2025
Crystal structure of Isthmin-1 and reassessment of its functional role in pre-adipocyte signaling
Li T, Stayrook S, Li W, Wang Y, Li H, Zhang J, Liu Y, Klein D. Crystal structure of Isthmin-1 and reassessment of its functional role in pre-adipocyte signaling. Nature Communications 2025, 16: 3580. PMID: 40234450, PMCID: PMC12000326, DOI: 10.1038/s41467-025-58828-w.Peer-Reviewed Original ResearchConceptsThrombospondin type I repeatsIsthmin-1Pre-adipocytesType I repeatsBacterial streptavidinSurface helicesI repeatsMolecular detailsDiverse functionsFunctional studiesAkt phosphorylationFunctional roleStructural plasticityInsulin-like propertiesCrystal structureAMOPGrowth factorDomainPhosphorylationApoptosisLiver steatosisProteinHelixAktStreptavidin
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 recruitmentProteinAktDPP8/9 inhibition attenuates the TGF-β1-induced excessive deposition of extracellular matrix (ECM) in human mesangial cells via Smad and Akt signaling pathways
Li K, Zhang Y, Zhao W, Wang R, Li Y, Wei L, Wang L, Chen X, Chen Z, Liu P, Nie N, Tian X, Fu R. DPP8/9 inhibition attenuates the TGF-β1-induced excessive deposition of extracellular matrix (ECM) in human mesangial cells via Smad and Akt signaling pathways. Toxicology Letters 2024, 395: 1-10. PMID: 38458339, DOI: 10.1016/j.toxlet.2024.03.001.Peer-Reviewed Original ResearchHuman mesangial cellsAkt signaling pathwayExtracellular matrixSignaling pathwayDipeptidyl peptidase IVMesangial cellsExpression of ECM-related proteinsPhosphorylation of AktECM-related proteinsAbnormal extracellular matrixECM depositionExcessive deposition of extracellular matrixPhosphorylation of Smad2DPP8/9 inhibitionDeposition of extracellular matrixGlomerular mesangial cellsDPP9Collagen IVDPP8AktMultiple diseasesDPP8/9SiRNAPathogenesis of glomerular diseaseCells
2023
An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells
Zhou W, Li W, Wang S, Salovska B, Hu Z, Tao B, Di Y, Punyamurtula U, Turk B, Sessa W, Liu Y. An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells. Nature Communications 2023, 14: 3803. PMID: 37365174, PMCID: PMC10293293, DOI: 10.1038/s41467-023-39514-1.Peer-Reviewed Original ResearchConceptsPhosphorylation sitesSerine/threonine kinase AktMass spectrometry-based phosphoproteomicsThreonine kinase AktAkt-dependent phosphorylationAberrant Akt activationEndothelial cellsKinase substrateKinase AktCell signalingPhosphorylation profilePhenotypic outcomesDownstream signalingAkt activationAkt1 phosphorylationHuman diseasesSystem-level analysisAKT1Vascular endothelial cellsRich resourcePhosphorylationSignalingGrowth factorAktCellsThe histamine H3 receptor modulates dopamine D2 receptor–dependent signaling pathways and mouse behaviors
Xu J, Pittenger C. The histamine H3 receptor modulates dopamine D2 receptor–dependent signaling pathways and mouse behaviors. Journal Of Biological Chemistry 2023, 299: 104583. PMID: 36871761, PMCID: PMC10139999, DOI: 10.1016/j.jbc.2023.104583.Peer-Reviewed Original ResearchConceptsStress-activated protein kinase 1Receptor-dependent signaling pathwaysSerine/threonineGlycogen synthase kinase 3 betaSynthase kinase 3 betaProtein kinase 1Phosphorylation of mitogenBiochemical approachesMolecular mechanismsKinase 1Signaling pathwaysProximity ligationBeta signalingBiochemical levelPhosphorylation levelsReceptorsActivationHistamine H3 receptorsPhosphorylationSignalingThreonineAktSpiny projection neuronsD2R functionBetter understanding
2020
Differential effects of the Akt pathway on the internalization of Klebsiella by lung epithelium and macrophages
