2013
Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling
Ersoy B, Tarun A, D’Aquino K, Hancer N, Ukomadu C, White M, Michel T, Manning B, Cohen D. Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling. Science Signaling 2013, 6: ra64. PMID: 23901139, PMCID: PMC3959124, DOI: 10.1126/scisignal.2004111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGlucoseHEK293 CellsHomeostasisHumansInhibitory Concentration 50InsulinLiverMechanistic Target of Rapamycin Complex 1MiceMice, TransgenicMultiprotein ComplexesPhospholipid Transfer ProteinsPhosphorylationSignal TransductionThiolester HydrolasesTOR Serine-Threonine KinasesTuberous Sclerosis Complex 2 ProteinTumor Suppressor ProteinsConceptsThioesterase superfamily member 2Insulin receptor substrate 2Phosphatidylcholine transfer proteinTSC1-TSC2 complexGenetic ablationRapamycin complex 1Transfer proteinSteady-state amountsMember 2Hepatic glucose homeostasisPhospholipid-binding proteinProtein exhibitInsulin signalingChemical inhibitionKey effectorsSubstrate 2Mammalian targetDiet-induced diabetesProteinTSC2KnockdownGlucose homeostasisPhospholipid-dependent mechanismsActivationComplexes 1
2011
IRS-2 Deficiency Impairs NMDA Receptor-Dependent Long-term Potentiation
Martín E, Sánchez-Perez A, Trejo J, Martin-Aldana J, Jaimez M, Pons S, Umanzor C, Menes L, White M, Burks D. IRS-2 Deficiency Impairs NMDA Receptor-Dependent Long-term Potentiation. Cerebral Cortex 2011, 22: 1717-1727. PMID: 21955917, PMCID: PMC3388895, DOI: 10.1093/cercor/bhr216.Peer-Reviewed Original ResearchConceptsLong-term potentiationInduction of LTPInsulin receptor substrate 2Activation of FynPotential new componentSynaptic transmissionSynaptic plasticityWild-type controlsSubstrate 2Alzheimer's diseasePostsynaptic N-methyl-D-aspartate receptorsIRS2 expressionN-methyl-D-aspartate receptorsImpairs long-term potentiationInsulin-like growth factor IMechanistic linkNMDA receptor-dependent long-term potentiationType 2 diabeticsBasal synaptic transmissionExpression of NR2AGroups of miceGrowth factor IPaired-pulse facilitationNeurodegenerative disordersTetanus stimulation
2009
Insulin-Like Growth Factor 2 and the Insulin Receptor, But Not Insulin, Regulate Fetal Hepatic Glycogen Synthesis
Liang L, Guo W, Esquiliano D, Asai M, Rodriguez S, Giraud J, Kushner J, White M, Lopez M. Insulin-Like Growth Factor 2 and the Insulin Receptor, But Not Insulin, Regulate Fetal Hepatic Glycogen Synthesis. Endocrinology 2009, 151: 741-747. PMID: 20032056, PMCID: PMC2817628, DOI: 10.1210/en.2009-0705.Peer-Reviewed Original ResearchConceptsGlycogen synthesisInsulin receptorFetal liverInsulin receptor substrate 2Insulin-like growth factor 2Knockout mouse strainIR-A isoformGlycogen synthaseMajor regulatorGrowth factor 2Akt proteinSubstrate 2Insulin receptor isoformsGlycogen metabolismIgf2 deficiencyPDX-1Factor 2Receptor isoformsHepatic glycogen synthesisHepatic glycogen metabolismINSRIGF2Fetal hepatocytesIsoformsMouse strainsInsulin Receptor Substrate-2 in β-Cells Decreases Diabetes in Nonobese Diabetic Mice
Norquay L, D'Aquino K, Opare-Addo L, Kuznetsova A, Haas M, Bluestone J, White M. Insulin Receptor Substrate-2 in β-Cells Decreases Diabetes in Nonobese Diabetic Mice. Endocrinology 2009, 150: 4531-4540. PMID: 19574401, PMCID: PMC2754683, DOI: 10.1210/en.2009-0395.Peer-Reviewed Original ResearchConceptsNonobese diabetic (NOD) miceBeta-cell destructionNOD miceInsulin receptor substrate 2Glucose toleranceDiabetes incidenceDiabetic miceIslet massAnti-CD3 antibody injectionNondiabetic NOD miceReduced diabetes incidenceRisk of diabetesBeta-cell massType 1 diabetesBetter glucose toleranceAnti-CD3 antibodyBeta-cell growthWk of ageDiabetic NODSevere insulitisOvert diabetesSubstrate 2C57BL/6 miceBeta-cell mitogenesisAntibody injection
2008
Response to Comment on "Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis"
