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Page1ProteomicsReceived:28-Apr-2014;Revised:14-Aug-2014;Accepted:06-Oct-2014Thisarticlehasbeenacceptedforpublicationandundergonefullpeerreviewbuthasnotbeenthroughthecopyediting,typesetting,paginationandproofreadingprocess,whichmayleadtodifferencesbetweenthisversionandtheVersionofRecord.
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InvestigationofPhosphoproteomeinRAGEsignalingKedarBBatkulwar,SnehaBBansode,GouriVPatil,RashmiKGodbole,RubinaSKazi,SubashchandraboseChinnathambi,DhanasekaranShanmugam,MaheshJKulkarni*ProteomicsFacility,DivisionofBiochemicalSciences,CSIR-NationalChemicalLaboratory,Pune-411008,India#Authors2to5haveequallycontributed*ForcorrespondenceMaheshJKulkarniProteomicsFacility,DivisionofBiochemicalSciences,CSIR-NationalChemicalLaboratory,Pune-411008,IndiaE-mail:mj.
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AbstractReceptorforAdvancedGlycationEndproducts(RAGE)isoneofthemostimportantfactorsimplicatedindiabetes,cardiovasculardiseases,neurodegenerativediseases,andcancer.
Itisapatternrecognitionreceptor,byvirtueofitsabilitytointeractwithmultipleligands;RAGEactivatesseveralsignaltransductionpathwaysthroughinvolvementofvariouskinases,whichphosphorylatetheirrespectivesubstrates.
OnlyfewsubstrateshavebeenknowntobephosphorylatedinresponsetoactivationbyRAGE(e.
g.
NF-кB),howeveritispossiblethatthesekinasescanphosphorylatemultiplesubstratesdependingupontheirexpressionandlocalization,leadingtoalteredcellularresponsesindifferentcelltypesandconditions.
Onesuchexample,Glycogensynthasekinase3beta(GSK3β)whichisknowntophosphorylateglycogensynthase,actsdownstreamtoRAGEandhyperphosphorylatesMicrotubuleAssociatedProteinTau(MAPT)causingneuronaldamage.
Thus,itisimportanttounderstandtheroleofvariousRAGEactivatedkinasesandtheirsubstrates.
Therefore,wehavereviewedherethedetailsofRAGEactivatedkinasesinresponsetodifferentligandsandtheirrespectivephosphoproteome.
Further,wediscusstheanalysisofthedataminedforknownsubstratesofthesekinasesfromPhosphoSitePlus(http://www.
phosphosite.
org)database,andtheroleofsomeoftheimportantsubstratesinvolvedincancer,diabetes,cardiovasculardiseasesandneurodegenerativediseases.
Insummary,thisreviewprovidesinformationonRAGEactivatedkinasesandtheirphosphoproteome,whichwillbehelpfulinunderstandingthepossibleroleofRAGEanditsligandsinprogressionofdiseases.
Keywords:disease,glycation,kinase,phosphoproteome,RAGEwww.
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Abbreviations1.
RAGE-Receptorforadvancedglycationendproducts2.
AGEs-Advancedglycationendproducts3.
NF-кB-NuclearfactorkappaB4.
GSK3β-Glycogensynthasekinase-3beta5.
HMGB1-Highmobilitygroupboxprotein16.
Aβ-Amyloidbeta7.
SP1-Specificityprotein18.
MAPK-Mitogenactivatedproteinkinase9.
PKC-ProteinkinaseC10.
JNK-c-JunN-terminalKinase11.
JAK-Janusactivatedkinase12.
ERK-Extracellularsignalregulatedkinase13.
iNOS-induciblenitricoxidesynthase14.
eNOS-Endothelialnitricoxidesynthase15.
mTOR-Mammaliantargetofrapamycin16.
MMP-Matrixmetalloproteinase17.
STAT-Signaltransducersandactivatorsoftranscription18.
TNFα-Tumornecrosisfactoralphawww.
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IntroductionRAGE,amulti-ligandpatternrecognitionreceptor,belongstotheimmunoglobulinsuperfamilyofproteins.
Althoughitwasfirstdescribedasareceptorforadvancedglycationendproducts(AGEs),itinteractswithdiverseclassesofligandincludingS100B,highmobilitygroupboxprotein(HMGB)-1,Mac-1,amyloidbeta(Aβ)peptideandbetasheetfibrils[1].
TheRAGEmRNAandmatureproteincanundergoalternativesplicingandproteolysis,respectivelyresultinginmanyvariants.
FulllengthRAGE(flRAGE)consistsof5domains,threeextracellular,asingletransmembranedomainandasmallcytosolictail.
ExtracellulardomainsarelabeledasV,C1andC2domain[2].
WhilethesolubleRAGE(sRAGE)lackstransmembraneandcytosolicdomain,andthereforeitisneitheranchoredincellmembranenorabletoactivatesignalingpathwayslikeflRAGE(Fig1)[3].
ThesRAGEinteractswithRAGEligandsandhelpsintheclearanceofthesefromthesystem[4].
TheinitiationofRAGEsignalingcommonlyoccursthroughproductionofROSviaNADPHoxidaseandactivationofvariouskinasesincludingMAPKlikeERK1/2,SAPK/JNK,p38;PI3K/Akt;JAK/STAT;GSK3βetc[5].
ThesekinasestriggerseveraldownstreamsignalingcascadesoftenviaactivationoftranscriptionfactorsNF-кBandSP1,therebymodulatingspecificcellularprocesses[6].
Becauseofitsroleinoxidativestressandinflammation,RAGEisimplicatedinseveraldiseases.
Indiabetes,AGEsarethepredominantligandsthatinteractwithRAGEandcontributetothepathogenesisofdiabeticcomplicationslikeglomerulopathy,atherosclerosis,vasculopathyetc[7].
AGEsareagroupofheterogeneousmoleculesformedasaresultofaseriesofnon-enzymaticreactionsbetweenreducingsugarsandproteins[8,9].
SomeofthepredominantAGEsincludecarboxymethyllysine(CML),carboxyethyllysinewww.
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(CEL),pentosidineetc[10-12].