Chang D, Feng J, Liu H, Liu W, Sharma L, Dela Cruz CS. Differential effects of the Akt pathway on the internalization of Klebsiella by lung epithelium and macrophages. Innate Immunity 2020, 26: 618-626. PMID: 32762278, PMCID: PMC7556185, DOI: 10.1177/1753425920942582.Peer-Reviewed Original ResearchConceptsAkt pathwayEpithelial cellsCell typesKey cellular pathwaysLung epitheliumActivation of AktPhagocytic abilityMultiple cell typesAkt inhibitor MK2206Particular bacterial infectionsCellular pathwaysLung epithelial cellsMacrophage cell lineHost cellsBacterial infectionsRespiratory epithelial cellsCell proliferationType of infectionCell linesPathwayHost defenseDifferential rolesAktSC-79Cells
2018
Sin1 (Stress-Activated Protein Kinase-Interacting Protein) Regulates Ischemia-Induced Microthrombosis Through Integrin αIIbβ3-Mediated Outside-In Signaling and Hypoxia Responses in Platelets
Xu Y, Ouyang X, Yan L, Zhang M, Hu Z, Gu J, Fan X, Zhang L, Zhang J, Xue S, Chen G, Su B, Liu J. Sin1 (Stress-Activated Protein Kinase-Interacting Protein) Regulates Ischemia-Induced Microthrombosis Through Integrin αIIbβ3-Mediated Outside-In Signaling and Hypoxia Responses in Platelets. Arteriosclerosis Thrombosis And Vascular Biology 2018, 38: 1. PMID: 30571167, DOI: 10.1161/atvbaha.118.311822.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdultAgedAged, 80 and overAnimalsBlood PlateletsCarrier ProteinsCell HypoxiaDisease Models, AnimalFemaleHumansMaleMechanistic Target of Rapamycin Complex 2Mice, Inbred C57BLMice, KnockoutMiddle AgedMyocardial InfarctionPhosphorylationPlatelet ActivationPlatelet Glycoprotein GPIIb-IIIa ComplexProto-Oncogene Proteins c-aktReactive Oxygen SpeciesSignal TransductionSirtuin 3Superoxide DismutaseThrombosisConceptsOxygen speciesTarget AktSIN1Reactive oxygen speciesHypoxia responseNovel roleMyocardial infarctionIntegrin αIIbβ3Downstream signalsValuable therapeutic targetCell proliferationAktDeficiency micePhosphorylationST-segment elevation myocardial infarctionPlatelet activationLeft anterior descending (LAD) obstructionPump coronary artery bypassSignalingSpeciesTherapeutic targetΑIIbβ3Coronary artery bypass
2017
Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages
Di Pietro C, Zhang PX, O’Rourke T, Murray TS, Wang L, Britto CJ, Koff JL, Krause DS, Egan ME, Bruscia EM. Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages. Scientific Reports 2017, 7: 10882. PMID: 28883468, PMCID: PMC5589856, DOI: 10.1038/s41598-017-11012-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytoskeletal ProteinsDisease Models, AnimalMacrophage ActivationMacrophagesMicePhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktPseudomonas aeruginosaPseudomonas InfectionsSignal TransductionToll-Like Receptor 4ConceptsCystic fibrosis transmembrane conductance regulatorPI3K/AktFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorPI3K/Akt signalingConductance regulatorAnti-bacterial immune responseAkt signalingAltered localizationEzrinCystic fibrosis diseaseMφ activationAktProtein levelsFibrosis diseaseActivationImmune regulationPhagocytosisInductionDirect linkSignalingRegulatorImmune responseMΦMacrophagesCorrection for Long et al., “Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways”
Long Y, Cheng Z, Copps K, White M. Correction for Long et al., “Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways”. Molecular And Cellular Biology 2017, 37: e00232-17. PMID: 28710120, PMCID: PMC5514452, DOI: 10.1128/mcb.00232-17.Peer-Reviewed Original ResearchAkt1 Controls the Timing and Amplitude of Vascular Circadian Gene Expression