Taguchi A, White M. Response to Comment on "Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis". Science 2008, 320: 1012-1012. DOI: 10.1126/science.1152620.Peer-Reviewed Original ResearchStructural 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
2007
Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis
Taguchi A, Wartschow L, White M. Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis. Science 2007, 317: 369-372. PMID: 17641201, DOI: 10.1126/science.1142179.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsBrainCircadian RhythmCrosses, GeneticDietFemaleGlucoseHomeostasisInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsLongevityMaleMiceMice, KnockoutMice, TransgenicOverweightOxidation-ReductionOxygen ConsumptionPhosphoproteinsRespirationSignal TransductionSuperoxide Dismutase
2005
Attenuation of Accumulation of Neointimal Lipid by Pioglitazone in Mice Genetically Deficient in Insulin Receptor Substrate-2 and Apolipoprotein E
Clough M, Schneider D, Sobel B, White M, Wadsworth M, Taatjes D. Attenuation of Accumulation of Neointimal Lipid by Pioglitazone in Mice Genetically Deficient in Insulin Receptor Substrate-2 and Apolipoprotein E. Journal Of Histochemistry & Cytochemistry 2005, 53: 603-610. PMID: 15872053, DOI: 10.1369/jhc.4a6590.2005.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAnimalsAortaApolipoproteins EArteriosclerosisHyperlipidemiasHypoglycemic AgentsInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsLipid MetabolismMiceMice, Inbred C57BLMice, KnockoutPhosphoproteinsPioglitazoneReceptor, InsulinThiazolidinedionesTunica IntimaConceptsInsulin resistanceApolipoprotein EAcute coronary syndromeVulnerable atherosclerotic plaquesInsulin receptor substrate 2Accumulation of lipidsCoronary syndromeProximal aortaInsulin sensitizersNeointimal accumulationAtheroma formationAortic intimaAtherosclerotic lesionsAtherosclerotic plaquesType 2PioglitazoneMiceLesionsCross-sectional areaHeterozygous deficiencyAtherogenesisSubstrate 2TreatmentLipidsAtheromaInsulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport*
Sadagurski M, Weingarten G, Rhodes C, White M, Wertheimer E. Insulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport*. Journal Of Biological Chemistry 2005, 280: 14536-14544. PMID: 15705592, DOI: 10.1074/jbc.m410227200.Peer-Reviewed Original ResearchMeSH KeywordsAdenoviridaeAnimalsBiological TransportDeoxyglucoseEpidermisFibroblastsGenotypeGlucoseHomozygoteImmunoblottingImmunoprecipitationInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsKeratinocytesMiceMice, KnockoutPhosphatidylinositol 3-KinasesPhosphoproteinsSkinThymidineTime FactorsConceptsIRS-2Glucose transportInsulin receptor substrate-2 proteinInsulin-induced glucose transportInsulin receptor substrate 2Insulin-stimulated glucose transportIRS-1 proteinCell specific associationIRS-2 proteinClassical insulin target tissuesCell-specific mannerSkin epidermal keratinocytesIRS-PICell-specific rolePositive regulatorInsulin target tissuesCell physiologyDermal fibroblastsKO cellsEpidermal keratinocytesAkt activationPhosphatidylinositolSubstrate 2Insulin receptorProteinInsulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells
Yi X, Schubert M, Peachey N, Suzuma K, Burks D, Kushner J, Suzuma I, Cahill C, Flint C, Dow M, Leshan R, King G, White M. Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells. Journal Of Neuroscience 2005, 25: 1240-1248. PMID: 15689562, PMCID: PMC6725974, DOI: 10.1523/jneurosci.3664-04.2005.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsAnimals, NewbornApoptosisCell SurvivalDiabetic RetinopathyEye ProteinsGene DeletionHomeodomain ProteinsHyperglycemiaHyperinsulinismInsulin Receptor Substrate ProteinsInsulin ResistanceInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutPhosphoproteinsPhosphorylationPhotic StimulationPhotoreceptor CellsProtein Processing, Post-TranslationalProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRetinal Ganglion CellsSignal TransductionTrans-ActivatorsConceptsIrs2-/- micePhotoreceptor cellsPlexiform layerInsulin receptor substrate 2Insulin receptor substrateInsulin-like growth factor 1 receptorGrowth factor 1 receptorMost photoreceptor cellsInner plexiform layerOuter plexiform layerFactor 1 receptorFinal common pathwaySurvival of photoreceptorsNormal electrical functionMonths of ageWeeks of ageReceptor substrateCellular growthSubstrate 2Akt phosphorylationGanglion cellsIRS2 expressionPharmacological strategiesControl littermatesPhotoreceptor degenerationDeletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