AGEformationisacceleratedindiabetesduetohyperglycemiccondition[13].
AccumulationofAGEsleadsto(i)alteredproteinstructureandfunction[14],(ii)proteinaggregation,fibrilformation,andproteaseresistance[15,16],(iii)dysfunctionofextracellularmatrix[14]and(iv)RAGEactivationanddownstreamsignaling[17].
AGE/RAGEinteractioncontributessubstantiallytotheprogressionofdiabeticcomplications,cardiovasculardiseases,acceleratedaging,neurodegenerativediseases,andcancer[18].
WhereasinAlzheimer'sdisease,AβistheprincipalligandthatinteractswithRAGE[19].
Itconsistsof36-43aminoacidresiduesproducedasaresultofsequentialcleavageofAPPbybetaandgammasecretases[20].
RAGEmediatedAβinternalizationresultsinmitochondrialdysfunctioncausingcellulardamage[21].
Whileincancer,S100B,acalciumbindingproteinisknowntobeinvolvedinRAGEactivationbydimerization[22].
S100B/RAGEinteractionelicitsvariouscellulareffectsincludingcellsurvivalandcellproliferation[23,24].
HMGB1alsocalledasHMG1oramphoterinisasmallnon-histonechromatinproteinwhichinteractswithRAGEandactivatesproinflammatorypathways[25,26].
BlockadeofRAGEmediatedsignalingsuppressestumorgrowthandmetastasis,suggestingitspotentialinvolvementincancer[27].
Hence,RAGEplaysanimportantroleintheregulationofvitalcellprocessessuchasapoptosis,autophagy,inflammationandproliferation.
TheinvolvementofRAGEindifferentdiseaseshasbeenreviewedingreatdetailearlier[28-31].
However,thedetailedmolecularmechanismofRAGEsignaling,especiallytheinvolvementofvariouskinasesandtheirsubstratesisnotwellunderstood.
MostofthereportedstudiesonRAGEsignalingfocusonactivationofspecifickinaseslikeMAPKs,PI3K,PKCandGSK3β.
ThephosphorylationofonlyfewimportantsubstratessuchasNF-кB,FOXO,andSP1isknown;butglobalphosphoproteomeinRAGEactivatedsignalingispoorlystudied.
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thefactorsthatfacilitatetherecruitmentofspecifickinases,alongwiththeirphosphoproteome,whichcangreatlyenhanceourunderstandingofthecellularresponsestoRAGEsignaling.
Therefore,inthisreviewwehavediscussedindetailaboutRAGEactivatedkinasesandtheirphosphoproteomeinresponsetodifferentligands.
RAGEactivatedkinasesOnceactivatedbyitsligands,RAGEcanrecruitseveralkinasesandtriggeracascadeofsignalingevents(Fig2).
SomeoftheimportantkinasesthatareactivateddownstreamtoRAGEaredescribedbelow.
Mitogenactivatedproteinkinases(MAPK)MAPKsareserine/threonineproteinkinasesthattranslateexternalstimuliintoawiderangeofcellularresponses.
ConventionalMAPKsincludeextracellularsignal-regulatedkinases1/2(ERK1/2),c-JunN-terminalkinases1/2/3(JNK1/2/3),p38isoforms(α,β,γ,andδ),andERK5.
AtypicalMAPKsincludeERK3/4,ERK7,andNemo-likekinase(NLK).
EachgroupofconventionalMAPKsiscomposedofasetofthreeevolutionarilyconserved,sequentiallyactingkinases:aMAPK,aMAPKkinase(MAPKK),andaMAPKKkinase(MAPKKK)[32].
SeveralligandsinteractwithRAGEandactivatedifferentMAPKsdependingoncelltypeanddisease.
p38MAPKisoneofthekeydownstreameffectorofRAGEthatmediatesactivationofNF-кBdependentsecretionofcytokinesresultinginacceleratedinflammation.
AGEinducedNF-кBactivationresultsinincreasedsecretionofTumorNecrosisFactoralpha(TNF-α),interleukin-1beta(IL-1β),andMonocytesChemoattractantProtein(MCP)-1.
RAGEhasbeenimplicatedintheformationofproinflammatorymilieu,whichplaysanimportantroleintheadvancementofseveraldisorders[33].
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Indiabetes,AGEinducedp38MAPKactivationresultsinincreasedalkalinephosphataseactivityviaRAGE,whichin-turninducesosteoblastlikedifferentiationofsmoothmusclecellsresultinginvascularcalcification[34].
Indiabeticnephropathy(DN),AGE/RAGEinteractionactivatesp38MAPKthatphosphorylatesATF2,atranscriptionfactorwhichinducesiNOSexpressioninmesangialcells[35].
Inpodocytes,thisinteractionresultsinactivationoftranscriptionfactorFOXO4viap38MAPK,leadingtoapoptosis[36].
AGEscaninduceexpressionofconnectivetissuegrowthfactor(CTGF),whichpromotestheadvancementofdiabeticnephropathy.
TheexpressionofCTGFdependsonRAGE-ERK/p38-Smad3cross-talkpathway[37].
AGEsalsoactivateERK1/2andEGFRviaRAGEmediatedROSinNRF-49Fkidneycells,whichareimplicatedindiabeticnephropathy[38].
AGEsactivateSmad2/3inhumanvasculopathyviaRAGEandERK/p38MAPKs[39].
AGEdepositionandRAGEexpressioncontributestotheprogressionofatherosclerosisviaERKactivationindiabeticandhypertensivemice[40].
OligomerizationofRAGEisbelievedtoplayanessentialroleinsignaltransduction.
HeparansulfateinduceshexamerizationoftheextracellularVandC1domainspresentinRAGE,resultinginactivationofERK1/2inendothelialcells[41].
S100A4demonstratedRAGEmediatedERKphoshorylationandMMP2activation,whichincreasescellmotilityinhumanpulmonaryarterysmoothmusclecells(hPASMCs)contributingtoprogressionofvasculardiseases[42].
AGEshavebeenalsoimplicatedindiabetickeratopathy,whereintheyinduceapoptosisincornealepithelialcellsbyROSgenerationthroughactivationofNADPHoxidase,JNKandp38MAPKinRAGEdependentmanner[43].
