2023
cAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning
Wang X, Zhou L, Dong B, Xu F, Wang D, Shen E, Cai X, Wang Y, Wang N, Ji S, Chen W, Schonewille M, Zhu J, De Zeeuw C, Shen Y. cAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning. ELife 2023, 12: e80875. PMID: 37159499, PMCID: PMC10171863, DOI: 10.7554/elife.80875.Peer-Reviewed Original ResearchConceptsPresynaptic long-term potentiationSignaling cascadesPresynaptic plasticityRelease of synaptic vesiclesLong-term potentiationThreonine phosphorylationSynaptic vesiclesFunctional relevancePurkinje cell synapsesMotor behaviorPresynaptic formLearning mechanismCerebellar learning mechanismsCascadeLearningCell synapsesBasic performanceMotor learningThreonineMotor skillsSignalVesiclesAn 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
2017
The role of physical exercise on Sestrin1 and 2 accumulations in the skeletal muscle of mice
Crisol B, Lenhare L, Gaspar R, Gaspar R, Muñoz V, da Silva A, Cintra D, de Moura L, Pauli J, Ropelle E. The role of physical exercise on Sestrin1 and 2 accumulations in the skeletal muscle of mice. Life Sciences 2017, 194: 98-103. PMID: 29273527, DOI: 10.1016/j.lfs.2017.12.023.Peer-Reviewed Original ResearchConceptsStress-related proteinsThreonine phosphorylationBXD miceSkeletal muscleSesn2 mRNATranscriptomic analysisProtein contentBioinformatics analysisIsogenic strainsSestrin 1SestrinsSESN1Phenotypic patternsSestrin1Sestrin2 expressionPhosphorylationMRNA levelsWestern blotProteinNew insightsExperimental approachBasal levelsLarge panelAccumulationMice
2014
Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation*
Hançer N, Qiu W, Cherella C, Li Y, Copps K, White M. Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation*. Journal Of Biological Chemistry 2014, 289: 12467-12484. PMID: 24652289, PMCID: PMC4007441, DOI: 10.1074/jbc.m114.554162.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnisomycinAntigens, CDBlotting, WesternCHO CellsCricetinaeCricetulusEnzyme InhibitorsHumansHypoglycemic AgentsInsulinInsulin Receptor Substrate ProteinsPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktRatsReceptor, InsulinRibosomal Protein S6 Kinases, 70-kDaSerineSignal TransductionThapsigarginThreonineTOR Serine-Threonine KinasesTunicamycinTyrosineConceptsTyrosine phosphorylationPhospho-specific monoclonal antibodiesSerine/threonine phosphorylationInsulin receptor tyrosine kinasePI3KInsulin receptor substrate-1Insulin-stimulated cellsHuman insulin receptorIRS1 tyrosine phosphorylationReceptor substrate-1Metabolic stressReceptor tyrosine kinasesThreonine phosphorylationThreonine residuesS6 kinasePI3K inhibitionSubstrate-1Mechanistic targetTyrosine kinaseInsulin stimulationMEK pathwayKey substrateInsulin receptorPresence of inhibitorsCHO cells
2012
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2
Copps K, White M. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012, 55: 2565-2582. PMID: 22869320, PMCID: PMC4011499, DOI: 10.1007/s00125-012-2644-8.Peer-Reviewed Original ResearchConceptsInsulin receptor substrateT phosphorylationReceptor substrateSerine/threonine residuesSerine/threonine phosphorylationInsulin receptor tyrosine kinaseInsulin-stimulated kinasesReceptor tyrosine kinasesThreonine phosphorylationThreonine residuesNegative regulationTyrosine kinasePhosphorylationCultured cellsKinaseMetabolic diseasesIRS2IRS1Hormonal controlKey targetAltered patternTail regionComplex mechanismsRegulationDysregulationInteraction of the Histone mRNA Hairpin with Stem–Loop Binding Protein (SLBP) and Regulation of the SLBP–RNA Complex by Phosphorylation and Proline Isomerization