Uchida T, Nakamura T, Hashimoto N, Matsuda T, Kotani K, Sakaue H, Kido Y, Hayashi Y, Nakayama K, White M, Kasuga M. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nature Medicine 2005, 11: 175-182. PMID: 15685168, DOI: 10.1038/nm1187.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Cycle ProteinsCell NucleusCyclin-Dependent Kinase Inhibitor p27Diabetes Mellitus, Type 2Disease Models, AnimalEnzyme InhibitorsHyperglycemiaHyperinsulinismInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsIslets of LangerhansLeptinMiceMice, KnockoutPhosphoproteinsProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptors, Cell SurfaceReceptors, LeptinSignal TransductionTumor Suppressor ProteinsConceptsCyclin-dependent kinasesInsulin receptor substrate 2Cell cycle progressionPancreatic beta cell proliferationPotential new targetsCompensatory hyperinsulinemiaCycle progressionProtein p27Kip1Substrate 2Type 2 diabetes mellitusPancreatic beta cellsP27Kip1Beta-cell failureBeta-cell proliferationType 2 diabetesLong formNew targetsDeletionDiabetes mellitusDiabetic miceIslet massLeptin receptorBeta cellsAnimal modelsMice
2004
Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis
Nagle J, Ma Z, Byrne M, White M, Shaw L. Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis. Molecular And Cellular Biology 2004, 24: 9726-9735. PMID: 15509777, PMCID: PMC525494, DOI: 10.1128/mcb.24.22.9726-9735.2004.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBase SequenceBreast NeoplasmsCell Line, TumorDNA, NeoplasmFemaleHumansInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMammary Neoplasms, ExperimentalMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMitosisNeoplasm InvasivenessPhosphoproteinsPhosphorylationConceptsIRS-2Insulin receptor substrate (IRS) proteinsMammary tumor cellsPolyoma virus middle T antigenInsulin receptor substrate 2Middle T antigenGrowth factor deprivationTumor cellsIRS-2 expressionSubstrate proteinsPyV mTMammary tumor metastasisApoptotic stimuliFactor deprivationAdaptor moleculeIncidence of metastasisMitotic cellsMammary fat padMammary tumor progressionBreast cancer metastasisHuman breast cancerSubstrate 2T antigenTumor initiationCancer metastasisDysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes
Lin X, Taguchi A, Park S, Kushner J, Li F, Li Y, White M. Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. Journal Of Clinical Investigation 2004, 114: 908-916. PMID: 15467829, PMCID: PMC518668, DOI: 10.1172/jci22217.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBody WeightBrainDiabetes Mellitus, Type 2DietEatingGene DeletionGene Expression RegulationGlucoseHomeostasisHumansHypothalamusInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansMaleMiceMice, Inbred C57BLMice, KnockoutObesityPhosphoproteinsRandom AllocationSignal TransductionConceptsInsulin receptor substrate 2Beta cellsInsulin resistanceSufficient beta cell functionPancreas beta cellsBeta-cell failureBeta-cell functionFunctional beta cellsMonths of ageAdult beta cellsFat body massSubstrate 2Obese miceDiabetesΒ-cellsObesityPromotes RegenerationConditional knockoutCell functionMiceBrainBody massMolecular linkCell failureCells
2000
IRS-2 pathways integrate female reproduction and energy homeostasis