Incancer,bindingofamphoterintoRAGEenhancestheRAGEboundERK1/2activity,asdemonstratedbyphosphorylationofmyelinbasicprotein,anERKsubstrate[44].
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myoblastsandrhabdomyosarcomacells,HMGB1/RAGEinteractionpreventstumorformationwhereasingliomasitfacilitatesmetastasisensuingininvasivephenotype.
RAGEactivationbyHMGB1leadstomyogenesisviaCdc42-Rac-MKK6-p38MAPKpathwayandisassociatedwithinhibitionofproliferation.
FunctionalinactivationofRAGEcausesdecreaseinactivityofp21Waf1,aproliferationinhibitorandincreaseinactivityofcyclinD1,retinoblastomaprotein,ERK1/2andJNK[45,46].
WhereasinC6gliomacells,RAGE/amphoterininteractionplaysanimportantroleintumorproliferation,invasionandmatrixmetalloproteinase(MMP)expression,whileblockingthisinteractiondecreasesgrowthandmetastasisbyinactivationofp44/p42,p38andJNKMAPKpathway[47].
S100A8/A9ligandhasadualroleintumorbiology;stimulatespseudopodiaformationandexertsgrowthpromotingactivity.
ItpromotescellgrowthinaRAGEdependentmannerbyphosphorylationofp38andp44/42MAPKsandactivationofNF-кB[48].
p38MAPKcausesactivationofMAPKAPkinase-2(MK2),Hsp27andSAPK/JNKpathways.
SimilarresponseswereobservedinHaCaTkeratinocytesandclearcellrenalcellcarcinoma(CCRCC)viaERK1/2activationinRAGEdependentmanner[49].
HMGB1/RAGEinteractionplaysanimportantroleintheadvancementofliverfibrosis.
RAGEmediatedHMGB1internalizationcausesSmad2andERK1/2phosphorylationresultingincollagentypeIandα-smoothmuscleactin(α-SMA)expression,andproliferationofhepaticstellatecellsleadingtothefibroticchangesofliver[50].
S100P,aRAGEligandthatisexpressedathighlevelsincoloncancer,interactswithRAGEandstimulatesgrowth,migration,ERKphosphorylation,andNF-кBactivationincancercells[51].
VEGFincardiacmyocytesrespondtoS100BandRAGEinteractioninducedERK1/2phosphorylationandmyofibroblastproliferationcontributingtomyocardialinfarction[52].
RAGE/S100BinteractionaftermyocardialinfarctionstimulatesmyocyteapoptosisbyactivatingERK1/2andp53signaling[53].
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Incorticalneurons,RAGEmediatesAβuptakeacrossthecellmembraneviaactivationofp38MAPK.
p38MAPKactivationcausesinflammatoryresponseandisimplicatedinthepathogenesisofAlzheimer'sdisease[54].
Aβimpairslong-termpotentiation(LTP)intheentorhinalcortexthroughRAGE-mediatedp38MAPKactivation[55].
Bloodbrainbarrier(BBB)ismainlycomposedofcerebralendothelialcells(CEC)andastrocytes.
BBBdamageisassociatedwithseveraldisordersincludingAlzheimer'sdisease.
AβinducedERK1/2andcytosolicphosphorilaseA2phosphorylationinCECsandastrocytesoccursviaRAGEdependentpathwayscausingcellulardamage[56].
APP/PS1transgenicalzheimermousemodeldemonstratesstrongincreaseintheexpressionofmouseformylpeptidereceptor(mFPR1/2)andRAGEexpressioninthecortexandhippocampus.
FPRandRAGEplayanimportantroleinAβ,S100BandAGE-BSAinducedERK1/2phosphorylationandregulationofcAMPlevelinglialcells[57].
AβstimulatedtransientactivationofERK1/2,p38MAPKinmicrogliaandmonocytesresultsinphosphorylationofcAMPresponseelement-binding(CREB)protein,providingamechanismforAβinducedchangesingeneexpression[58].
Inaddition,RAGEviaMAPKisalsoinvolvedinasthma,chronicobstructivepulmonarydisease,cysticfibrosis,andrheumatoidarthritis.
S100A12/RAGEinteractioninducesoverexpressionofMUC5AC,amajormucinprotein,viaERKactivationinairwayepithelialcells[59].
RAGEinducesdamageinhumanpulmonaryarteryendothelialcellsviap38MAPKactivationandHsp27phosphorylationresultinginacutelunginjury[60].
HMGB1inpresenceofLPSupregulatesTLR4andRAGEexpressioninSynovialfibroblasts,whichinducesp38MAPKandNF-кBactivationresultingintheproductionofIL-6,MMP3,andMMP13inrheumatoidarthritis[61,62].
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c-JunN-terminalkinase(JNK)JNKisaprolinedirectedSerine/Threoninekinase,andbelongstotheMAPKfamilywhichintegrateavarietyofenvironmentalstimulitocauseproliferation,differentiation,development,inflammatoryresponseandapoptosis.
TheJNKarmofMAPKsisactivatedinconditionsofintracellularandenvironmentalstress;henceitisalternativelyreferredtoasStressActivatedProteinKinase(SAPK).
JNKisactivatedbydualphosphorylationataspecificthreonineandtyrosineresiduesbyMKK4andMKK7kinases(MAPKKs)[63].
JNKactivationcausesphosphorylationoftranscriptionfactorsaswellasotherproteinstoeitheractivateorinactivatethem.
Itpredominantlyphosphorylatesandactivatesthec-JunandATF-2transcriptionfactorsoftheAP1complex.
JNKisactivatedbyERstress,osmoticstress,redoxstress,UVradiation,thecytokinesTNF-αandIL-1β,microbialinvasion,aswellasbyRAGEactivationinmanypathologicalconditions[64].
Inosteoarthritis,accumulationofAGEsinthearticularcartilagechondrocyteshasbeenassociatedwithinflammation.
AGEinducesexpressionofCOX-2andmicrosomalprostaglandinEsynthase-1byRAGEmediatedactivationofJNK,whichleadstoincreasedproductionofProstaglandinE2,amediatorofinflammation[65].
