Featured Publications
The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor
Peng J, Ramatchandirin B, Wang Y, Pearah A, Namachivayam K, Wolf R, Steele K, MohanKumar K, Yu L, Guo S, White M, Maheshwari A, He L. The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor. Journal Of Biological Chemistry 2022, 298: 101621. PMID: 35074429, PMCID: PMC8850660, DOI: 10.1016/j.jbc.2022.101621.Peer-Reviewed Original ResearchConceptsAbsence of insulinP300 acetyltransferase activityTyrosine kinase activityAcetyltransferase activityInsulin receptorObese patientsTyrosine phosphorylationRole of acetylationInsulinNormal functionMembrane translocationSubsequent activationC646PatientsLiver hepatocytesProtein substratesInhibitionReceptorsMolecular mechanismsHepatocytesPhosphorylationBeta subunitKinase activityObesityUnique effects
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
2005
Deletion 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
Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation
Carlson C, White M, Rondinone C. Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation. Biochemical And Biophysical Research Communications 2004, 316: 533-539. PMID: 15020250, DOI: 10.1016/j.bbrc.2004.02.082.Peer-Reviewed Original ResearchConceptsSerine 307 phosphorylationSerine 307Rapamycin-sensitive mannerInsulin receptor substrateRole of mTORAmino acid stimulationActivation of mTORPhosphatase PP2AKinase mTOROkadaic acidReceptor substrateInsulin signalingIRS-1MTOR activityPhosphorylationMammalian targetMTORCytosolic fractionRapamycinPP2AAcid stimulationPKBInhibitorsSignalingJNK
2003
Nutrient-dependent and Insulin-stimulated Phosphorylation of Insulin Receptor Substrate-1 on Serine 302 Correlates with Increased Insulin Signaling*
Giraud J, Leshan R, Lee Y, White M. Nutrient-dependent and Insulin-stimulated Phosphorylation of Insulin Receptor Substrate-1 on Serine 302 Correlates with Increased Insulin Signaling*. Journal Of Biological Chemistry 2003, 279: 3447-3454. PMID: 14623899, DOI: 10.1074/jbc.m308631200.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino AcidsAndrostadienesAnimalsBlotting, WesternBromodeoxyuridineCell DivisionCell LineCHO CellsCricetinaeCulture Media, Serum-FreeDose-Response Relationship, DrugEnzyme InhibitorsGlucoseGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaInsulinInsulin Receptor Substrate ProteinsJNK Mitogen-Activated Protein KinasesMiceMitogen-Activated Protein KinasesMolecular Sequence DataMutagenesis, Site-DirectedMutationPhosphoproteinsPhosphorylationPoint MutationPrecipitin TestsRatsSerineSignal TransductionSirolimusTime FactorsWortmanninConceptsInsulin/IGFIRS-1Insulin-stimulated signal transductionInsulin receptor substrate IRS-1Ser/Thr phosphorylationSequence-specific polyclonal antibodiesInsulin-stimulated tyrosine phosphorylationInsulin receptor substrate-1Synthase kinase-3beta phosphorylationSubstrate IRS-1IRS-1-mediated signalingRibosomal S6 proteinC-Jun kinaseInsulin-stimulated phosphorylationReceptor substrate-1IGF-I stimulationThr phosphorylationKinase associatesP85 bindingPhosphorylated residuesSignal transductionInsulin-stimulated AktTyrosine phosphorylationS6 proteinNutrient availabilityInsulin 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 growthDiseaseMice
2002
Specificity of Interleukin-2 Receptor γ Chain Superfamily Cytokines Is Mediated by Insulin Receptor Substrate-dependent Pathway*
Xiao H, Yin T, Wang X, Uchida T, Chung J, White M, Yang Y. Specificity of Interleukin-2 Receptor γ Chain Superfamily Cytokines Is Mediated by Insulin Receptor Substrate-dependent Pathway*. Journal Of Biological Chemistry 2002, 277: 8091-8098. PMID: 11788580, DOI: 10.1074/jbc.m106650200.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid MotifsAnimalsCell DivisionCell LineCytokinesDose-Response Relationship, DrugEnzyme InhibitorsGRB2 Adaptor ProteinInsulin Receptor Substrate ProteinsInterleukin-4Interleukin-9MicePhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationPlasmidsProtein BindingProtein Structure, TertiaryProteinsReceptors, Interleukin-2Signal TransductionTransfectionTyrosineConceptsIRS proteinsCytokine specificityIL-4-mediated functionsPleckstrin homology domainJak tyrosine kinasesUnique biological functionsPI3K activityPhosphotyrosine bindingHomology domainPH domainSHP-2Different structural domainsPhosphatidylinositol 3IL-4 stimulationBinding domainsIL-2 receptor gamma chainBiological functionsPathways workProliferative effectTyrosine kinaseIRS-2IRS-1Structural domainsAkt activationIRS-4Stat6 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
1999
Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells.
