2016
G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway*
Law N, White M, Hunzicker-Dunn M. G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway*. Journal Of Biological Chemistry 2016, 291: 27160-27169. PMID: 27856640, PMCID: PMC5207145, DOI: 10.1074/jbc.m116.763235.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCells, CulturedCyclic AMP-Dependent Protein KinasesFemaleGranulosa CellsHumansInsulin Receptor Substrate ProteinsOvarian FolliclePhosphatidylinositol 3-KinasePhosphorylationProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleyReceptors, G-Protein-CoupledSignal TransductionThyroid NeoplasmsConceptsG protein-coupled receptorsInsulin receptor substrate-1PI3K/Akt cascadeProtein-coupled receptorsAkt cascadeSer/ThrReceptor substrate-1PI3K/Akt activationInsulin-like growth factor-1PI3K/Akt pathwayGranulosa cellsConserved mechanismPI3K/AktCellular functionsProtein kinaseSer residuesSubstrate-1Myosin phosphataseSubunit 1Akt activationCell survivalAutocrine/paracrine mannerViral oncoproteinsAkt pathwayPreantral granulosa cells
2011
Inhibition of Insulin Signaling in Endothelial Cells by Protein Kinase C-induced Phosphorylation of p85 Subunit of Phosphatidylinositol 3-Kinase (PI3K)*
Maeno Y, Li Q, Park K, Rask-Madsen C, Gao B, Matsumoto M, Liu Y, Wu I, White M, Feener E, King G. Inhibition of Insulin Signaling in Endothelial Cells by Protein Kinase C-induced Phosphorylation of p85 Subunit of Phosphatidylinositol 3-Kinase (PI3K)*. Journal Of Biological Chemistry 2011, 287: 4518-4530. PMID: 22158866, PMCID: PMC3281670, DOI: 10.1074/jbc.m111.286591.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCattleCells, CulturedClass Ia Phosphatidylinositol 3-KinaseEndothelial CellsEnzyme ActivationInsulinInsulin Receptor Substrate ProteinsMetabolic DiseasesNitric Oxide Synthase Type IIIPhosphorylationProtein Kinase CProto-Oncogene Proteins c-aktSignal TransductionVascular Endothelial Growth Factor AConceptsP85/PI3KPI3KPKC activationInsulin receptor substrateProtein kinase C activationEndothelial nitric oxide synthaseProtein kinase CAkt/endothelial nitric oxide synthaseKinase C activationPI3K/Akt pathwayP85 subunitDeletion mutantsGeneral activatorTyrosine phosphorylationReceptor substrateEndothelial cellsInsulin signalingInsulin activationKinase CAkt pathwayPhosphorylationC activationThr-86SignalingIRS1
2010
Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1
Wei D, Tao R, Zhang Y, White M, Dong X. Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1. AJP Endocrinology And Metabolism 2010, 300: e312-e320. PMID: 21081708, PMCID: PMC3043623, DOI: 10.1152/ajpendo.00524.2010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedChromatin ImmunoprecipitationDNAFeedback, PhysiologicalForkhead Box Protein O1Forkhead Transcription FactorsGluconeogenesisHepatocytesInsulin Receptor Substrate ProteinsLiverMiceMice, KnockoutPyruvic AcidReceptors, Cytoplasmic and NuclearReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSirtuin 1TransfectionConceptsGene expressionForkhead transcription factor FOXO1PDK4 gene expressionWild-type backgroundChromatin immunoprecipitation analysisProtein deacetylase SIRT1Transcription factor FOXO1Orphan nuclear receptorHepatic gluconeogenesisCatalytic domainDNA sequencesSmall heterodimer partnerImmunoprecipitation analysisInactivation of SIRT1Physiological processesDeacetylase SIRT1Luciferase reporterInsulin receptorFeedback regulationNuclear receptorsFOXO1Heterodimer partnerGenesHepatic insulin receptorSystemic glucose tolerance
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 strainsFoxo1 integrates insulin signaling with mitochondrial function in the liver
Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers J, Depinho R, Puigserver P, White M. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nature Medicine 2009, 15: 1307-1311. PMID: 19838201, PMCID: PMC3994712, DOI: 10.1038/nm.2049.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsCells, CulturedElectron Transport Chain Complex ProteinsForkhead Box Protein O1Forkhead Transcription FactorsGene Expression RegulationHeme Oxygenase-1HepatocytesInsulinInsulin Receptor Substrate ProteinsLiverMembrane Potential, MitochondrialMembrane ProteinsMiceMice, KnockoutMicroscopy, Electron, TransmissionMitochondriaMutationNADPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaSignal TransductionTrans-ActivatorsTranscription Factors
2007
The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis
Li D, Yin X, Zmuda E, Wolford C, Dong X, White M, Hai T. The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis. Diabetes 2007, 57: 635-644. PMID: 18057093, DOI: 10.2337/db07-0717.Peer-Reviewed Original ResearchMeSH KeywordsActivating Transcription Factor 3AnimalsApoptosisCell LineCells, CulturedDown-RegulationInsulinInsulin Receptor Substrate ProteinsInsulin-Secreting CellsIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutPhosphoproteinsPromoter Regions, GeneticRatsStress, PhysiologicalTime FactorsConceptsStress-inducible genesIRS2 gene expressionIRS2 promoterBinding of ATF3Gene transcriptionGene expressionExpression of IRS2Chromatin immunoprecipitation assaysIRS2 genePancreatic β-cell apoptosisEnvironmental stress factorsΒ-cell apoptosisTranscription factor 3Effect of ATF3Stress signalsImmunoprecipitation assaysBeta-cell survivalTarget genesProapoptotic genesExpression of ATF3GenesTranscriptionIRS2 expressionATF3PromoterInsulin receptor substrate 1 (IRS‐1) plays a unique role in normal epidermal physiology
Sadagurski M, Nofech‐Mozes S, Weingarten G, White M, Kadowaki T, Wertheimer E. Insulin receptor substrate 1 (IRS‐1) plays a unique role in normal epidermal physiology. Journal Of Cellular Physiology 2007, 213: 519-527. PMID: 17508357, DOI: 10.1002/jcp.21131.Peer-Reviewed Original ResearchConceptsNull miceIRS-1IRS-1 null miceIRS-2Skin physiologySkin cellsNormal epidermal physiologyInsulin receptor substrate-1Primary skin cellsSkin differentiationIRS-2 proteinReceptor substrate-1Skin epidermal cellsInsulin actionAdvanced stageExpression of K1Histological analysisNull skinSkin sectionsInsulin receptor substrate (IRS) proteinsEpidermal physiologyMiceSkin keratinocytesMarked decreaseEffects of inactivation
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
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 growthDiseaseMiceEssential role of protein kinase Cζ in the impairment of insulin‐induced glucose transport in IRS‐2‐deficient brown adipocytes
Arribas M, Valverde A, Burks D, Klein J, Farese R, White M, Benito M. Essential role of protein kinase Cζ in the impairment of insulin‐induced glucose transport in IRS‐2‐deficient brown adipocytes. FEBS Letters 2003, 536: 161-166. PMID: 12586357, DOI: 10.1016/s0014-5793(03)00049-8.Peer-Reviewed Original ResearchConceptsGLUT4 translocationIRS-2/PIBrown adipocytesInsulin-induced glucose transportProtein kinase C zetaIRS-2-associated phosphatidylinositolKinase-inactive mutantGlucose uptakeWild-type cellsProtein kinase CζEssential roleInsulin receptor substrate-2-deficient (IRS2(-/-)) miceC zetaPKC-zetaMolecular mechanismsIRS-2Impaired glucose uptakeGlucose transportAdipocytesTranslocationCellsUptakeMutantsPhosphatidylinositolCζ
2002
Interleukin-4-mediated Protection of Primary B Cells from Apoptosis through Stat6-dependent Up-regulation of Bcl-xL*
Wurster A, Rodgers V, White M, Rothstein T, Grusby M. Interleukin-4-mediated Protection of Primary B Cells from Apoptosis through Stat6-dependent Up-regulation of Bcl-xL*. Journal Of Biological Chemistry 2002, 277: 27169-27175. PMID: 12023955, DOI: 10.1074/jbc.m201207200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBcl-X ProteinBlotting, NorthernB-LymphocytesCell DeathCells, CulturedImmunoblottingInterleukin-4LuciferasesLymphocytesMicePromoter Regions, GeneticPropidiumProtein BindingProto-Oncogene Proteins c-bcl-2RetroviridaeSignal TransductionSTAT6 Transcription FactorTime FactorsTrans-ActivatorsTranscription, GeneticTransfectionUp-RegulationConceptsFas-induced cell deathIL-4B cellsPrimary B cellsBcl-xLCell deathBcl-2 family membersBcl-xL transcriptionB lymphocyte developmentB lymphocyte apoptosisSTAT6-dependent mannerAnti-apoptotic cytokinesActivation of STAT6Splenic B cellsAnti-apoptotic activityIL-4 stimulationInterleukin-4Lymphocyte apoptosisBcl-xL.B lymphocytesMolecular eventsSubsequent transcriptionCytokine receptorsLymphocyte developmentCell survivalStat6 and IRS-2 Cooperate in Interleukin 4 (IL-4)-Induced Proliferation and Differentiation but Are Dispensable for IL-4-Dependent Rescue from Apoptosis