AGEBSAinducessecretionofMMP1,3and13inhumanosteoarthriticchondrocytesbyinteractionwithRAGEandactivationofJNKandp38kinase[66].
Onthecontrary,AGE/RAGEsignalingintheinfiltratingmacrophagescausesphosphorylationofp44/42ERK,p38,JNK,andPI3KandinhibitionofJNKactivitysignificantlyenhancedthestimulatoryeffectofAGEonMMP9secretion[67].
InDiabeticcondition,osteoblastapoptosisanddeficientbonemarrowformationismediatedbyAGE/RAGEinteraction.
CMLmodifiedcollagenactivatesp38,JNK,andtranscriptionfactor,FOXO1,leadingtoincreasedcaspase-3activityinfibroblastsresultinginwww.
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apoptosis,whileinhibitionofthesekinasesreducedCML-collagenstimulatedapoptosis[68].
InMyocardialinfarction,stroke,andvenousthromboembolism,AGE/RAGEinteractioncausestranslocationofPKC-β2thatphosphorylatesJNKleadingtoincreasedtranscriptionofearlygrowthresponse-1(EGR-1).
EGR-1playsanintegralroleinthebiologicalresponsetohypoxia,itsupregulationmediatesincreasedexpressionofinflammatoryandprothromboticgenesresultingincellulardamage[69].
RAGEactivationbyAGEs,S100andHMGB1hasbeenimplicatedinischemicrepurfusion(I/R)injuryofcardiomyocytes.
CML/RAGEinteractionduringI/RincardiomyocytesandmousemodelcausesactivationofJNKandSTAT3leadingtocellulardamage[70,71].
LigationoftheheterodimericS100A8/A9proteinwithRAGEinpostischemiccardiacfibroblastsincreasedNF-кBnucleartranslocationandexpressionofpro-inflammatorycytokinesbyactivationofallthethreearmsofMAPKsnamelyERK,JNKandp38[72].
WhereasinteractionofHMGB1withRAGEinI/RcausedtheactivationofERK1/2andJNKMAPKsonly,alongwithincreasednucleartranslocationofNF-кB[73].
SimilareffectsofHMGB1/RAGEinteractionwereobservedinadiabeticmousemodelexposedtoI/R,thereforeimplyingaroleofHMGB1inheartfailureasacomplicationofdiabetes[74].
InconditionsofhepaticI/R,apartfromactivationofthesekinases,RAGEsignalingalsoactivatesc-Jun,leadingtoincreasedserumalanineaminotransferaseactivity,TNF-αandIL-6levels,NF-кBactivityandultimatelyapoptosisinlivertissue[75].
HMGB1functionsasacytokineandactivatesmacrophagesbybindingtoRAGE.
ThisinteractioncausesincreasedexpressionofMHCclassII,TNF-αandNObyactivationofp38,p42/44,JNKMAPKsalongwithincreasednucleartranslocationofNF-кB[76].
JNKactivationviaRAGEisimplicatedinpathogenesisofatherosclerosis.
S100B,andoxidizedLDLs(oxLDL)containingAGEepitopesinteractwithRAGEinaorticendothelialcellstocauseactivationofJNKleadingtoincreasedMMP2activityandupregulationofVCAM-1www.
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whichmarksthesitesdestinedfordevelopmentofatheroscleroticplaques[77].
AGE/RAGEinteractionisreportedtocauseactivationofJNK,whichfurtherphosphorylatesAP1transcriptionfactortocauseexpressionofE-selectin,whichmediatesatherosclerosis[78].
Inendothelialcells,HMGB1stimulatesproinflammatoryresponsebyupregulationofleukocyteadhesionmoleculesnamelyICAM-1,VCAM-1,TNFα,IL-8,MCP-1,plasminogenactivatorinhibitor1(PAI-1),andtissueplasminogenactivator(tPA).
ThiseffectwasobservedbytransientphosphorylationoftheERK,p38andJNKandincreasednucleartranslocationofNF-кB[79].
S100B/RAGEInteractioninBV-2microglialcellsshowedupregulationofCOX2,IL-1βandTNF-αexpressionandchemokinesecretionbyparallelactivationofCdc42-Rac1-JNK-AP1andRas-Rac1-NF-кBpathwayscausinginflammation[80-82].
S100B/RAGEinteractioninamixedpopulationofneuronalandglialcellscausedactivationofJNK,whichspecificallyphosphorylatedthec-Jun.
c-JuncausestheexpressionofDickopff-1whichdisruptsWntsignalingpathwayandactivatesGSK3βresultinginTauhyperphosphorylation,apathologicalhallmarkofAD[83].
AβcausesapoptosisthroughinteractionwithRAGEviaactivationofp38,JNKpathways,andNF-кB,thusimplyingtheroleofRAGEinneurodegenerationincybridsofsporadicAD[84].
Incaseofbraininjury,HMGB1releasedfromreactiveastrocytescausesproliferationofneuronalstemandprogenitorcellsbyinteractionwithRAGEanddownstreamJNKphosphorylation[85].
ProteinkinaseC(PKC)ProteinkinaseC,amultifunctionalprotein,belongstoafamilyofserinethreoninekinase.
Thereare11isoformsofPKCandthesecanbeclassifiedintothreesubgroups;1)conventionalPKCs(α,β1,β2,andγ)thatareCa2+dependentandactivatedbywww.
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phosphatidylserineandthesecondmessengerdiacylglycerol(DAG);2)novelPKCs(δ,η,ε,β)thatareCa2+independentandstimulatedbyDAG;and3)atypicalPKCs(ζandι/λ),neitherofwhichareknowntorequirecalciumorDAGforactivation.
AllPKCsappeartobephosphorylatedbyphosphoinositide-dependentproteinkinase1(PDPK1)[86].
PKChasbeenassociatedwithvascularalterationssuchasincreasedpermeability,contractility,extracellularmatrixsynthesis,cellgrowth,apoptosis,angiogenesis,leukocyteadhesionandcytokineactivation[87].
PKCphosphorylatescytoplasmicdomainofRAGEuponbindingofligands.