Zhang M, Lam TT, Tonelli M, Marzluff WF, Thapar R. Interaction of the Histone mRNA Hairpin with Stem–Loop Binding Protein (SLBP) and Regulation of the SLBP–RNA Complex by Phosphorylation and Proline Isomerization. Biochemistry 2012, 51: 3215-3231. PMID: 22439849, PMCID: PMC3328597, DOI: 10.1021/bi2018255.Peer-Reviewed Original ResearchConceptsStem-loop binding proteinStem-loop structureHistone mRNAProline isomerizationThreonine phosphorylationEnd formationC base pairsReplication-dependent histone mRNAsBase pairsBinding proteinPossible structural roleAdjacent prolineHistone proteinsRibonucleoprotein complexesHelix motifMRNA hairpinsMRNA complexesUntranslated regionStructural roleFirst binding sitePhosphorylationProteinComplex dissociationCritical hingeMRNA
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
2001
Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways
Rui L, Aguirre V, Kim J, Shulman G, Lee A, Corbould A, Dunaif A, White M. Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. Journal Of Clinical Investigation 2001, 107: 181-189. PMID: 11160134, PMCID: PMC199174, DOI: 10.1172/jci10934.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnisomycinCHO CellsCricetinaeInsulinInsulin AntagonistsInsulin ResistanceInsulin-Like Growth Factor IMAP Kinase Kinase 1Mitogen-Activated Protein Kinase KinasesPhosphatidylinositol 3-KinasesPhosphorylationProtein Serine-Threonine KinasesReceptor, InsulinSerineSignal TransductionTumor Necrosis Factor-alphaTyrosineConceptsPhosphorylation of Ser307IRS-1Serine/threonine phosphorylationTNF-alpha-stimulated phosphorylationInsulin-stimulated tyrosine phosphorylationRelevant phosphorylation sitesDistinct kinase pathwaysInsulin/IGFInsulin-stimulated phosphorylationThreonine phosphorylationStimulates PhosphorylationPhosphorylation sitesJun kinaseTyrosine phosphorylationKinase pathwaySer307PhosphorylationCultured cellsDistinct pathwaysHeterologous inhibitionPolyclonal antibodiesPreadipocytesPathwayAdipocytesCells
2000
Platelet-Endothelial Cell Adhesion Molecule-1 (CD31), a Scaffolding Molecule for Selected Catenin Family Members Whose Binding Is Mediated by Different Tyrosine and Serine/Threonine Phosphorylation*
Ilan N, Cheung L, Pinter E, Madri J. Platelet-Endothelial Cell Adhesion Molecule-1 (CD31), a Scaffolding Molecule for Selected Catenin Family Members Whose Binding Is Mediated by Different Tyrosine and Serine/Threonine Phosphorylation*. Journal Of Biological Chemistry 2000, 275: 21435-21443. PMID: 10801826, DOI: 10.1074/jbc.m001857200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsbeta CateninBinding SitesCadherinsCell Adhesion MoleculesCell LineCells, CulturedCytoskeletal ProteinsCytoskeletonDesmoplakinsEmbryo, MammalianEndothelium, Vasculargamma CateninHumansMicePhosphorylationPhosphoserinePhosphothreoninePhosphotyrosinePlatelet Endothelial Cell Adhesion Molecule-1Protein Kinase CRecombinant Fusion ProteinsSignal TransductionTrans-ActivatorsUmbilical VeinsYolk SacConceptsSerine/threonine phosphorylationThreonine phosphorylationCell-cell junctionsSpecific tyrosine residuesSignal transduction pathwaysPECAM-1 functionsTyrosine phosphorylation levelsInsoluble cytoskeletal fractionPECAM-1Beta-catenin localizationCytoskeleton interactionsPKC enzymeTransduction pathwaysCell adhesion moleculeCytoskeletal fractionTyrosine residuesMolecular mechanismsDifferent tyrosinePlatelet endothelial cell adhesion molecule-1Phosphorylation levelsITAM domainSW480 cellsEndothelium-specific markersPhosphorylationPlatelet endothelial cell adhesion molecule
1998
Differential Regulation of Insulin Receptor Substrate-2 and Mitogen-Activated Protein Kinase Tyrosine Phosphorylation by Phosphatidylinositol 3-Kinase Inhibitors in SH-SY5Y Human Neuroblastoma Cells*This work was supported by NIH Grants R29-NS-32843 and R01-NS-36778, grants from the American Diabetes Association and Juvenile Diabetes Foundation (to E.L.F.), and a grant from the Millie Schembechler Adrenal Research Fund of the University of Michigan Comprehensive Cancer Center (to E.L.F. and P.S.L.).
