2021
Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice
Takatani T, Shirakawa J, Shibue K, Gupta M, Kim H, Lu S, Hu J, White M, Kennedy R, Kulkarni R. Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice. Journal Of Biological Chemistry 2021, 296: 100646. PMID: 33839150, PMCID: PMC8131928, DOI: 10.1016/j.jbc.2021.100646.Peer-Reviewed Original ResearchConceptsAKT Ser/Thr kinaseInsulin receptor substrate (IRS) proteinsSer/Thr kinaseAlpha-cell functionGlobal protein translationCell functionInsulin receptor substrate-1Pancreatic alpha-cell functionDownstream target genesReceptor substrate-1Alpha cellsAlpha-cell lineGlucagon secretionSubstrate proteinsProtein translationTarget genesSubstrate-1Downstream proteinsDominant regulatorPancreatic alpha cellsMitochondrial dysfunctionCognate receptorsIRS2Normal glucose toleranceCell lines
2013
Insulin receptor substrate signaling suppresses neonatal autophagy in the heart
Riehle C, Wende A, Sena S, Pires K, Pereira R, Zhu Y, Bugger H, Frank D, Bevins J, Chen D, Perry C, Dong X, Valdez S, Rech M, Sheng X, Weimer B, Gottlieb R, White M, Abel E. Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. Journal Of Clinical Investigation 2013, 123: 5319-5333. PMID: 24177427, PMCID: PMC3859408, DOI: 10.1172/jci71171.Peer-Reviewed Original ResearchMeSH KeywordsAmino AcidsAnimalsApoptosisApoptosis Regulatory ProteinsAutophagyBeclin-1Cardiomyopathy, DilatedFetal HeartHeartHeart FailureInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IMiceMitochondria, HeartMyocytes, CardiacOxidative PhosphorylationPhosphorylationProtein Processing, Post-TranslationalReceptor, IGF Type 1Signal TransductionTOR Serine-Threonine KinasesConceptsInsulin receptor substrateInduction of autophagyActivation of mTORIGF-1R signalingPostnatal cardiac developmentUnrestrained autophagyCardiomyocyte-specific deletionGenetic suppressionCardiac developmentReceptor substrateIGF-1 receptorEssential adaptationProsurvival signalingAutophagic fluxAutophagy suppressionAutophagyMitochondrial dysfunctionMammalian heartPhysiological suppressionNeonatal starvationAutophagic activationSignalingIRS1IRS2Insulin actionIrs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis
Sadagurski M, Dong X, Myers M, White M. Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Molecular Metabolism 2013, 3: 55-63. PMID: 24567904, PMCID: PMC3929908, DOI: 10.1016/j.molmet.2013.10.004.Peer-Reviewed Original ResearchFed blood glucose levelsBlood glucose levelsLepRb neuronsSevere obesityInsulin resistanceInsulin receptor substrateGlucose levelsLeptin receptorGlucose homeostasisBody weightInsulin/IGF1MiceMetabolic homeostasisEnergy expenditureNeuronsWhole bodyReceptor substrateIRS2Metabolic sensingHomeostasisMetabolic regulationHyperglycemiaLepRbObesityHypothalamus
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 mechanismsRegulationDysregulationIRS2 Signaling in LepR-b Neurons Suppresses FoxO1 to Control Energy Balance Independently of Leptin Action
