T-cell receptor is a protein complex found on T cells that is responsible for recognizing fragments of antigens bound to MHC molecules. It is composed of two protein chains, usually an alpha and beta chain, that form the ligand-binding site. The TCR complex also includes CD3 proteins that contain immunoreceptor tyrosine-based activation motifs involved in signal transduction upon TCR engagement with antigenic peptide-MHC complexes. TCR diversity arises from genetic recombination during T cell development in the thymus. Each recombined TCR confers unique antigen specificity determined by the antigen-binding site formed by its alpha and beta chains.

1. T-cell receptor
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CD3 zetachainand FCER1G family
TCRComplex.png
The T-cell receptorcomplex withTCR-α andTCR-βchains,CD3 andζ-chain(CD247) accessorymolecules.
Identifiers
Symbol TCR_zetazeta
Pfam PF11628
InterPro IPR021663
OPMsuperfamily 166
OPMprotein 2hac
Membranome 26
Available proteinstructures:
AntigenpresentationstimulatesTcellstobecome either"cytotoxic"CD8+cellsor"helper"CD4+ cells.
T-cell receptoralphalocus
Identifiers
Symbol TRA
Alt.symbols TCRA,TRA@
NCBIgene 6955
HGNC 12027
OMIM 186880
Otherdata

2. Locus Chr. 14 q11.2
T-cell receptorbetalocus
Identifiers
Symbol TRB
Alt.symbols TCRB, TRB@
NCBIgene 6957
HGNC 12155
OMIM 186930
Otherdata
Locus Chr. 7 q34
T-cell receptordeltalocus
Identifiers
Symbol TRD
Alt.symbols TCRD, TRD@, TCRDV1
NCBIgene 6964
HGNC 12252
Otherdata
Locus Chr. 14 q11.2
T-cell receptorgammalocus
Identifiers
Symbol TRG
Alt.symbols TCRG, TRG@
NCBIgene 6965
HGNC 12271
Otherdata
Locus Chr. 7 p14
The T-cell receptor(TCR) isa proteincomplex foundonthe surface of T cells,orT lymphocytes,[1] thatis
responsible forrecognizingfragmentsof antigenaspeptidesboundtomajorhistocompatibilitycomplex
(MHC) molecules.The bindingbetweenTCRand antigenpeptidesisof relativelylow affinityandis

3. degenerate:thatis,manyTCRsrecognize the same antigenpeptide andmanyantigenpeptidesare
recognizedbythe same TCR.[2]
The TCR iscomposedof twodifferentproteinchains(thatis,itis a heterodimer).Inhumans,in95%of T
cellsthe TCR consistsof an alpha(α) chainand a beta(β) chain (encodedbyTRA andTRB, respectively),
whereasin5% of T cellsthe TCRconsistsof gamma and delta(γ/δ) chains(encodedbyTRG andTRD,
respectively).Thisratiochangesduringontogenyandindiseasedstates(suchasleukemia).Italso
differsbetweenspecies.Orthologuesof the 4 loci have beenmappedinvariousspecies.[3][4] Eachlocus
can produce a varietyof polypeptideswithconstantandvariableregions.[3]
Whenthe TCR engageswithantigenicpeptide andMHC(peptide/MHC),the Tlymphocyte isactivated
throughsignal transduction,thatis,a seriesof biochemical eventsmediatedbyassociatedenzymes,co-
receptors,specializedadaptormolecules,andactivatedorreleasedtranscriptionfactors.Basedonthe
initial receptortriggeringmechanism, the TCRbelongstothe familyof non-catalytictyrosine-
phosphorylatedreceptors(NTRs).[5]
Contents
1 History
2 Structural characteristics
3 Generationof the TCR diversity
4 The TCR complex
5 Antigendiscrimination
6 Signalingpathway
6.1 Receptoractivation
6.2 Proximal TCRsignaling
6.3 Signal transductiontothe nucleus
6.3.1 NFAT
6.3.2 NF-κB
6.3.3 AP1
7 See also
8 References