Wurster A, Withers D, Uchida T, White M, Grusby M. Stat6 and IRS-2 Cooperate in Interleukin 4 (IL-4)-Induced Proliferation and Differentiation but Are Dispensable for IL-4-Dependent Rescue from Apoptosis. Molecular And Cellular Biology 2002, 22: 117-126. PMID: 11739727, PMCID: PMC134231, DOI: 10.1128/mcb.22.1.117-126.2002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell Cycle ProteinsCell DifferentiationCell DivisionCell SeparationCells, CulturedCyclin-Dependent Kinase Inhibitor p27Enzyme InhibitorsFlow CytometryInsulin Receptor Substrate ProteinsInterleukin-4Intracellular Signaling Peptides and ProteinsMiceMice, KnockoutPhosphatidylinositol 3-KinasesPhosphoproteinsSignal TransductionSTAT6 Transcription FactorTh2 CellsT-LymphocytesTrans-ActivatorsTumor Suppressor ProteinsConceptsIRS-2Protein tyrosine phosphatase activityProtein tyrosine phosphatase inhibitorTyrosine phosphatase activityTyrosine phosphatase inhibitorWild-type cellsIL-4 signal transductionIRS-2 expressionIL-4-induced proliferationCDK inhibitor p27Kip1Antiapoptotic effectPrimary T cellsPhosphatase inhibitorCytoplasmic tailSignal transductionDifferentiation eventsCooperative regulationGene expressionAntiapoptotic signalsCell developmentAntiapoptotic activityInterleukin-4 receptorPhosphatase activityPrimary lymphocytesSTAT6
2001
Association of Insulin Receptor Substrate 1 (IRS-1) Y895 with Grb-2 Mediates the Insulin Signaling Involved in IRS-1-Deficient Brown Adipocyte Mitogenesis
Valverde A, Mur C, Pons S, Alvarez A, White M, Kahn C, Benito M. Association of Insulin Receptor Substrate 1 (IRS-1) Y895 with Grb-2 Mediates the Insulin Signaling Involved in IRS-1-Deficient Brown Adipocyte Mitogenesis. Molecular And Cellular Biology 2001, 21: 2269-2280. PMID: 11259577, PMCID: PMC86861, DOI: 10.1128/mcb.21.7.2269-2280.2001.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseGrb-2Tyrosine phosphorylationIRS-1Brown adipocytesMAPK activationBrown adipocyte cell lineDNA synthesisActivation of MAPKWild-type IRS-1IRS-2 tyrosine phosphorylationShc tyrosine phosphorylationProtein kinase kinaseInhibition of phosphatidylinositolWild-type cell linesIRS-1 deficiencyInsulin-induced IRS-1Cell linesInsulin receptor substrate-1 (IRS-1) knockout miceAdipocyte cell lineG2/M phaseKinase kinaseMutant cellsProtein kinaseCell cycle
2000
Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes*
Fasshauer M, Klein J, Ueki K, Kriauciunas K, Benito M, White M, Kahn C. Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes*. Journal Of Biological Chemistry 2000, 275: 25494-25501. PMID: 10829031, DOI: 10.1074/jbc.m004046200.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose Tissue, BrownAnimalsArabidopsis ProteinsAzo CompoundsBiological TransportCell DifferentiationCell MembraneCells, CulturedColoring AgentsDose-Response Relationship, DrugGlucoseGlucose Transporter Type 4ImmunoblottingInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutMonosaccharide Transport ProteinsMuscle ProteinsPhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationPlant ProteinsPlasmidsPotassium ChannelsPrecipitin TestsProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRetroviridaeSignal TransductionSubcellular FractionsTime FactorsConceptsInsulin-stimulated GLUT4 translocationGLUT4 translocationInsulin-induced glucose uptakeIRS-2Plasma membraneDownstream effectorsWild typeInsulin receptor substrate (IRS) proteinsBrown adipocyte cell lineInsulin stimulationGlycogen synthase kinase-3IRS-2-associated phosphatidylinositolGlucose uptakeAkt-dependent phosphorylationInsulin receptor substrate 2Synthase kinase-3Brown adipocytesMajor downstream effectorActivity of AktMature brown adipocytesAdipocyte cell lineSubstrate proteinsWild-type counterpartsKO cellsKinase 3
1997
The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action.
Sun X, Pons S, Wang L, Zhang Y, Yenush L, Burks D, Myers M, Glasheen E, Copeland N, Jenkins N, Pierce J, White M. The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Endocrinology 1997, 11: 251-62. PMID: 9013772, DOI: 10.1210/mend.11.2.9885.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAmino Acid SequenceAnimalsBase SequenceCell DifferentiationCells, CulturedChromosome MappingChromosomesCytokinesInsulinInsulin Receptor Substrate ProteinsInterleukin-4Intracellular Signaling Peptides and ProteinsMiceMolecular Sequence DataPhosphoproteinsPhosphorylationSequence Homology, Amino AcidSignal TransductionTissue DistributionTyrosineConceptsMurine chromosome 8IRS-2IRS-1IRS-2 geneIRS proteinsExpression patternsSrc homology 2 domainChromosome 8Recombinant SH2 domainsSpecific expression patternsMurine chromosome 1Amino acid sequenceDifferential tyrosine phosphorylationMurine hematopoietic cellsDistinct phosphorylation patternsSH2 domainSignal transductionSingle exonPhosphorylation patternTyrosine phosphorylationIL-4 stimulationAcid sequenceChromosome 1Signaling adapterCytokine signaling