2021
Insulin action at a molecular level – 100 years of progress
White M, Kahn C. Insulin action at a molecular level – 100 years of progress. Molecular Metabolism 2021, 52: 101304. PMID: 34274528, PMCID: PMC8551477, DOI: 10.1016/j.molmet.2021.101304.Peer-Reviewed Original ResearchConceptsAmino acid sequenceType 2 diabetesFunction of insulinAcid sequenceMolecular knowledgeHuman diseasesInsulin-sensitive tissuesPhysiological functionsPhysiological roleInsulin receptorInsulin-resistant statesInsulin 100 yearsInsulin actionBlood glucoseCascadeInsulinDiabetesTissueDiscoveryRegulationTreatmentRemarkable advancesRoleSequenceYearsInsulin 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
2018
Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver
Kalvisa A, Siersbæk M, Præstholm S, Christensen L, Nielsen R, Stohr O, Vettorazzi S, Tuckermann J, White M, Mandrup S, Grøntved L. Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver. PLOS Biology 2018, 16: e2006249. PMID: 30532187, PMCID: PMC6301715, DOI: 10.1371/journal.pbio.2006249.Peer-Reviewed Original ResearchConceptsCircadian gene transcriptionGene transcriptionGene expressionCircadian-regulated genesInsulin-regulated genesGenomic approachesGlucocorticoid receptorGene programEnhancer activityCistromic analysisGlucocorticoid receptor activityGenesMechanistic insightsTranscriptionFeeding behaviorSelective disruptionDiet-induced obese animalsEnhancerReceptor activityFeeding responseDiet-induced obesityExpressionDysregulationChromatinFOXO1Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Huang H, Lee S, Sousa-Lima I, Kim S, Hwang W, Dagon Y, Yang W, Cho S, Kang M, Seo J, Shibata M, Cho H, Belew G, Bhin J, Desai B, Ryu M, Shong M, Li P, Meng H, Chung B, Hwang D, Kim M, Park K, Macedo M, White M, Jones J, Kim Y. Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. Journal Of Clinical Investigation 2018, 128: 5335-5350. PMID: 30226474, PMCID: PMC6264719, DOI: 10.1172/jci63562.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic lipid accumulationLiver diseaseInsulin resistanceRisk factorsNovo lipogenesisObesity-related metabolic disordersLipid accumulationObesity-induced steatosisChronic liver diseaseObese diabetic miceDiet-induced obesityMajor risk factorSevere hepatic steatosisHigh-fat dietDe novo lipogenesisThermogenic gene expressionRho kinase 1Antidiabetes drugsDiabetic miceHepatic steatosisActivation of AMPKHepatocellular carcinomaMetabolic disordersInactivating hepatic follistatin alleviates hyperglycemia
Tao R, Wang C, Stöhr O, Qiu W, Hu Y, Miao J, Dong X, Leng S, Stefater M, Stylopoulos N, Lin L, Copps K, White M. Inactivating hepatic follistatin alleviates hyperglycemia. Nature Medicine 2018, 24: 1058-1069. PMID: 29867232, PMCID: PMC6039237, DOI: 10.1038/s41591-018-0048-0.Peer-Reviewed Original ResearchConceptsHepatic glucose productionAdipose tissue insulinGlucose toleranceTissue insulinSuppression of HGPGastric bypass surgeryFed obese miceHepatic insulin resistanceWhite adipose tissuePotential clinical significanceInsulin receptor substrate-1Bypass surgeryGlucose intoleranceHepatic inactivationObese miceInsulin resistanceObese individualsGlycated hemoglobinTranscription factor FOXO1Insulin sensitivityNormal suppressionClinical significanceReceptor substrate-1Adipose tissueExpression of FstAblation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis
Xu H, Lee M, Tsai P, Adler A, Curry N, Challa S, Freinkman E, Hitchcock D, Copps K, White M, Bronson R, Marcotrigiano M, Wu Y, Clish C, Kalaany N. Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: 4228-4233. PMID: 29610318, PMCID: PMC5910837, DOI: 10.1073/pnas.1718414115.Peer-Reviewed Original ResearchMeSH KeywordsA549 CellsAmino AcidsAnimalsAutophagyCarcinogenesisCarcinoma, Non-Small-Cell LungCodon, TerminatorGenes, rasHumansInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor ILung NeoplasmsMiceNeoplasm ProteinsProteolysisProto-Oncogene Proteins c-aktProto-Oncogene Proteins p21(ras)Signal TransductionConceptsIR/IGF1RLung cancerLung tumorigenesisInsulin receptorTumor cellsInsulin-like growth factor 1 receptorCell lung cancerGrowth factor 1 receptorHuman NSCLC cellsEffective therapeutic strategyLung cancer initiationIntracellular levelsKirsten rat sarcomaFactor 1 receptorTumor burdenCancer deathLeading causeMutant NSCLCNSCLC cellsIGF1R inhibitionMouse modelTherapeutic strategiesInsulin/IGF1Acute lossRat sarcoma
2017
Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Cao J, Peng J, An H, He Q, Boronina T, Guo S, White M, Cole P, He L. Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity. Nature Communications 2017, 8: 131. PMID: 28743992, PMCID: PMC5526866, DOI: 10.1038/s41467-017-00163-w.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorE1A-Associated p300 ProteinEndoplasmic Reticulum StressEndotoxemiaGene Expression ProfilingImmunoblottingInsulinInsulin ResistanceLipopolysaccharidesLiverMaleMembrane ProteinsMice, Inbred C57BLMice, ObeseObesityProtein Serine-Threonine KinasesReceptor, InsulinSignal TransductionX-Box Binding Protein 1ConceptsInsulin resistanceP300 acetyltransferase activityHigh-fat diet-fedChronic low-grade inflammationObese ob/ob miceOb/ob miceLow-grade inflammationDiet-induced obesityAcetyltransferase activityElevated plasma concentrationsPromising therapeutic targetCytoplasm of hepatocytesEndoplasmic reticulum stressObese patientsObese miceInsulin sensitivityIntestinal permeabilityOb micePlasma concentrationsDisrupts insulinTherapeutic targetImpairs insulinPharmacological inhibitionGlucose productionObesity
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 cellsIRS proteins and diabetic complications
Lavin D, White M, Brazil D. IRS proteins and diabetic complications. Diabetologia 2016, 59: 2280-2291. PMID: 27514532, PMCID: PMC5506098, DOI: 10.1007/s00125-016-4072-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiabetes ComplicationsDiabetes Mellitus, Type 2FemaleHumansInsulin Receptor Substrate ProteinsMaleMiceSignal TransductionConceptsIRS proteinsType 2 diabetesDiabetic complicationsMitogen-activated protein kinaseElicit cellular responsesCoronary artery diseaseElevated blood glucoseComplications of diabetesProtein kinaseDownstream effectorsAdaptor moleculeInsulin signalingCellular responsesNumber of organsInsulin receptorMacrovascular complicationsMicrovascular complicationsArtery diseasePatient morbidityBlood glucoseProteinMale micePatient outcomesCell proliferationComplicationsInsulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma
Metz H, Kargl J, Busch S, Kim K, Kurland B, Abberbock S, Randolph-Habecker J, Knoblaugh S, Kolls J, White M, Houghton A. Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 8795-8800. PMID: 27439864, PMCID: PMC4978299, DOI: 10.1073/pnas.1601989113.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate-1Janus kinase/signal transducerKinase/signal transducerTumor burdenActivator of transcriptionReceptor substrate-1IRS-1 deficiencyKRAS-mutant lung adenocarcinomaInsulin-like growth factor receptorAdenoviral Cre recombinaseIL-22 receptorMutant lung adenocarcinomaTumor-promoting inflammationAdaptor proteinSignificant survival disadvantageGrowth factor receptorSignal transducerSubstrate-1PI3KProinflammatory phenotypeLung cancerLung adenocarcinomaMutant subgroupTissue microarrayCre recombinaseSerine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase*
Copps K, Hançer N, Qiu W, White M. Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase*. Journal Of Biological Chemistry 2016, 291: 8602-8617. PMID: 26846849, PMCID: PMC4861431, DOI: 10.1074/jbc.m116.714915.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAnimalsCHO CellsCricetinaeCricetulusGene DeletionGlucose IntoleranceInsulinInsulin Receptor Substrate ProteinsLiverMechanistic Target of Rapamycin Complex 1MiceMice, TransgenicMultiprotein ComplexesMutation, MissensePhosphatidylinositol 3-KinasesPhosphorylationProto-Oncogene Proteins c-aktRibosomal Protein S6 KinasesSerineSignal TransductionTOR Serine-Threonine KinasesTuberous Sclerosis Complex 1 ProteinTumor Suppressor ProteinsConceptsInsulin receptor substrate-1Receptor substrate-1PI3K associationS6 kinaseSubstrate-1Insulin-stimulated Akt activityAkt phosphorylationK associationRapamycin complex 1S6K signalingInsulin-stimulated IRS1 tyrosine phosphorylationSer-302IRS1 tyrosine phosphorylationMTORC1 inhibitor rapamycinRibosomal S6 proteinTsc1 deletionFeedback phosphorylationIntracellular amino acidsInsulin sensitivityTyrosine phosphorylationAlanine mutationsS6 proteinS6KAkt activityInsulin signaling
2014
IRS2 integrates insulin/IGF1 signalling with metabolism, neurodegeneration and longevity
White M. IRS2 integrates insulin/IGF1 signalling with metabolism, neurodegeneration and longevity. Diabetes Obesity And Metabolism 2014, 16: 4-15. PMID: 25200290, DOI: 10.1111/dom.12347.Peer-Reviewed Original ResearchConceptsInsulin/IGF1Central nervous systemInsulin-like signalingLife spanOrganisms showsCellular functionsNutrient homeostasisInsulin resistanceGenetic manipulationSystemic insulin resistanceClinical Alzheimer's diseaseType 2 diabetesEnergy homeostasisNeurodegenerative diseasesMetabolismNeurodegenerationCompensatory hyperinsulinaemiaHomeostasisProgressive neurodegenerationSystemic metabolismIGF1Excess insulinNervous systemAlzheimer's diseaseClinical perspectiveInsulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training