TIRAPandMyD88functionasadaptorproteinsforRAGEwhichfurtherrecruitIRAK4,whichinturnactivatesdownstreamkinasessuchasAkt,p38,JNKandIKKs.
Thisultimatelyleadstoproductionofinflammatorycytokines,IL-6,IL-8,andTNFαthroughactivationofNF-кB,whichregulatesinflammation,immuneresponseandothercellularfunctions[88].
PKCactivationinRAGEsignalingplaysanimportantroleintheprogressionofdiseasessuchasdiabetesandAlzheimer's.
ImpairmentofinsulinactioninthemuscleismediatedthroughtheformationofamultimolecularcomplexincludingAGE/RAGE/IRS-1/SrcandPKCα.
ThiscomplexrequiresIRS-1,oneofthekeymoleculesininsulinsignaling.
PKCmediatestheformationofthiscomplex,whichinhibitinsulinactioninskeletalmusclecellsinvitroand,possibly,invivo[89].
AGE/RAGEinteractioncausesPKCmediatedNADPHoxidaseactivationthatleadstoincreasedretinalcapillarypermeability,whichisassociatedwithinitialstagesofmacularedemaanddiabeticretinopathy[90].
AGEassociatedRAGEexpressionisfoundtobesignificantlyincreasedincaseofdiabeticnephropathy.
NADPHoxidase,whichplaysanimportantroleinROSproduction,isactivatedbyAGE/RAGEinteraction.
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activatedbyPKCαmediatedphosphorylation,whichfurtherresultsinoxidativestress[91].
Conversely,AGE/RAGEmediatedROSproductionactivatesPKC,whichphosphorylatesp47phoxthatinturnactivatesNADPHoxidase,resultinginapositivefeedbackloopforROSproduction[92].
AGE/RAGEinteractionelevatesCx43expression,themajorconnexininventricularcardiomyocytesthroughactivationofPKCandERKpathway.
ItalsoenhancesCx43redistributioninvivo,whichmaycontributetothearrhythmiasindiabetes[93].
Indiabeticmononuclearphagocytes,RAGEactivatesPKCwhichphosphorylatespleckstrin,acriticalmoleculeforproinflammatorycytokinesecretion[94].
AGEscanaugmentinflammatoryresponsesbyup-regulatingCOX-2viaRAGEandPKC,ERKandp38MAPKsignalingpathways,therebyleadingtomonocyteactivationandvascularcelldysfunction[95].
Inneuronalcells,AGE/RAGEinteractioncausesapoptosisduetoactivationofNADPHoxidase,PKCdeltaandredoxsensitivetranscriptionfactorAP1[66].
RAGEplaysacrucialroleinactivationofepithelialsodiumchannel(ENaC)throughPKC-gp91phoxsignaling,whichregulateslungfluidbalance[96].
Phosphoinositide3kinases/Akt(PI3K/Akt)Phosphoinositide3kinases(PI3K)areaclassofenzymeswhichphosphorylatethethirdhydroxylgroupintheinositolringofphosphotidylinositols(PtdIns)presentontheinnerleafletofplasmamembrane.
ThereareeightdistinctPI3Kcatalyticsubunitsthatarecapableofphosphorylatinginositollipids.
PhosphorylationofPtdInsbyvariousPI3KsleadstoformationofPhosphatidylinositol3phosphate(PI(3)P),Phosphatidylinositol(3,4)-bisphosphate(PI(3,4)P2),andPhosphatidyl-inositol(3,4,5)-trisphosphate(PI(3,4,5)P3),whichareimportantsignalingmolecules.
Thesephosphoinositidesparticipateinsignaltransductionpathwaysbybindingtolipidbindingdomainslikethepleckstrindomainofwww.
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Akt/PKBandphosphoinositidedependentkinase-1(PDK1),zincfingerFYVEdomainandPXdomainsofproteins[97].
ActivationofPI3Kislinkedtoanincrediblydiversesetofkeycellularfunctions,includingcellgrowth,proliferation,motility,differentiation,survivalandintracellulartrafficking.
CellularPI3Kactivitiesarebalancedbyphosphoinositide3-phosphataseactivity,foundinthetumorsuppressorproteinPTENandinmembersofthemyotubularinfamily.
Alteredactivationofthesekinasesisassociatedwithvarioushumandiseasesincludingcancer.
PI3KsareactivateddownstreamtoGproteincoupledreceptors(GPCRs),receptortyrosinekinase(RTK),aswellasRAGE[98].
AGE/RAGEaxishasbeenreportedtotransactivateInsulinlikegrowthfactor1receptor(IGF-1R)causingactivationofPI3K/Aktin3T3adipocytesleadingtotheirdifferentiation.
UponbindingofAGEstoRAGE,itwasobservedthatRAGEcouplestoNADPHoxidasetostimulateSrckinase.
TheactivatedSrckinaseinturnphosphorylatesandactivatesIGF-1receptorandPI3K-Aktpathway.
ThisadipogenesiscausedduetoAGE/RAGEandactivationofPI3K/Aktcanleadtoobesity,orpredisposeapersontodiabetes,orcausediabeticcomplications[99].
Furthermore,activationofPI3KduetoAGE/RAGEhasbeenimplicatedindiabeticnephropathy,whichisassociatedwithdepositionofextracellularmatrixproteins(e.
g.
collagen)intheglomerularbasementmembrane.
AGE/RAGEinteractioncausedproductionofROSandactivationofSrckinasecausingPI3Kphosphorylation.
InterestinglyPI3KcauseddownstreamactivationofPKBandki-Ras,whichrecruitsERKarmoftheMAPK[100].
Diabeticnephropathyischaracterizedbyproteinuriawhichreflectsmalfunctioningofglomerularvisceralepithelialcells,namelypodocytes.
Clinicalandexperimentalevidenceshowsthatdiabeticnephropathyischaracterizedbypodocytehypertrophycausinganincreaseinslitlengthandwidth,andalsoreductioninthewww.
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numberofpodocytesperglomerulus[101,102].
AGE/RAGEsignalinginpodocyteshasbeenshowntocausepodocyteapoptosis.
Inculturedmurinepodocytes,AGE/RAGEaxiscausesdephosphorylationofAktensuingintranscriptionalactivationofFOXO4andtherebyapoptosis[36].