Jiang Z, Zhou Q, Chatterjee A, Feener E, Myers M, White M, King G. Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells. Diabetes 1999, 48: 1120-1130. PMID: 10331419, DOI: 10.2337/diabetes.48.5.1120.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEndothelin Receptor AntagonistsEndothelin-1Enzyme InhibitorsGTP-Binding ProteinsHumansInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMaleMuscle, Smooth, VascularPeptides, CyclicPertussis ToxinPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphoserineProtein Kinase CRatsRats, ZuckerSignal TransductionTetradecanoylphorbol AcetateVirulence Factors, BordetellaConceptsInsulin-stimulated phosphatidylinositolProtein kinase CIRS-2P85 subunitSerine phosphorylationSmooth muscle cellsInsulin receptor beta subunitInsulin-induced phosphatidylinositolInsulin receptor substrateReceptor beta subunitMuscle cellsTreatment of cellsArterial smooth muscle cellsReceptor substratePretreatment of cellsVascular smooth muscle cellsBeta subunitKinase CPhosphatidylinositolIndependent pathwaysSpecific inhibitorET-1SubunitsPhosphorylationPathwayEarly biochemical events in insulin-stimulated fluid phase endocytosis
Pitterle D, Sperling R, Myers M, White M, Blackshear P. Early biochemical events in insulin-stimulated fluid phase endocytosis. American Journal Of Physiology 1999, 276: e94-e105. PMID: 9886955, DOI: 10.1152/ajpendo.1999.276.1.e94.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate-1Fluid-phase endocytosisMitogen-activated protein kinase kinaseRat-1 cellsInsulin receptorDominant negative mutant RasHematopoietic precursor cell lineBat cellsHIRc-B cellsInhibitor of PIProtein kinase kinaseWild-type RasMEK inhibitor PD 98059Active insulin receptorEndogenous IRS-1Receptor substrate-1Inhibitor PD 98059Certain cell typesPrecursor cell lineInitial molecular mechanismsIRS-1 expressionKinase kinaseEarly biochemical eventsMutant RasSubstrate-1
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 IInsulin Receptor Substrate-1 is the Predominant Signaling Molecule Activated by Insulin-like Growth Factor-I, Insulin, and Interleukin-4 in Estrogen Receptor-positive Human Breast Cancer Cells*
Jackson J, White M, Yee D. Insulin Receptor Substrate-1 is the Predominant Signaling Molecule Activated by Insulin-like Growth Factor-I, Insulin, and Interleukin-4 in Estrogen Receptor-positive Human Breast Cancer Cells*. Journal Of Biological Chemistry 1998, 273: 9994-10003. PMID: 9545345, DOI: 10.1074/jbc.273.16.9994.Peer-Reviewed Original ResearchMeSH KeywordsAndrostadienesBreast NeoplasmsCalcium-Calmodulin-Dependent Protein KinasesEnzyme InhibitorsFemaleFlavonoidsHumansInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IInterleukin-4Intracellular Signaling Peptides and ProteinsKineticsMitogen-Activated Protein Kinase KinasesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphorylationPhosphotyrosineProtein Kinase InhibitorsProtein KinasesReceptor, InsulinReceptors, EstrogenSignal TransductionTumor Cells, CulturedWortmanninConceptsIRS-1Tyrosine phosphorylationIRS-2Insulin-like growth factorBreast cancer cellsIGF-I treatmentGreater tyrosine phosphorylationInterleukin-4Substrate adaptor proteinMitogen-activated protein kinase activityCancer cellsCell linesInsulin receptor substrate-1Mitogen-activated protein kinaseP85 regulatory subunitProtein kinase activityActivation of phosphatidylinositolReceptor substrate-1Estrogen receptor-positive human breast cancer cellsGrowth factorPrimary breast tumor specimensIGF-stimulated growthAdaptor proteinRegulatory subunitT47-D breast cancer cells
1997
Calmodulin Activates Phosphatidylinositol 3-Kinase*
Joyal J, Burks D, Pons S, Matter W, Vlahos C, White M, Sacks D. Calmodulin Activates Phosphatidylinositol 3-Kinase*. Journal Of Biological Chemistry 1997, 272: 28183-28186. PMID: 9353264, DOI: 10.1074/jbc.272.45.28183.Peer-Reviewed Original ResearchConceptsSrc homology 2 domainIntact cellsPhosphorylation of phosphatidylinositolActivates PhosphatidylinositolVesicular traffickingEukaryotic cellsEffector proteinsRegulatory subunitCytoskeletal organizationUbiquitous Ca2PhosphatidylinositolIntracellular eventsNovel mechanismAffinity chromatographyGrowth factorCalmodulinCalmodulin antagonistsMultiple processesCellsCoimmunoprecipitationDirect linkPhosphorylationTraffickingSubunitsCa2
1996
Insulin-induced egr-1 and c-fos Expression in 32D Cells Requires Insulin Receptor, Shc, and Mitogen-activated Protein Kinase, but Not Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase Activation*
Harada S, Smith R, Smith J, White M, Jarett L. Insulin-induced egr-1 and c-fos Expression in 32D Cells Requires Insulin Receptor, Shc, and Mitogen-activated Protein Kinase, but Not Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase Activation*. Journal Of Biological Chemistry 1996, 271: 30222-30226. PMID: 8939974, DOI: 10.1074/jbc.271.47.30222.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCell LineCHO CellsCricetinaeDNA-Binding ProteinsEarly Growth Response Protein 1Enzyme ActivationEnzyme InhibitorsGene Expression RegulationGRB2 Adaptor ProteinImmediate-Early ProteinsInsulinInsulin Receptor Substrate ProteinsMicePhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationPhosphotransferases (Alcohol Group Acceptor)Protein KinasesProteinsProto-Oncogene Proteins c-fosReceptor, InsulinRNA, MessengerTranscription FactorsTyrosineConceptsC-fos expressionInsulin receptor substrate-1Egr-1 expressionInsulin receptorReceptor substrate-1Mitogen-activated protein kinase activationEgr-1Protein kinase activationMultiple signal transduction pathwaysBlot analysisEffect of insulinSignal transduction pathwaysSubstrate-1Tyrosine phosphorylationImmediate early gene Egr-1Mitogen-activated protein kinase kinase inhibitorWestern blot analysisProtein kinase kinase inhibitorInsulin receptor tyrosine phosphorylationInsulin treatmentKinase activationIRS-1 phosphorylationTransduction pathwaysKinase kinase inhibitorGene Egr-1