Sadagurski M, Leshan R, Patterson C, Rozzo A, Kuznetsova A, Skorupski J, Jones J, Depinho R, Myers M, White M. IRS2 Signaling in LepR-b Neurons Suppresses FoxO1 to Control Energy Balance Independently of Leptin Action. Cell Metabolism 2012, 15: 703-712. PMID: 22560222, PMCID: PMC3361909, DOI: 10.1016/j.cmet.2012.04.011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCytoskeletal ProteinsEnergy MetabolismFemaleForkhead Box Protein O1Forkhead Transcription FactorsGene ExpressionGlucoseGlucose IntoleranceHomeostasisInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLeptinMaleMiceMice, TransgenicNerve Tissue ProteinsNeuronsObesityReceptors, LeptinSignal TransductionConceptsLeptin actionGlucose homeostasisGlucose intoleranceInsulin resistanceHormone leptinFoxO1 nuclear exclusionIRS2 expressionLeptin receptorMetabolic actionsNeuronsMiceEnergy balanceFOXO1Metabolic sensingIRS2HomeostasisGene expressionNuclear exclusionObesityLeptinExpressionCNSInsulinIntoleranceBrain
2010
Irs1 Serine 307 Promotes Insulin Sensitivity in Mice
Copps K, Hancer N, Opare-Ado L, Qiu W, Walsh C, White M. Irs1 Serine 307 Promotes Insulin Sensitivity in Mice. Cell Metabolism 2010, 11: 84-92. PMID: 20074531, PMCID: PMC3314336, DOI: 10.1016/j.cmet.2009.11.003.Peer-Reviewed Original Research
2009
The Irs1 Branch of the Insulin Signaling Cascade Plays a Dominant Role in Hepatic Nutrient Homeostasis
Guo S, Copps K, Dong X, Park S, Cheng Z, Pocai A, Rossetti L, Sajan M, Farese R, White M. The Irs1 Branch of the Insulin Signaling Cascade Plays a Dominant Role in Hepatic Nutrient Homeostasis. Molecular And Cellular Biology 2009, 29: 5070-5083. PMID: 19596788, PMCID: PMC2738277, DOI: 10.1128/mcb.00138-09.Peer-Reviewed Original ResearchConceptsHigh-fat dietHepatic nutrient homeostasisIntracerebroventricular insulin infusionSuppression of HGPImpaired glucose toleranceHyperinsulinemic-euglycemic clampHepatic insulin actionHepatic glucose productionHepatic Irs1Cre-loxP approachLivers of controlGlucose toleranceInsulin infusionInsulin Signaling CascadeInsulin sensitivityPostprandial hyperglycemiaGlucose homeostasisInsulin actionPrincipal mediatorGlucose productionLipogenic genesMiceTyrosine phosphorylationLiverIRS2
2008
Irs2 Inactivation Suppresses Tumor Progression in Pten +/− Mice
Szabolcs M, Keniry M, Simpson L, Reid L, Koujak S, Schiff S, Davidian G, Licata S, Gruvberger-Saal S, Murty V, Nandula S, Efstratiadis A, Kushner J, White M, Parsons R. Irs2 Inactivation Suppresses Tumor Progression in Pten +/− Mice. American Journal Of Pathology 2008, 174: 276-286. PMID: 19095950, PMCID: PMC2631340, DOI: 10.2353/ajpath.2009.080086.Peer-Reviewed Original ResearchConceptsPI3KInsulin receptor substrate-2 expressionProstatic intraepithelial neoplasiaHuman prostate cancerCancer cell growthSuppresses tumor progressionIntraepithelial neoplasiaInitiation of neoplasiaProstate cancerIRS2 expressionMultiple organsExpression of MYCTumor progressionTumor samplesMiceHuman cancersMYC expressionProgressionExpression levelsPTEN levelsBasement membraneIRS2NeoplasiaTumorsCancerStructural 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
2006
The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling.
