzymeProtein dephosphorylationBiology approachProtein substratesTranscriptional activationProtein phosphorylationCatalytic subunitCell biologyReporter geneProtein activityRetinoblastoma proteinOff-target effectsCritical proteinsDephosphorylationTernary complexPhosphorylationKinase inhibitorsFOXO3aPROTACsProteinChimerasPhosphataseDrug resistancePreservation of vision after CaMKII-mediated protection of retinal ganglion cells
Guo X, Zhou J, Starr C, Mohns EJ, Li Y, Chen EP, Yoon Y, Kellner CP, Tanaka K, Wang H, Liu W, Pasquale LR, Demb JB, Crair MC, Chen B. Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. Cell 2021, 184: 4299-4314.e12. PMID: 34297923, PMCID: PMC8530265, DOI: 10.1016/j.cell.2021.06.031.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsBrainCalcium-Calmodulin-Dependent Protein Kinase Type 2Cyclic AMP Response Element-Binding ProteinCytoprotectionDependovirusDisease Models, AnimalEnzyme ActivationGlaucomaMice, Inbred C57BLNeurotoxinsOptic Nerve InjuriesRetinal Ganglion CellsSignal TransductionVision, OcularConceptsRetinal ganglion cellsRGC survivalRGC somataGanglion cellsDiverse insultsRGC axon projectionOptic nerve injurySole output neuronsPreservation of visionElevated intraocular pressureIrreversible vision lossPathological statesExcitotoxic injuryNerve injuryGlaucoma modelIntraocular pressureRGC axonsVision lossVisual functionNormal retinaVisual cortexAxon projectionsGenetic deficiencyInjuryRetinaDevelopmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer
Sadras T, Martin M, Kume K, Robinson ME, Saravanakumar S, Lenz G, Chen Z, Song JY, Siddiqi T, Oksa L, Knapp AM, Cutler J, Cosgun KN, Klemm L, Ecker V, Winchester J, Ghergus D, Soulas-Sprauel P, Kiefer F, Heisterkamp N, Pandey A, Ngo V, Wang L, Jumaa H, Buchner M, Ruland J, Chan WC, Meffre E, Martin T, Müschen M. Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer. Molecular Cell 2021, 81: 2094-2111.e9. PMID: 33878293, PMCID: PMC8239336, DOI: 10.1016/j.molcel.2021.03.043.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD19AutoimmunityB-LymphocytesCalciumCell DifferentiationCell Transformation, NeoplasticEnzyme ActivationHumansImmune ToleranceLymphoma, B-CellMiceModels, GeneticNeoplasm ProteinsNeoplasmsNFATC Transcription FactorsPhosphatidylinositol 3-KinasesProtein BindingReceptors, Antigen, B-CellSignal TransductionSyk KinaseZAP-70 Protein-Tyrosine KinaseComputational 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 ResearchMeSH KeywordsAnaplastic Lymphoma KinaseEnzyme ActivationHumansMachine LearningMolecular Dynamics SimulationMutationProtein Conformation, alpha-Helical
2020
Temperature-Induced uncoupling of cell cycle regulators
Falahati H, Hur W, Di Talia S, Wieschaus E. Temperature-Induced uncoupling of cell cycle regulators. Developmental Biology 2020, 470: 147-153. PMID: 33278404, PMCID: PMC8106975, DOI: 10.1016/j.ydbio.2020.11.010.Peer-Reviewed Original ResearchConceptsCell cycle eventsCycle eventsEarly cell cycle eventsMajor mitotic kinaseCell cycle stepsEarly Drosophila embryoCell cycle progressionCell cycle regulatorsDrosophila embryosMitotic kinasesChromosome condensationDifferent kinasesCdk1 activityEmbryo activationCycle progressionCycle regulatorsEnvironmental variabilityCell cycle transition timesPrometaphaseCDK1KinaseMitosisVivo biosensorsEmbryosGlycogen synthase kinase-3β inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction
Wang S, Su X, Xu L, Chang C, Yao Y, Komal S, Cha X, Zang M, Ouyang X, Zhang L, Han S. Glycogen synthase kinase-3β inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction. Journal Of Molecular And Cellular Cardiology 2020, 149: 82-94. PMID: 32991876, DOI: 10.1016/j.yjmcc.2020.09.009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCARD Signaling Adaptor ProteinsEnzyme ActivationFibroblastsGlycogen Synthase Kinase 3 betaIndolesInflammasomesInflammationMaleMaleimidesMyocardial InfarctionMyocardial IschemiaMyocytes, CardiacNLR Family, Pyrin Domain-Containing 3 ProteinProtein Kinase InhibitorsProtein MultimerizationRats, Sprague-DawleyVascular RemodelingConceptsNLRP3 inflammasome activationGSK-3β inhibitionMyocardial infarctionInflammasome activationNOD-like receptor family pyrin domainGSK-3βFamily pyrin domainGlycogen synthase kinase-3β inhibitionCardiac dysfunctionMyocardial dysfunctionCardiac damageHeart dysfunctionHeart diseaseSterile inflammationInflammatory responseRat modelDay 2Pyrin domainCardiac fibroblastsSuccessful inductionHypoxia treatmentDysfunctionGSK-3 activityHuman cardiomyocytesInflammasome stimulationKinetics 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 ResearchSignalling input from divergent pathways subverts B cell transformation
Chan LN, Murakami MA, Robinson ME, Caeser R, Sadras T, Lee J, Cosgun KN, Kume K, Khairnar V, Xiao G, Ahmed MA, Aghania E, Deb G, Hurtz C, Shojaee S, Hong C, Pölönen P, Nix MA, Chen Z, Chen CW, Chen J, Vogt A, Heinäniemi M, Lohi O, Wiita AP, Izraeli S, Geng H, Weinstock DM, Müschen M. Signalling input from divergent pathways subverts B cell transformation. Nature 2020, 583: 845-851. PMID: 32699415, PMCID: PMC7394729, DOI: 10.1038/s41586-020-2513-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCell Line, TumorCell Transformation, NeoplasticEnzyme ActivationExtracellular Signal-Regulated MAP KinasesFemaleHumansLeukemia, B-CellMiceProtein Tyrosine Phosphatase, Non-Receptor Type 6Proto-Oncogene Proteins c-bcl-6Proto-Oncogene Proteins c-mycSignal TransductionSTAT5 Transcription FactorConceptsPre-B cell receptorPrincipal oncogenic driverDivergent pathwaysSignal transduction proteinsPro-B cell stageSingle-cell mutationTranscription factor MYCOncogenic driversDivergent signaling pathwaysSingle oncogenic pathwayCentral oncogenic driverMore mature cellsGenetic reactivationTranscriptional programsB-cell transformationProtein kinasePathway componentsERK activationIndividual mutationsOncogenic STAT5Signaling pathwaysCell transformationCytokine receptorsGenetic lesionsDivergent circuitsAnti-PfGARP activates programmed cell death of parasites and reduces severe malaria
Raj DK, Das Mohapatra A, Jnawali A, Zuromski J, Jha A, Cham-Kpu G, Sherman B, Rudlaff RM, Nixon CE, Hilton N, Oleinikov AV, Chesnokov O, Merritt J, Pond-Tor S, Burns L, Jolly G, Ben Mamoun C, Kabyemela E, Muehlenbachs A, Lambert L, Orr-Gonzalez S, Gnädig NF, Fidock DA, Park S, Dvorin JD, Pardi N, Weissman D, Mui BL, Tam YK, Friedman JF, Fried M, Duffy PE, Kurtis JD. Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria. Nature 2020, 582: 104-108. PMID: 32427965, PMCID: PMC7372601, DOI: 10.1038/s41586-020-2220-1.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnimalsAntibodies, ProtozoanAntigens, ProtozoanAotidaeApoptosisCaspasesChildCohort StudiesDNA, ProtozoanEnzyme ActivationErythrocytesFemaleHumansIntercellular Signaling Peptides and ProteinsKenyaMalaria VaccinesMalaria, FalciparumMaleMiceParasitesPlasmodium falciparumProtozoan ProteinsTanzaniaTrophozoitesVacuolesConceptsTrophozoite-infected erythrocytesSevere malariaParasite antigensLongitudinal cohort studyPlasma of childrenCell deathNon-human primatesCohort studyEffective vaccineTanzanian childrenParasite densityInvasion of hepatocytesStage parasitesMalariaPlasmodium falciparumAntibodiesFalciparumKenyan adolescentsVaccineAntigenErythrocytesDeathChildrenInvasionParasitesFlexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation
Bhattacharyya M, Lee YK, Muratcioglu S, Qiu B, Nyayapati P, Schulman H, Groves JT, Kuriyan J. Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation. ELife 2020, 9: e53670. PMID: 32149607, PMCID: PMC7141811, DOI: 10.7554/elife.53670.Peer-Reviewed Original ResearchConceptsInhibitory autophosphorylationResidue linkerDependent protein kinase IISingle-molecule assaysMammalian cell expressionProtein kinase IICaMKII variantsShort linkerTransphosphorylation ratesKinase domainCaMKII holoenzymeKinase IIAutophosphorylationHoloenzymeFlexible linkerPrincipal isoformCalcium signalsRelative levelsIsoformsCaMKIIHuman CaCell expressionLinkerVariantsSequenceGlucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis
Perry RJ, Zhang D, Guerra MT, Brill AL, Goedeke L, Nasiri AR, Rabin-Court A, Wang Y, Peng L, Dufour S, Zhang Y, Zhang XM, Butrico GM, Toussaint K, Nozaki Y, Cline GW, Petersen KF, Nathanson MH, Ehrlich BE, Shulman GI. Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis. Nature 2020, 579: 279-283. PMID: 32132708, PMCID: PMC7101062, DOI: 10.1038/s41586-020-2074-6.Peer-Reviewed Original ResearchConceptsHepatic steatosisType 2Nonalcoholic fatty liver diseaseDiet-induced hepatic steatosisFatty liver diseasePlasma glucagon concentrationsHepatic adipose triglyceride lipaseHepatic acetyl-CoA contentHepatic glucose productionRatio of insulinHepatic glucose metabolismInositol triphosphate receptorAdipose triglyceride lipaseMitochondrial oxidationMitochondrial fat oxidationGlucose intoleranceLiver diseaseGlucagon concentrationsInsulin resistancePortal veinAcetyl-CoA contentHepatic lipolysisGlucagon biologyGlucose metabolismKnockout mice
2019
An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors
Zhang W, Sviripa VM, Kril L, Yu T, Xie Y, Hubbard W, Sullivan P, Chen X, Zhan CG, Yang-Hartwich Y, Evers BM, Spear B, Gedaly R, Watt DS, Liu C. An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors. Journal Of Medicinal Chemistry 2019, 62: 11348-11358. PMID: 31774672, PMCID: PMC7560992, DOI: 10.1021/acs.jmedchem.9b01685.Peer-Reviewed Original ResearchAdipose tissue–derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases
Akoumianakis I, Sanna F, Margaritis M, Badi I, Akawi N, Herdman L, Coutinho P, Fagan H, Antonopoulos AS, Oikonomou EK, Thomas S, Chiu AP, Chuaiphichai S, Kotanidis CP, Christodoulides C, Petrou M, Krasopoulos G, Sayeed R, Lv L, Hale A, Naeimi Kararoudi M, McNeill E, Douglas G, George S, Tousoulis D, Channon KM, Antoniades C. Adipose tissue–derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases. Science Translational Medicine 2019, 11 PMID: 31534019, PMCID: PMC7212031, DOI: 10.1126/scitranslmed.aav5055.