TherenninangiotensinsystemresponsibleformaintainingbloodvolumeandpressureisalsoaffectedbyAGE/RAGEsignalingtocausepodocyteapoptosis.
ThiseffectwasdependentonPI3K/Aktmediatedphosphorylation[103].
Indiabeticuremia,neutrophilsexhibitedanincreasedadhesiontoAGE-collagenthroughinteractionwithRAGEbyactivationofPI3K/Aktpathway[104].
ThePI3K/Akt/mTORpathwayisanegativeregulatorofautophagy.
AGEsinduceproliferationofrataorticvascularsmoothmusclecells(VSMCs)byinducingautophagyviainactivationofPI3K/Aktpathwaytherebyacceleratingatherosclerosisindiabeticconditions[105].
Inhumanumbilicalvascularendothelialcells(HUVECs),AGEscauseROSmediatedactivationofPI3K/Akt/IкB/NF-кBandJNK/AP1leadingtoincreasedexpressionofE-selectin,whichisassociatedwithprogressionofatherosclerosis[78].
HyperlipidemiaisshowntoincreasetheexpressionofHMGB1inserum,heartandlungtissuesofatheroscleroticmice,whichstimulatesRAGEsignalingthroughactivationofAktandproductionofproinflammatorycytokines[106].
Lectinlikeoxidizedlowdensitylipoproteinreceptor1(LOX1)isascavengerreceptorofoxidizedlowdensitylipoproteins(oxLDL),knowntobeelevatedinatheroscleroticplaquesandimplicatedintheinitiationandprogressionofatherosclerosis.
AGE/RAGEinteractionisproposedtocausetheupregulationofLOX1inaorticendothelialcellsbydownstreamactivationofPI3KwhichphosphorylatesmTORC2andAkt,indirectlyplayingaroleinatherosclerosis[107].
Indiabeticcardiovascularwww.
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disorders,AGE/RAGEinteractioninducestheexpressionofheparinaseandPI3K/Aktphosphorylationleadingtomigrationofmacrophages[108].
Indorsalrootgangliasensoryneurons,S100B/RAGEinteractionactivatesPI3K/AktandERKpathways,whichfurthercauseslipidperoxidationandcaspase-3activationresultinginneuronaldamage[109].
S100B/RAGEinteractionincreasestheexpressionandreleaseofchemokinesinmicrogliaresultinginactivationofSrc/Ras/PI3K/RhoA/ROCKpathwayalongwithp38,ERK,JNK-AP1andNF-кB[82].
Incarcinogenesis,hypoxiainducedexpressionofRAGEandP2X7RcausedincreasedphosphorylationofAktandERK,andNF-кBnucleartranslocation.
Further,NF-кBincreasedtheexpressionofMMP2and9contributingtocellularinvasivenessuponHMGB1treatment[110].
HMGB1/RAGEinteractionleadstogrowth,migrationandinvasionofcolorectalcarcinomacellsbythephosphorylationofERK1/2,Rac1,AktandproductionofMMP9.
WhereasAGEsledtotheproductionofiNOSandNF-кBp65toagreaterextentthanHMGB1highlightingthedifferentialeffectsofboththeligandsandsuggestingamorecloseassociationofHMGB1withcancer[111].
BindingofHMGB1toRAGEandTLR4inlungcancercellsisshowntocausetheactivationofPI3K/AktandERK1/2leadingtoincreasedproliferation.
Thiseffectwasobservedduetodecreasedexpressionofpro-apoptoticBaxproteinandincreasedlevelsofanti-apoptoticBcl-2protein[112].
TreatmentofCML-BSAtoHEK293causedphosphorylationofthep66adaptorproteintocausedownstreamphosphorylationofAkt.
ActivatedAktcausesthephosphorylationofforkheadtranscriptionfactor3referredtoasFKHRL1leadingtoitsinactivationandpreventingitsnucleartranslocationtherebysuppressingtheexpressionofmanganesesuperoxidedismutase(MnSOD).
DownregulationofMnSODfacilitatesROSproduction.
TheseeffectsweresuppressedinAGEReceptor-1(AGER1)overexpressingwww.
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HEK293cellssuggestingtheprotectiveeffectofAGER-1againstoxidativestresscausedbyAGE/RAGEinteraction[113].
S100A8/A9causesgrowthofnormalaswellastransformedhumanepidermalkeratinocytesbyinteractionwithRAGE/DNAX-activatingprotein(DAP10)heterodimersanddownstreamactivationofAkt.
Thisinteractioninducedapoptosisbyactivationofcaspase8innormalhumanepidermalkeratinocytes,whereassustainedgrowthwasobservedinthetransformedcelllinesHaCaTandA431duetoenhancedactivationofAkt,suggestingvariableeffectsofAktdownstreamtoRAGE/DAP10[114].
JanusActivatedkinase(JAK)JAKisafamilyoftyrosinekinasesthatactivatesignaltransducersandactivatorsoftranscription(STAT)inresponsetocytokinesandgrowthfactorsaswellasbyRAGEactivation.
JAKphosphorylatesSTATresultinginitsdimerizationandnucleartranslocation.
STATregulatestheexpressionofgenesinvolvedinantiviraldefence,embryogenesis,cellgrowth,cellsurvival,andcellmotility[115-120].
ConstitutiveactivationofmembersofSTATfamilyisassociatedwithseveraltypesofcancers.
TyrosinephosphorylatedSTAT1,3,and5arepersistentlyfoundinmostofthemalignancies.
AGE/RAGEaxisactivatesJAKinmyeloidleukemiawhereitinducesSTAT3phosphorylation[121-124].
RAGEpromotespancreaticcancerbyregulatingconjugationofATG12-ATG5,autophagyrelatedproteins;andBECN1-PIK3C3(Beclin1-Phosphatidylinositol3-kinasecatalyticsubunittype3)complexformation,whichresultsinsecretionofIL6,andmitochondrialSTAT3activation[125,126].
AGE/RAGEinteractionincreasestyrosinephosphorylationofHsp70,cyclinE,andcyclinD1inJAKdependentmanner.