Luciano AK, Santana JM, Velazquez H, Sessa WC. Akt1 Controls the Timing and Amplitude of Vascular Circadian Gene Expression. Journal Of Biological Rhythms 2017, 32: 212-221. PMID: 28452287, PMCID: PMC5703205, DOI: 10.1177/0748730417704534.Peer-Reviewed Original ResearchConceptsCircadian gene expressionCircadian regulatorsAmplitude of expressionGene expressionAkt isoformsIsoforms of AktCircadian transcriptionOrganismal levelPositive regulatorNormal behavioral rhythmsCircadian rhythmPeripheral clocksBehavioral rhythmsAKT1RegulatorAktIsoformsMammalsAmplitude rhythmsDaily rhythmsDifferent functionsLow-amplitude rhythmExpressionEndothelial cellsMice exhibit
2016
d-3-Deoxy-dioctanoylphosphatidylinositol induces cytotoxicity in human MCF-7 breast cancer cells via a mechanism that involves downregulation of the D-type cyclin-retinoblastoma pathway
Gradziel CS, Jordan PA, Jewel D, Dufort FJ, Miller SJ, Chiles TC, Roberts MF. d-3-Deoxy-dioctanoylphosphatidylinositol induces cytotoxicity in human MCF-7 breast cancer cells via a mechanism that involves downregulation of the D-type cyclin-retinoblastoma pathway. Biochimica Et Biophysica Acta 2016, 1861: 1808-1815. PMID: 27600289, PMCID: PMC5115159, DOI: 10.1016/j.bbalip.2016.09.001.Peer-Reviewed Original ResearchMeSH KeywordsBreast NeoplasmsCell DeathCyclin D1Down-RegulationFemaleHumansMagnetic Resonance SpectroscopyMCF-7 Cellsp38 Mitogen-Activated Protein KinasesPhosphatidic AcidsPhosphatidylinositolsPhosphorylationPleckstrin Homology DomainsProto-Oncogene Proteins c-aktRetinoblastoma ProteinRNA, Small InterferingSignal TransductionConceptsMCF-7 breast cancer cellsBreast cancer cellsAkt PH domainPhosphatidylinositol analoguesD-type cyclinsCancer cellsCyclin D1Cleavage of PARPPH domainProtein phosphorylationMembrane translocationActive AktHuman MCF-7 breast cancer cellsGrowth arrestCaspase-9Endogenous levelsCyclin D3Cell proliferationAlkylphospholipid perifosineMCF-7 cell proliferationAnti-proliferative activityAktPathwayDownregulationOptogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action
Xu Y, Nan D, Fan J, Bogan JS, Toomre D. Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action. Journal Of Cell Science 2016, 129: 2085-2095. PMID: 27076519, PMCID: PMC4878990, DOI: 10.1242/jcs.174805.Peer-Reviewed Original ResearchConceptsPI3KGLUT4 translocationDistinct rolesAkt-independent pathwayNew optogenetic toolsGlucose transporter 4Drug-mediated inhibitionTranslocation responseIntracellular vesiclesOverall insulin actionPlasma membraneInsulin actionN-terminusOptogenetic toolsInsulin stimulationTransporter 4Biochemical assaysAktTranslocationAdipose cellsVesiclesPathwayCIB1PIP3CellsPre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition
Köhrer S, Havranek O, Seyfried F, Hurtz C, Coffey G, Kim E, ten Hacken E, Jäger U, Vanura K, O'Brien S, Thomas D, Kantarjian H, Ghosh D, Wang Z, Zhang M, Ma W, Jumaa H, Debatin K, Müschen M, Meyer L, Davis R, Burger J. Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition. Leukemia 2016, 30: 1246-1254. PMID: 26847027, PMCID: PMC5459356, DOI: 10.1038/leu.2016.9.Peer-Reviewed Original ResearchConceptsB-cell acute lymphoblastic leukemiaSpleen tyrosine kinaseAcute lymphoblastic leukemiaPI3K/AktLymphoblastic leukemiaTherapeutic targetPrecursor B-cell acute lymphoblastic leukemiaPromising new therapeutic targetNew therapeutic targetsGene expression signaturesImmune phenotypeImportant downstream mediatorSYK inhibitionMouse modelPre-BCR signalingReceptor signalingDownstream mediatorExpression signaturesGenetic disruptionLeukemiaExquisite dependencyTyrosine kinaseAktFOXO1Signaling