Riehle C, Wende A, Zhu Y, Oliveira K, Pereira R, Jaishy B, Bevins J, Valdez S, Noh J, Kim B, Moreira A, Weatherford E, Manivel R, Rawlings T, Rech M, White M, Abel E. Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training. Molecular And Cellular Biology 2014, 34: 3450-3460. PMID: 25002528, PMCID: PMC4135616, DOI: 10.1128/mcb.00426-14.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEnergy MetabolismGene Expression RegulationGlycogenHeartInsulin Receptor Substrate ProteinsMiceMice, Inbred C57BLMice, KnockoutMitochondriaPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPhosphatidylinositol 3-KinasesProtein IsoformsSignal TransductionSwimmingTranscription FactorsConceptsInsulin receptor substrate-1IRS isoformsProtein phosphatase 2AReceptor substrate-1Insulin receptor substrateInsulin-like growth factor 1 receptorGrowth factor 1 receptorSynthase kinase-3βPeroxisome proliferator-activated receptor gamma coactivatorPhosphatase 2AProliferator-activated receptor gamma coactivatorFactor 1 receptorPGC-1α protein contentCardiomyocyte-specific deletionDevelopmental regulationProtein contentHypertrophic responseReceptor substrateReceptor gamma coactivatorFatty acid oxidationSubstrate-1Kinase-3βDivergent rolesMetabolic adaptationNonredundant roleAPPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor
Ryu J, Galan A, Xin X, Dong F, Abdul-Ghani M, Zhou L, Wang C, Li C, Holmes B, Sloane L, Austad S, Guo S, Musi N, DeFronzo R, Deng C, White M, Liu F, Dong L. APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor. Cell Reports 2014, 7: 1227-1238. PMID: 24813896, PMCID: PMC4380268, DOI: 10.1016/j.celrep.2014.04.006.Peer-Reviewed Original ResearchInsulin 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
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 actionMyocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
Qi Y, Xu Z, Zhu Q, Thomas C, Kumar R, Feng H, Dostal D, White M, Baker K, Guo S. Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance. Diabetes 2013, 62: 3887-3900. PMID: 24159000, PMCID: PMC3806607, DOI: 10.2337/db13-0095.Peer-Reviewed Original ResearchConceptsIRS2 proteinGene expressionType 2 diabetesEnergy metabolism gene expressionInsulin resistanceMetabolic gene expressionBox class ODouble knockout miceHeart failureActivation of p38Chronic insulin exposureActivation of p38αMetabolism gene expressionProtein kinaseRole of IRS1Cellular metabolismMolecular mechanismsInsulin receptorNeonatal rat ventricular cardiomyocytesP38α MAPKCause heart failureCellular dysfunctionIRS1Myocardial insulin resistanceClass OPhosphatidylcholine 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 1Direct Autocrine Action of Insulin on β-Cells: Does It Make Physiological Sense?
Rhodes C, White M, Leahy J, Kahn S. Direct Autocrine Action of Insulin on β-Cells: Does It Make Physiological Sense? Diabetes 2013, 62: 2157-2163. PMID: 23801714, PMCID: PMC3712043, DOI: 10.2337/db13-0246.Peer-Reviewed Original ResearchConceptsΒ-cellsDirect autocrine effectsTransgenic mouse studiesSignal transductionPancreatic β-cellsDownstream elementsAutocrine actionRelevant ligandsΒ-cell functionAutocrine effectsMouse studiesCircumstantial evidencePhysiological senseTransductionAvailable experimental evidencePathwayInsightsExperimental evidenceInsulinNerve Growth Factor Receptor TrkA, a New Receptor in Insulin Signaling Pathway in PC12 Cells*
Geetha T, Rege S, Mathews S, Meakin S, White M, Babu J. Nerve Growth Factor Receptor TrkA, a New Receptor in Insulin Signaling Pathway in PC12 Cells*. Journal Of Biological Chemistry 2013, 288: 23807-23813. PMID: 23749991, PMCID: PMC3745327, DOI: 10.1074/jbc.m112.436279.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceAnimalsEnzyme ActivationGlucoseHumansInsulinInsulin Receptor Substrate ProteinsMitogen-Activated Protein Kinase 7Molecular Sequence DataNerve Growth FactorPC12 CellsPhosphorylationPhosphotyrosineProtein BindingProto-Oncogene Proteins c-aktRatsReceptor, InsulinReceptor, trkASignal TransductionConceptsInsulin receptor substrate-1Insulin receptorPC12 cellsTrkA kinase domainTransmembrane receptor tyrosine kinaseKinase-inactive mutantInsulin Signaling PathwayReceptor substrate-1Nerve growth factor receptor TrkAReceptor tyrosine kinasesNerve growth factorActivation of AktNPXY motifKinase domainTyrosine phosphorylationSubstrate-1Regulatory loopTyrosine kinaseSignaling pathwaysGrowth factorNew receptorsReceptor TrkACellsPathwayTrkA