Burks D, de Mora J, Schubert M, Withers D, Myers M, Towery H, Altamuro S, Flint C, White M. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 2000, 407: 377-382. PMID: 11014193, DOI: 10.1038/35030105.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEnergy IntakeEnergy MetabolismEstrusFemaleFertilityGonadal Steroid HormonesHomeostasisInfertilityInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsLeptinLuteinizing HormoneMaleMiceMice, Inbred C57BLMice, KnockoutOvaryPhosphoproteinsPituitary GlandReceptor, InsulinReproductionSignal TransductionSteroidsConceptsInsulin receptor substrate 2Insulin/insulin-like growth factor-1Insulin-signaling pathwayEnergy homeostasisC. elegansIRS-2 pathwayLower organismsSubstrate 2Female reproductionRegulation of fertilityMetabolic signalsInsulin-like growth factor-1Reproductive statusFactor 1Infertile conditionsSevere dietary restrictionMammalsGrowth factor-1HomeostasisReproductionAnovulatory ovariesHypothalamic controlFemale infertilityPlasma concentrationsCatabolic state
1999
Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle*
Higaki Y, Wojtaszewski J, Hirshman M, Withers D, Towery H, White M, Goodyear L. Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle*. Journal Of Biological Chemistry 1999, 274: 20791-20795. PMID: 10409618, DOI: 10.1074/jbc.274.30.20791.Peer-Reviewed Original ResearchConceptsExercise-stimulated glucose transportInsulin-stimulated 2DG uptakeBlood glucose concentrationGlucose transportInsulin resistanceSkeletal muscleInsulin receptor substrate 2Glucose concentrationSkeletal muscle glucose transportHigher blood glucose concentrationsInsulin receptor substrate-2-deficient (IRS2(-/-)) miceOnset of diabetesType 2 diabetesWild-type miceMuscle glucose transportIRS2 proteinAbsence of insulinMuscle GLUT4 contentSubstrate 2WT animalsSoleus muscleGLUT4 contentLower basalMiceInsulin
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 IMapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role
Kalidas K, Wasson J, Glaser B, Meyer J, Duprat L, White M, Permutt M. Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role. Diabetologia 1998, 41: 1389-1391. PMID: 9833949, DOI: 10.1007/s001250051081.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceChromosome MappingChromosomes, Human, Pair 13Diabetes Mellitus, Type 1Europe, EasternGenetic Carrier ScreeningGenetic LinkageGenetic MarkersGenotypeHumansInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsJewsMiceMicrosatellite RepeatsPhosphoproteinsPolymorphism, GeneticStatistics, NonparametricConceptsIRS-2 geneRadiation hybrid panel mappingPolymorphic markersInsulin receptor substrate 2Nonparametric linkage analysisMap positionChromosome 13q34Evidence of linkageInsulin receptor substrate-2 (IRS-2) geneGene regionLinkage analysisGenesSubstrate 2Excess alleleInsulin receptorNearby markersType II diabetesAshkenazi Jewish familiesMice resultsII diabetesSusceptibility roleMarkersFamilyPeripheral insulin resistance
1996
Growth Hormone, Interferon-γ, and Leukemia Inhibitory Factor Utilize Insulin Receptor Substrate-2 in Intracellular Signaling*
Argetsinger L, Norstedt G, Billestrup N, White M, Carter-Su C. Growth Hormone, Interferon-γ, and Leukemia Inhibitory Factor Utilize Insulin Receptor Substrate-2 in Intracellular Signaling*. Journal Of Biological Chemistry 1996, 271: 29415-29421. PMID: 8910607, DOI: 10.1074/jbc.271.46.29415.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAnimalsCHO CellsCricetinaeGrowth InhibitorsHuman Growth HormoneHumansInsulin Receptor Substrate ProteinsInterferon-gammaInterleukin-6Intracellular Signaling Peptides and ProteinsLeukemia Inhibitory FactorLymphokinesMicePhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationPhosphotransferases (Alcohol Group Acceptor)Signal TransductionTyrosineConceptsInsulin receptor substrate 2Tyrosyl phosphorylationLeukemia inhibitory factorProtein tyrosine phosphatase SHP2Substrate 2JAK2 associationPhosphatase SHP2Regulatory subunitJAK kinasesMaximal phosphorylationTyrosine phosphorylationTyrosine residuesIntracellular signalingPhosphorylationMultiple membersGH receptorInhibitory factorCytokine familyGrowth hormoneReceptorsSHP2KinasePhosphatidylinositolSubstantial signal