ItalsoincreasesHsp70proteininteractionwithSTAT1,STAT3,STAT5b,cyclinD1,andcyclinE.
ThesefindingsindicatethatAGEsinducemitogenesisbyactivatingtheJAK2,STAT1,STAT3,andSTAT5-www.
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cyclinD1pathwayinNRK-49Fcells[127].
Whileinhepatocytes,RAGEshowsanti-tumoureffectsbydecreasingp65levels,NF-кBactivation,cyclinD1productionandIL6mediatedSTAT3phosphorylation,therebydownregulatingPim1andsuppressingthehyperplasticresponse.
BlockadeofRAGErescuesliverremnantsfromadaptiveproliferationtriggeredbyMyd88signaling[128].
Indiabeticnephropathy,JAK2-STAT1/STAT3pathwayisinvolvedinAGE-inducedtype-1collagenproductioninkidneyfibroblastcells,whichisconsideredasamajorcauseofrenalfibrosis[129].
JAK/STATsignalingisalsoinvolvedinthedevelopmentofosteoarthritis.
IL-7activatesJAK/STATpathwayinchondrocytesleadingtoincreasedsecretionofS100A4whichinteractswithRAGEinautocrinemannerandstimulatesMMP13production[130].
AGEinducesactivationofMMP13,disintegrinandmetalloproteinasewiththrombospondinmotifs(ADAMTS)inaJAK/STAT3dependentmanner,whichisinvolvedincollagenIIandproteoglycanproductionandcontributestoosteoarthritis[131].
Duringembryogenesis,RAGEisinvolvedinneuronaldifferentiation.
LigandssuchasHumanglycatedalbumin,S100BandHMGB1arefoundtoincreasetheneuritegrowth.
TheseligandsactivateJAK/STAT,ERKandNF-кBwhichplayanimportantroleinaxonaloutgrowth[132].
GlycogenSynthaseKinase-3beta(GSK3β)GSK3βisaprolinedirectedserine/threoninekinase.
Itwasinitiallyidentifiedasakinasethatphosphorylatesglycogensynthase,akeyenzymeinglycogensynthesis[133,134].
Apartfromitsinvolvementinglycogensynthesis,itplaysanimportantroleinseveralbiologicalprocessessuchasdifferentiation,neurogenesis,cellfatedetermination,proliferation,andsurvival[135].
GSK3βactivityisdeterminedbyitsphosphorylationstatus;phosphorylationofser9decreasesitsactivity,whereasdephosphorylationactivatesit.
Itsactivityisalsowww.
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enhancedbyphosphorylationoftyrosine216[136-138].
GSK3βphosphorylationisregulatedbyseveralkinasesincludingERKs,MAPKAPK-1,Akt,fewisoformsofPKC,proteinkinaseAandp70S6kinase.
Itisassociatedwithnumerousdisordersincludingdiabetes,cardiovasculardisorders,Parkinson's,Alzheimer'sdisease,amyotrophiclateralsclerosis,multiplesclerosisandcancer[139-141].
AGE/RAGEdependentGSK3βactivationinducesTauhyperphosphorylationinSK-N-SHcells,primaryhippocampalcellsandratbrain.
Inneuronalcells,AGE/RAGEinteractionleadstoactivationofGSK3β,ERK,p38MAPK,whichareassociatedwithmemorydeterioration,declineofsynapticproteins,andimpairmentoflong-termpotentiation.
BlockadeofRAGEattenuatedalltheAGEinducedimpairments,suggestingavitalroleofAGE/RAGEmediatedGSK3βstimulationinprogressionofAlzheimer'sdisease[142,143].
MethylglyoxalinducesGSK3βandp38MAPKactivationwhichleadstotauhyperphosphorylationinNeuro-2acells[144,145].
ThisisperhapsduetoincreasedRAGEsignalingasaresultofAGEformationpromotedbymethylglyoxal.
Apartfromtaupathology,GSK3βisalsoinvolvedinAβsynthesisandapoptoticneuronaldeath,whicharethemajorhallmarksofAD[146].
AGE/RAGEinteractionleadstoGSK3βactivationduringhypoxia/reoxygenationofcardiomyocyte[70].
AGEaccumulationandRAGEexpressionissignificantlyincreasedindiabeticratswithcardiomyopathyalongwithmarkedincreaseinGSK3βactivitywhichisreducedaftercurcumintreatmentbyAktphosphorylation[147].
However,therearenostudiesshowingRAGEdependentGSK3βactivationwithrespecttootherRAGEligandsincludingAβ,HMGB1andS100B,whicharefoundtobesignificantlyincreasedinAlzheimer'sdisease,cardiovasculardisordersandcancer[148-151].
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AnalysisofglobalphosphoproteomeinRAGEsignalingRAGEcanpotentiallyinteractwithmultipleligandsandactivateseveraldifferentsignaltransductionpathwaysinvolvingvariousproteinkinasesasdescribedabove.
Thesekinasesphosphorylatedownstreamsignalingmoleculesandcausespecificcellularresponse.
Askinaseshavemultiplesubstrates,thephosphorylationofasubstratedependsonitsexpression,localization,andcelltype.
OnesuchexampleisGSK3β,whichphosphorylatesglycogensynthaseinhepatocytesandregulatesglycogenmetabolism.
Whereas,inhumanembryonickidneycells(HEK293T),itphosphorylatesbetacateninrenderingittoproteasomaldegradation[152],andinneuronalcells,GSK3βactsdownstreamtoRAGEandhyperphosphorylatestaucausingneuronaldamage.
ThisobservationimpelledustoanalysephosphorylationsubstratesofkinasesinvolvedinRAGEsignaling.
Here,wehavefocusedonfewmajorkinases,namelyPKC,ERK,PI3K/Akt,p38,JAK,GSK3βandJNK,allofwhichareknowntoactdownstreamofRAGE.
AcomprehensivelistofproteinsubstratesforthesekinaseswasminedfromPhosPhoSitePlusdatabase[153].
Adetailedworkflowofdataminingandanalysisofphosphosubstratesisdepictedintheflowchart(Fig3).
Altogether,1045differentsubstrateswerefoundtobeassociatedwiththese7kinases(SupplementaryFig1).