Kim B, Leventhal P, White M, Feldman E. Differential Regulation of Insulin Receptor Substrate-2 and Mitogen-Activated Protein Kinase Tyrosine Phosphorylation by Phosphatidylinositol 3-Kinase Inhibitors in SH-SY5Y Human Neuroblastoma Cells*This work was supported by NIH Grants R29-NS-32843 and R01-NS-36778, grants from the American Diabetes Association and Juvenile Diabetes Foundation (to E.L.F.), and a grant from the Millie Schembechler Adrenal Research Fund of the University of Michigan Comprehensive Cancer Center (to E.L.F. and P.S.L.). Endocrinology 1998, 139: 4881-4889. PMID: 9832424, DOI: 10.1210/endo.139.12.6348.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdaptor Proteins, Vesicular TransportCalcium-Calmodulin-Dependent Protein KinasesElectrophoresis, Polyacrylamide GelEnzyme InhibitorsGRB2 Adaptor ProteinHumansInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsIsoenzymesMitogen-Activated Protein Kinase 1NeuritesNeuroblastomaPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphorylationProteinsShc Signaling Adaptor ProteinsSrc Homology 2 Domain-Containing, Transforming Protein 1Tumor Cells, CulturedTyrosineConceptsInsulin receptor substrate 2IRS-2 tyrosine phosphorylationMitogen-activated protein kinase activationTyrosine phosphorylationProtein kinase activationKinase activationSerine/threonine phosphorylationSubstrate 2Association of Grb2Neurite outgrowthSH-SY5Y human neuroblastomaThreonine phosphorylationNegative regulationSH-SY5Y human neuroblastoma cellsIRS-1Grb2Nervous system growthDifferential regulationPhosphorylationHuman neuroblastoma cellsNeuronal cellsPhosphatidylinositolPI 3Concentration-dependent mannerInsulin-like growth factor IInteraction of insulin receptor substrate-1 (IRS-1) with phosphatidylinositol 3-kinase: effect of substitution of serine for alanine in potential IRS-1 serine phosphorylation sites.
Delahaye L, Mothe-Satney I, Myers M, White M, Van Obberghen E. Interaction of insulin receptor substrate-1 (IRS-1) with phosphatidylinositol 3-kinase: effect of substitution of serine for alanine in potential IRS-1 serine phosphorylation sites. Endocrinology 1998, 139: 4911-9. PMID: 9832428, DOI: 10.1210/endo.139.12.6379.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate-1Protein kinase B activitySerine phosphorylation sitesRegulatory subunitReceptor substrate-1Phosphorylation sitesPotential binding sitesTyrosine phosphorylationSubstrate-1Potential tyrosine phosphorylation sitesIRS-1 interactsPotential serine phosphorylation sitesWild-type IRS-1Two-hybrid systemTyrosine phosphorylation sitesInsulin-stimulated phosphatidylinositolPhosphorylate IRS-1P85alpha regulatory subunitBinding sitesYeast kinasesThreonine phosphorylationSerine mutantsYXXM motifsB activityP85alpha
1991
TPA inhibits the tyrosine kinase activity of the neu protein in vivo and in vitro.
Cao H, Decker S, Stern DF. TPA inhibits the tyrosine kinase activity of the neu protein in vivo and in vitro. Oncogene 1991, 6: 705-11. PMID: 1675782.Peer-Reviewed Original ResearchConceptsImmune complex kinase assayReceptor-like proteinTyrosine kinase activityProtein kinase CThreonine phosphorylationThreonine residuesTransmembrane domainKinase assaysTyrosine phosphorylationKinase activityAntiphosphotyrosine antibodyIncubation of cellsKinase CPhosphorylationPoint mutationsProteinNeu/Neu proteinLabeling experimentsSerineP185PhosphotyrosineTPAOncogenicMutationsSpk1, a new kinase from Saccharomyces cerevisiae, phosphorylates proteins on serine, threonine, and tyrosine.
Stern DF, Zheng P, Beidler DR, Zerillo C. Spk1, a new kinase from Saccharomyces cerevisiae, phosphorylates proteins on serine, threonine, and tyrosine. Molecular And Cellular Biology 1991, 11: 987-1001. PMID: 1899289, PMCID: PMC359764, DOI: 10.1128/mcb.11.2.987.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceBinding SitesCell Cycle ProteinsCheckpoint Kinase 2Cloning, MolecularEscherichia coliFungal ProteinsGene LibraryGenes, FungalImmunoblottingMolecular Sequence DataProtein KinasesProtein Serine-Threonine KinasesProtein-Tyrosine KinasesRecombinant ProteinsSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSequence Homology, Nucleic AcidSerineSubstrate SpecificityThreonineTyrosineConceptsSerine/threonine kinaseProtein kinaseFusion proteinThreonine kinaseTyrosine phosphorylationGlutathione S-transferase fusion proteinCyclic AMP-dependent protein kinaseAMP-dependent protein kinaseSerine protein kinaseSerine/threonineCalmodulin-dependent protein kinase IICalcium/calmodulin-dependent protein kinase IITyrosine protein kinaseOpen reading frameProtein kinase IILambda gt11 libraryPutative kinaseNew kinasesThreonine phosphorylationCatalytic subunitSaccharomyces cerevisiaeBacterial proteinsReading frameAntiphosphotyrosine antibodyKinase II
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