Guo S, Dunn S, White M. The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Endocrinology 2006, 20: 3389-99. PMID: 16916938, DOI: 10.1210/me.2006-0092.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedFibroblastsForkhead Box Protein O1Forkhead Transcription FactorsInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMiceMice, Mutant StrainsPhosphatidylinositol 3-KinasesPhosphoproteinsProtein KinasesProto-Oncogene Proteins c-aktRecombinant ProteinsSignal TransductionTOR Serine-Threonine KinasesTyrosineConceptsInsulin stimulationWild-type mouse embryo fibroblastsInsulin-receptor substrate IRS1Metastatic mammary tumor cellsProlonged insulin stimulationMouse embryo fibroblastsTranscription factor FOXO1Substrates IRS1FoxO phosphorylationRegulatory circuitsNuclear exclusionWT MEFsTyrosine phosphorylationGene expressionMetabolic regulationEmbryo fibroblastsIRS1 expressionMammary tumor cellsIRS2 expressionCell growthIRS2AktIRS1MEFsPancreatic beta cells
2005
Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth
Dong X, Park S, Lin X, Copps K, Yi X, White M. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. Journal Of Clinical Investigation 2005, 116: 101-114. PMID: 16374520, PMCID: PMC1319221, DOI: 10.1172/jci25735.Peer-Reviewed Original ResearchConceptsSystemic growthHundreds of genesInsulin receptor substrateHepatic nutrient homeostasisHepatic glucose homeostasisHeterologous pathwaysNutrient homeostasisReceptor substrateGene expressionGSK3beta phosphorylationReceptor signalsHepatic gene expressionLKO miceInsulin receptorGlucose homeostasisIRS2IRS1Hepatic genesHepatic insulin receptorAkt-FoxO1 pathwayHomeostasisGenesHepatic glycogen storesLKO liversPathway
2004
Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance
Duan C, Yang H, White M, Rui L. Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance. Molecular And Cellular Biology 2004, 24: 7435-7443. PMID: 15314154, PMCID: PMC506995, DOI: 10.1128/mcb.24.17.7435-7443.2004.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdipose TissueAgingAnimalsBlood GlucoseCarrier ProteinsCell LineDietary FatsGlucose IntoleranceHomeostasisHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, Inbred StrainsMice, KnockoutMitogen-Activated Protein KinasesMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptor, InsulinSignal TransductionConceptsSrc homology 2Insulin receptor substrate-1Insulin receptor activationInsulin receptorTyrosine phosphorylationSH2 domain-dependent mannerPleckstrin homology domain-containing adaptor proteinDomain-containing adaptor proteinDomain-dependent mannerReceptor substrate-1Skeletal muscleSH2 domainHomology 2Adaptor proteinReceptor activationSubstrate-1Physiological roleCultured cellsGlucose homeostasisERK1/2 pathwayDependent insulin resistancePhysiological enhancerSystemic deletionPhosphorylationIRS2Insulin receptor substrate proteins and diabetes
Lee Y, White M. Insulin receptor substrate proteins and diabetes. Archives Of Pharmacal Research 2004, 27: 361-370. PMID: 15180298, DOI: 10.1007/bf02980074.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate (IRS) proteinsSubstrate proteinsPancreatic β-cell growthInsulin/IGFIntracellular signaling cascadesReceptor tyrosine kinasesΒ-cell growthCell surface receptorsIRS proteinsGrowth factor actionProtein signalingSerine phosphorylationSignaling cascadesInsulin resistanceTyrosine kinaseInsulin-like growth factor actionIrs2 branchCell growthSurface receptorsFactor actionPeripheral insulin responsePeripheral insulin resistanceIRS2ProteinImportant mechanismIslet-Sparing Effects of Protein Tyrosine Phosphatase-1b Deficiency Delays Onset of Diabetes in IRS2 Knockout Mice
Kushner J, Haj F, Klaman L, Dow M, Kahn B, Neel B, White M. Islet-Sparing Effects of Protein Tyrosine Phosphatase-1b Deficiency Delays Onset of Diabetes in IRS2 Knockout Mice. Diabetes 2004, 53: 61-66. PMID: 14693698, DOI: 10.2337/diabetes.53.1.61.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseCrosses, GeneticDiabetes Mellitus, Type 1Glucose Tolerance TestInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsIslets of LangerhansKineticsLeptinMaleMiceMice, KnockoutModels, AnimalPhosphoproteinsProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine PhosphatasesSignal TransductionConceptsPeripheral insulin sensitivityBeta-cell areaBeta-cell functionInsulin sensitivityPancreatic beta cell areaPancreatic beta-cell functionDecreased insulin requirementIrs2 knockout miceBeta cell homeostasisMonths of ageInsulin requirementsPeripheral actionsGlucose toleranceGlucose homeostasisKnockout miceDelay onsetMiceInsulin receptorPTP1B deficiencyDiabetesReceptor complexIRS2Novel roleInsulinDownstream targets