Amongstthese7kinases,PKCandERKappeartophosphorylatemaximumnumberofsubstrates,andsignificantnumbersofthesephosphosubstratesareuniquetothesetwokinases(SupplementaryTable1and2),manyarealsosharedwithotherkinases.
Oneinterestingexampleisp21Cip1(p21Waf1),aproteininvolvedincellcycleregulation,wasfoundtobephosphorylatedbysixdifferentkinasesinthisanalysis.
Interestingly,itwasalsoshowntobephosphorylatedinresponsetoRAGEmediatedsignaling.
Overexpressionofwww.
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RAGEcausedsignificantincreaseinp21Waf1induction,whichregulatescellproliferationinL6myoblasts[40].
Further,wehaveanalyzedtheassociationofthesephosphosubstrateswithdiseasessuchascancer,diabetes,cardiovascularandneurodegenerativediseases(Fig4).
Outofthe1045phosphosubstrates,thereare772,65,27and10phosphosubstratesfoundtobeassociatedwithcancer,neurodegenerativediseases,diabetesandcardiovasculardisordersrespectively(Fig3,SupplementaryTable3).
AninterestingobservationisthatthenumberofphosphosubstratesassociatedwithcancerisquitelargeandmanyofthesecanbepotentiallyphophorylatedbyrespectivekinasesinresponsetoRAGEactivation.
Insupportofthisnotion,involvementofRAGEincancerisbecomingincreasinglyevidentfromseveralstudies[44-53].
ERK2,akeyplayerinMAPKsignalingistheonlyphosphosubstratethatisassociatedwithallfourdiseases.
Inaddition,wehaveidentified11phosphosubstratesassociatedwiththreeofthediseases,whichincludeMARCKS,MAP4,Tau-8,Akt1,GSK3β,eNOS,ERK1,p70S6K,JNK1,AMPKA1andCREB.
ExceptMARCKSandMAP4,allotherproteinsareshowntobeinvolvedinRAGEsignaling,whichsupportsthisanalysis.
Tauiso8andMAP4arecytoskeletalproteinswhichplayanimportantroleinmicrotubuleassembly.
FunctionallossofTauiso8isassociatedwithseveralneurodegenerativedisordersincludingfrontotemporaldementia,Alzheimer'sdisease,pick'sdiseaseetc[154].
Endothelialnitricoxidesynthase(eNOS)producesnitricoxideinbloodvesselsandactsasaregulatorofenergymetabolisminthebody.
Itisassociatedwithseveraldisordersincludingdiabetes,hypertension,cancer,Alzheimer's,cardiovasculardisease,stroke,andatherosclerosis[155].
AGEshaveshowntoreduceeNOSphosphorylationanddown-regulationviaRAGEcausingendothelialdysfunction[156,157].
p70S6Kisaserinethreoninekinasethatactswww.
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downstreamtoPI3K/Akt/mTORpathway.
Itphosphorylatesribosomalproteinandinducesproteinsynthesis.
ChronicintakeofAGEsmediatesp70S6KphosphorylationandRAGEup-regulationinrats.
Itisimplicatedinmultiplediseasesincludinginsulinresistance,skeletalmusclehypertrophyaswellasageing[158-160].
AMPKA1isacatalyticsubunitofAMPactivatedproteinkinaseknowntobeinvolvedinseveralbiologicalprocessessuchaslipidbiosynthesis,glucosehomeostasis,apoptosis,signaltransductionetc.
AβinducestheformationofautophagosomesinbrainsofAPP/PS1transgenicmiceaswellasinSH-SY5YcellsbyinteractionwithRAGEbyAMPKactivation[161,162].
CREBisatranscriptionfactorwhichbindswiththecAMPresponsiveelementandregulatestheexpressionofseveralgenes.
DeregulationofCREBfunctionisassociatedwithdisorderslikeAlzheimer'sdisease,huntington'sdiseaseandcancer.
AmphoterininducedCREBphosphorylationviaRAGEisinvolvedintheexpressionofchromograninsAandBinneuroblastomacellsleadingtotheirdifferentiation[163-165].
Myristoylatedalanine-richC-kinasesubstrate(MARCKS)isanacidicproteininvolvedintheregulationofcellproliferation,cellularsecretionandtransport,cellintegrityandmotility.
ThephosphorylationstatusofthisproteininRAGEsignalingneedstobeinvestigated[166,167].
ThisanalysisclearlysuggestedthatRAGEmediatedkinaseactivationcanpotentiallyresultinphosphorylationofseveraloftheirsubstrates.
Thepossibilityofaproteingettingphosphorylatedismorewhenitisasharedasasubstratebymultiplekinases.
Therefore,itisimportantnottounderminetheinvolvementofvariousknownsubstratesofthekinasesactivatedinRAGEsignaling.
Inconclusion,thisreviewemphasizesonthevitalroleofRAGEsignalinginvariouscellularprocessessuchasproliferation,apoptosis,migration,inflammation,immuneresponse,autophagyetc,andprovidesinsightintheplausibleroleofRAGEactivatedphosphoproteomeinseveraldiseases.
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Acknowledgement:ThisworkissupportedbyCSIR-NetworkProjectBSC0111.
KBB,SBBandRSKacknowledgeCSIRandUGCforresearchfellowship.
GVPisgratefultoLadyTataMemorialTrustforaresearchfellowship.
Theauthorshavedeclarednoconflictofinterest.
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Figure1.
SchematicrepresentationofRAGEanditsisoforms(esRAGE-endogenoussecretoryRAGE,sRAGE-solubleRAGE,flRAGE-fulllengthRAGE)www.
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Figure2.
DepictionofRAGEactivatedsignalingpathwayindifferentdiseases.
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Figure3.
WorkflowusedtoanalyzethesubstratesofRAGEactivatedkinasesfromPhosphositeplusdatabasewww.
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Figure4.
TheplotdepictsassociationofphosphosubstrateswithdifferentdiseasesandRAGEactivatedkinases,andcolourcodeindicatesthediseaseassociation.
ForexampleERK2isasubstrateforERKandJNK,andisassociatedwithallfourdiseases.