2015
Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+NIK+ signalosome on Rab5+ endosomes
Jane-wit D, Surovtseva YV, Qin L, Li G, Liu R, Clark P, Manes TD, Wang C, Kashgarian M, Kirkiles-Smith NC, Tellides G, Pober JS. Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+NIK+ signalosome on Rab5+ endosomes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 9686-9691. PMID: 26195760, PMCID: PMC4534258, DOI: 10.1073/pnas.1503535112.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBaculoviral IAP Repeat-Containing 3 ProteinClathrinComplement Membrane Attack ComplexCoronary VesselsEndocytosisEndosomesEnzyme StabilityFlow CytometryHuman Umbilical Vein Endothelial CellsHumansHydrazonesInhibitor of Apoptosis ProteinsMice, SCIDNF-kappa BProtein BiosynthesisProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktrab5 GTP-Binding ProteinsRNA, Small InterferingSecretory VesiclesSignal TransductionTNF Receptor-Associated Factor 3Ubiquitin-Protein LigasesConceptsNF-κB-inducing kinaseMembrane attack complexNoncanonical NF-κBGenome-wide siRNA screenComplement membrane attack complexNIK stabilizationDynamin-dependent mannerNoncanonical NF-κB signalingEndothelial cellsActive Rab5Attack complexSiRNA screenNF-κBAkt activationCytokine-mediated activationNF-κB signalingIκB kinaseSignalosomeRab5EndosomesKinaseAktInternalizationCoronary endothelial cellsActivationmTORC1 Activation Blocks Braf V600E -Induced Growth Arrest but Is Insufficient for Melanoma Formation
Damsky W, Micevic G, Meeth K, Muthusamy V, Curley DP, Santhanakrishnan M, Erdelyi I, Platt JT, Huang L, Theodosakis N, Zaidi MR, Tighe S, Davies MA, Dankort D, McMahon M, Merlino G, Bardeesy N, Bosenberg M. mTORC1 Activation Blocks Braf V600E -Induced Growth Arrest but Is Insufficient for Melanoma Formation. Cancer Cell 2015, 27: 41-56. PMID: 25584893, PMCID: PMC4295062, DOI: 10.1016/j.ccell.2014.11.014.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsCell Line, TumorCell ProliferationCyclin-Dependent Kinase Inhibitor p16HumansMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MelanocytesMelanoma, ExperimentalMiceMicroRNAsMolecular Sequence DataMultiprotein ComplexesMutationNevusProtein Serine-Threonine KinasesProto-Oncogene Proteins B-rafSignal TransductionSkin NeoplasmsTOR Serine-Threonine KinasesConceptsMelanoma formationGrowth arrestStable growth arrestMTORC2/AktSTK11 lossCDKN2A lossAkt activationIGF1R signalingMice resultsActivationArrestMTORC2Nevus developmentMTORC1/2SignalingAktMelanocytic nevus developmentMelanomagenesisMTORProgressionCDKN2AMelanocytesInactivationUpregulationComplete progression
2013
Fibroblast engraftment in the decellularized mouse lung occurs via a β1-integrin-dependent, FAK-dependent pathway that is mediated by ERK and opposed by AKT
Sun H, Calle E, Chen X, Mathur A, Zhu Y, Mendez J, Zhao L, Niklason L, Peng X, Peng H, Herzog EL. Fibroblast engraftment in the decellularized mouse lung occurs via a β1-integrin-dependent, FAK-dependent pathway that is mediated by ERK and opposed by AKT. American Journal Of Physiology - Lung Cellular And Molecular Physiology 2013, 306: l463-l475. PMID: 24337923, PMCID: PMC3949086, DOI: 10.1152/ajplung.00100.2013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingBioartificial OrgansCell AdhesionCell LineCell ProliferationCell SurvivalExtracellular Signal-Regulated MAP KinasesFibroblastsFocal Adhesion Kinase 1Integrin beta1LungMicePhosphorylationProto-Oncogene Proteins c-aktRatsrho-Associated KinasesTissue EngineeringTissue ScaffoldsConceptsExtracellular signal-regulated kinase (ERK) inhibitorSignal-regulated kinase inhibitorKinase inhibitorsERK-dependent mannerFAK-dependent pathwayFocal adhesion kinase (FAK) inhibitorFibroblast cell lineMouse fibroblast cell lineTissue-engineered lungsMinimal cell deathCell survivalCell deathMouse lungAkt inhibitorMouse fibroblastsProteinaceous componentsMammalian lungCell proliferationCell linesNumber of mechanismsAktTime-dependent increaseLung scaffoldsCell numberCell densityIncreased Hippocampal CREB Phosphorylation in Dopamine D3 Receptor Knockout Mice Following Passive Avoidance Conditioning
D’Amico A, Scuderi S, Leggio G, Castorina A, Drago F, D’Agata V. Increased Hippocampal CREB Phosphorylation in Dopamine D3 Receptor Knockout Mice Following Passive Avoidance Conditioning. Neurochemical Research 2013, 38: 2516-2523. PMID: 24100927, DOI: 10.1007/s11064-013-1164-3.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseCAMP response element-binding proteinNuclear transcription factor cAMP response element-binding proteinTranscription factor cAMP response element-binding proteinExtracellular signal-regulated kinase 1/2C-Jun N-terminal kinaseCREB phosphorylationSignal-regulated kinase 1/2Response element-binding proteinElement-binding proteinProtein kinaseDe novo synthesisKinase 1/2ERK signalingAkt activationBinding proteinPhosphorylationPhosphorylation levelsP38 phosphorylationGenetic backgroundKnockout mice displayNovo synthesisKinaseSynaptic functionAktChitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2
He CH, Lee CG, Dela Cruz CS, Lee CM, Zhou Y, Ahangari F, Ma B, Herzog EL, Rosenberg SA, Li Y, Nour AM, Parikh CR, Schmidt I, Modis Y, Cantley L, Elias JA. Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2. Cell Reports 2013, 4: 830-841. PMID: 23972995, PMCID: PMC3988532, DOI: 10.1016/j.celrep.2013.07.032.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisChitinase-3-Like Protein 1GlycoproteinsHumansInflammasomesInterleukin-13Interleukin-13 Receptor alpha2 SubunitLung NeoplasmsMacrophagesMAP Kinase Signaling SystemMelanomaMiceMice, Inbred C57BLOxidative StressProtein BindingTransforming Growth Factor betaWnt Signaling PathwayConceptsProtein kinase B/AktWnt/β-catenin signalingΒ-catenin signalingCritical roleGene familyMultimeric complexesProtein kinaseMacrophage mitogenDisease toleranceCell deathAntibacterial responseReceptor α2Antipathogen responsesChitinase 3IL-13Rα2IL-13 receptor α2Inflammasome activationBacterial killingKinaseOxidant injuryReceptorsMelanoma metastasesCHI3L1SignalingAkt
2012
Less Is More: Unveiling the Functional Core of Hematopoietic Stem Cells through Knockout Mice
Rossi L, Lin K, Boles N, Yang L, King K, Jeong M, Mayle A, Goodell M. Less Is More: Unveiling the Functional Core of Hematopoietic Stem Cells through Knockout Mice. Cell Stem Cell 2012, 11: 302-317. PMID: 22958929, PMCID: PMC3461270, DOI: 10.1016/j.stem.2012.08.006.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHematopoietic stem cellsHSC functionSomatic stem cell typesCell cycle controlStem cellsPTEN/AKTKey regulatory pathwaysStem cell typesTGF-β signalingKnockout miceHSC biologyRegulatory pathwaysCycle controlGenetic analysisCell typesFunctional coreFunctional modulesCellsWntCohesive pictureGenesSignalingBiologyAktMiceRecruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling
Bohdanowicz M, Balkin D, De Camilli P, Grinstein S. Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling. The FASEB Journal 2012, 26: 1065.1-1065.1. DOI: 10.1096/fasebj.26.1_supplement.1065.1.Peer-Reviewed Original Research
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