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdipose TissueAnimalsArteriesAtherosclerosisBlood VesselsCell MovementEndopeptidasesEnzyme ActivationLigandsMice, Inbred C57BLMuscle, Smooth, VascularMyocytes, Smooth MuscleNADPH OxidasesObesityOxidantsOxidation-Reductionrac1 GTP-Binding ProteinSignal TransductionVascular DiseasesWnt-5a ProteinConceptsAdipose tissueArterial wallFrizzled-related protein 5Oxidative stressArterial oxidative stressVascular disease pathogenesisNADPH oxidaseCoronary plaque progressionCoronary artery diseaseVascular oxidative stressVascular smooth muscle cellsFrizzled-2Smooth muscle cellsVascular redoxArtery diseaseHuman arterial wallPlasma concentrationsPlaque progressionParacrine mechanismsObesityParacrine effectsDisease pathogenesisMuscle cellsTranslational implicationsVascular signalingStructural insights into the activation of ATM kinase
Xiao J, Liu M, Qi Y, Chaban Y, Gao C, Pan B, Tian Y, Yu Z, Li J, Zhang P, Xu Y. Structural insights into the activation of ATM kinase. Cell Research 2019, 29: 683-685. PMID: 31320732, PMCID: PMC6796860, DOI: 10.1038/s41422-019-0205-0.Peer-Reviewed Original ResearchCaveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation
Ramírez CM, Zhang X, Bandyopadhyay C, Rotllan N, Sugiyama MG, Aryal B, Liu X, He S, Kraehling JR, Ulrich V, Lin CS, Velazquez H, Lasunción MA, Li G, Suárez Y, Tellides G, Swirski FK, Lee WL, Schwartz MA, Sessa WC, Fernández-Hernando C. Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation. Circulation 2019, 140: 225-239. PMID: 31154825, PMCID: PMC6778687, DOI: 10.1161/circulationaha.118.038571.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseDiet-induced atherosclerosisNO productionVascular inflammationENOS activationEndothelial nitric oxide synthase activationNitric oxide synthase activationAthero-protective functionsLipid metabolic factorsEndothelial cell inflammationNitric oxide synthaseWild-type miceMice Lacking ExpressionProduction of NOExtracellular matrix remodelingInflammatory primingHyperlipidemic miceInflammatory pathwaysAortic archCell inflammationOxide synthaseMetabolic factorsMouse modelAtherosclerosisInflammationBuparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial
Wen PY, Touat M, Alexander BM, Mellinghoff IK, Ramkissoon S, McCluskey CS, Pelton K, Haidar S, Basu SS, Gaffey SC, Brown LE, Martinez-Ledesma JE, Wu S, Kim J, Wei W, Park MA, Huse JT, Kuhn JG, Rinne ML, Colman H, Agar NYR, Omuro AM, DeAngelis LM, Gilbert MR, de Groot JF, Cloughesy TF, S. A, Roberts TM, Zhao JJ, Lee EQ, Nayak L, Heath JR, Horky LL, Batchelor TT, Beroukhim R, Chang SM, Ligon AH, Dunn IF, Koul D, Young GS, Prados MD, Reardon DA, Yung WKA, Ligon KL. Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. Journal Of Clinical Oncology 2019, 37: jco.18.01207. PMID: 30715997, PMCID: PMC6553812, DOI: 10.1200/jco.18.01207.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAminopyridinesAntineoplastic AgentsBrain NeoplasmsChemotherapy, AdjuvantDisease ProgressionEnzyme ActivationFemaleGlioblastomaHumansMaleMiddle AgedMorpholinesNeoadjuvant TherapyNeoplasm Recurrence, LocalPhosphatidylinositol 3-KinasePhosphoinositide-3 Kinase InhibitorsProgression-Free SurvivalTime FactorsConceptsPhase II trialCohort 2Cohort 1PI3K pathwayTumor tissueII trialRecurrent glioblastomaBrain penetrationPan-PI3K inhibitor buparlisibPathway inhibitionPathway activationCommon grade 3K pathwayPrimary end pointGreater adverse eventsProgression-free survivalPI3K pathway inhibitionPI3K pathway activationPlasma drug levelsSingle-agent efficacySignificant brain penetrationPI3K inhibitorsMedian PFSOpen labelAdverse events
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