2003
Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation
Schubert M, Brazil D, Burks D, Kushner J, Ye J, Flint C, Farhang-Fallah J, Dikkes P, Warot X, Rio C, Corfas G, White M. Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation. Journal Of Neuroscience 2003, 23: 7084-7092. PMID: 12904469, PMCID: PMC6740672, DOI: 10.1523/jneurosci.23-18-07084.2003.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsApoptosisBody WeightBrainCell CountCell DivisionCell SurvivalCells, CulturedCerebellumCrosses, GeneticEnzyme InhibitorsHeterozygoteIn Situ Nick-End LabelingInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutNeuronsOrgan SizePhosphoproteinsPhosphorylationReceptor, IGF Type 1Signal TransductionTau ProteinsConceptsMolecular linkInsulin receptor substrate (IRS) proteinsBrain growthNeurodegenerative diseasesPancreatic beta-cell functionPeripheral insulin actionSubstrate proteinsBeta-cell functionTyrosine phosphorylationLike growth factorIrs2 branchInsulin resistanceTau phosphorylationIRS2 geneNeuronal proliferationInsulin actionMouse brainInsulin-IGFGrowth factorPhosphorylationIRS2DiabetesBody growthDiseaseMicecAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2
Jhala U, Canettieri G, Screaton R, Kulkarni R, Krajewski S, Reed J, Walker J, Lin X, White M, Montminy M. cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2. Genes & Development 2003, 17: 1575-1580. PMID: 12842910, PMCID: PMC196130, DOI: 10.1101/gad.1097103.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell LineCell SurvivalColforsinCyclic AMPCyclic AMP Response Element-Binding ProteinDiabetes MellitusGene Expression RegulationGlucagonGlucagon-Like Peptide 1GlucoseGlucose IntoleranceHumansInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsIslets of LangerhansMiceMice, TransgenicPeptide FragmentsPhosphoproteinsPhosphorylationPromoter Regions, GeneticProtein PrecursorsProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktSignal TransductionTransfectionTransgenesTumor Cells, CulturedConceptsPancreatic β-cell survivalActivity of CREBSecond messenger cAMPSurvival kinase AktΒ-cell survivalKinase AktPathway componentsA-CREBCREB actionExpression of IRS2Cell survivalBeta-cell apoptosisDirect targetIslet cell survivalNovel mechanismCREBIRS2ExpressionCAMPInductionTransgeneAktIGF-1ApoptosisSurvivalChapter 72 IRS-Protein Scaffolds and Insulin/IGF Action
White M. Chapter 72 IRS-Protein Scaffolds and Insulin/IGF Action. 2003, 409-419. DOI: 10.1016/b978-012124546-7/50433-2.Peer-Reviewed Original ResearchIRS protein familyMultiple biological processesIRS proteinsIL-9 signalingTissue agingBiological processesIRS-2Growth controlPeripheral insulin sensitivityPeripheral insulin actionType 2 diabetesPancreatic p-cellsCell functionIRS2IGF actionIL-4Insulin sensitivityInflammatory responseInsulin actionInsulin secretionIL-7Immune responseFundamental roleTumor growthP cells
2002
SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2*
Rui L, Yuan M, Frantz D, Shoelson S, White M. SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2*. Journal Of Biological Chemistry 2002, 277: 42394-42398. PMID: 12228220, DOI: 10.1074/jbc.c200444200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsElonginGlucoseHomeostasisHumansInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsMaleMiceMice, Inbred C57BLPhosphoproteinsProteinsRepressor ProteinsSuppressor of Cytokine Signaling 1 ProteinSuppressor of Cytokine Signaling 3 ProteinSuppressor of Cytokine Signaling ProteinsTranscription FactorsUbiquitinConceptsUbiquitin ligase complexCritical signaling moleculesIRS2 protein levelsDegradation of IRS1Multiple cell typesIRS proteinsSOCS boxSOCS proteinsNutrient homeostasisUbiquitin ligaseSignaling moleculesInflammation-induced insulin resistanceInsulin signalingSOCS-1Expression of SOCS1Cell typesSubsequent degradationHepatic Irs1IRS1IRS2General mechanismUbiquitinationProtein levelsSOCS1Mutants