4. 9 External links
History
In 1982, Nobel laureate JamesP.Allisonfirstdiscoveredthe T-cellreceptor.[6] Then,TakWahMak[7]
and Mark M. Davis[8] identifiedthe cDNA clonesencodingthe humanandmouse TCRrespectivelyin
1984. These findingsallowedthe entityandstructure of the elusive TCR,knownbefore asthe "Holy
Grail of Immunology",tobe revealed.Thisallowedscientistsfromaroundthe worldtocarry out studies
on the TCR, leadingtoimportantstudiesinthe fieldsof CAR-T,cancerimmunotherapyandcheckpoint
inhibition.
Structural characteristics
The TCR isa disulfide-linkedmembrane-anchoredheterodimericproteinnormallyconsistingof the
highlyvariable alpha(α) andbeta(β) chainsexpressedaspartof a complex withthe invariantCD3chain
molecules.Tcellsexpressingthisreceptorare referredtoasα:β (orαβ) T cells,thougha minorityof T
cellsexpressanalternate receptor,formedbyvariablegamma(γ) anddelta(δ) chains,referredasγδT
cells.[9]
Each chain iscomposedof twoextracellulardomains:Variable (V) regionandaConstant(C) region,both
of Immunoglobulinsuperfamily(IgSF) domainformingantiparallelβ-sheets.The Constantregionis
proximal tothe cell membrane,followedbyatransmembrane regionanda shortcytoplasmictail,while
the Variable regionbindstothe peptide/MHCcomplex.
The variable domainof boththe TCR α-chainandβ-chaineachhave three hypervariableor
complementarity-determiningregions(CDRs).There isalsoanadditional areaof hypervariabilityonthe
β-chain(HV4) that doesnotnormallycontactantigenand,therefore,isnotconsideredaCDR.[citation
needed]
The residuesinthese variabledomainsare locatedintworegionsof the TCR,at the interface of the α-
and β-chainsandinthe β-chainframeworkregionthatisthoughttobe in proximitytothe CD3 signal-
transductioncomplex.[10] CDR3isthe mainCDR responsible forrecognizingprocessedantigen,
althoughCDR1 of the alphachainhas alsobeenshowntointeractwiththe N-terminal partof the
antigenicpeptide,whereasCDR1of the β-chaininteractswiththe C-terminal partof the peptide.
CDR2 isthoughtto recognize the MHC.CDR4 of the β-chainisnot thoughttoparticipate inantigen
recognition,buthasbeenshowntointeractwith superantigens.

5. The constant domainof the TCR consistsof short connectingsequencesinwhichacysteine residue
formsdisulfidebonds,whichformalinkbetweenthe twochains.
The TCR isa memberof the immunoglobulinsuperfamily,alarge groupof proteinsinvolvedinbinding,
recognition,andadhesion;the familyisnamedafterantibodies(alsocalledimmunoglobulins).The TCR
issimilartoa half-antibodyconsistingof a single heavyandsinglelightchain,exceptthe heavychainis
withoutitscrystallisable fraction(Fc).The twosubunitsof TCRare twistedtogether.Whereasthe
antibodyusesitsFc regiontobindto Fc Receptorsonleukocytes,TCRisalreadydockedontothe cell
membrane.However,itisnotable to mediate signal transductionitself due toitsshortcytoplasmictail,
so TCR still requiresCD3andzeta to carry out the signal transductioninitsplace[citationneeded],just
as antibodiesrequire bindingtoFcRs to initiate signaltransduction.Inthiswaythe MHC-TCR-CD3
interactionforT cellsisfunctionallysimilartothe antigen(Ag)-immunoglobulin(Ig)-FcRinteractionfor
myeloidleukocytes,andAg-Ig-CD79interactionforBcells.
Generationof the TCR diversity
The generationof TCR diversityissimilartothatfor antibodiesand B-cellantigenreceptors.Itarises
mainlyfromgeneticrecombinationof the DNA-encodedsegmentsinindividual somaticTcellsby
somaticV(D)JrecombinationusingRAG1andRAG2 recombinases.Unlike immunoglobulins,however,
TCR genesdonot undergosomatichypermutation,andTcellsdonot expressactivation-induced
cytidine deaminase(AID).The recombinationprocessthatcreatesdiversityinBCR(antibodies) andTCRis
unique tolymphocytes(TandB cells) duringthe earlystagesof theirdevelopmentinprimarylymphoid
organs (thymusforT cells,bone marrowforB cells).
Each recombinedTCRpossessunique antigenspecificity,determinedbythe structure of the antigen-
bindingsite formedbythe α andβ chainsin case of αβT cellsorγ and δ chainson case of γδT cells.[11]
The TCR alphachainis generatedbyVJrecombination,whereasthe betachainisgeneratedbyVDJ
recombination(bothinvolvingarandomjoiningof gene segmentstogeneratethe completeTCRchain).
Likewise,generationof the TCRgamma chaininvolvesVJrecombination,whereasgenerationof the TCR
deltachainoccurs by VDJrecombination.
The intersectionof these specificregions(V andJforthe alphaor gamma chain;V,D, and J for the beta
or deltachain) correspondstothe CDR3 regionthatisimportantforpeptide/MHCrecognition(see
above).
It isthe unique combinationof the segmentsatthisregion,alongwithpalindromicandrandom
nucleotide additions(respectivelytermed"P-"and"N-"),whichaccountsforthe evengreaterdiversity
of T-cell receptorspecificityforprocessedantigenicpeptides.

6. Later duringdevelopment,individualCDRloopsof TCR can be re-editedinthe peripheryoutside thymus
by reactivationof recombinasesusingaprocesstermedTCRrevision(editing) andchange itsantigenic
specificity.
The TCR complex
In the plasmamembrane the TCRreceptorchainsα and β associate withsix additional adaptorproteins
to forman octamericcomplex.The complex containsbothα andβ chains,formingthe ligand-binding
site,andthe signalingmodulesCD3δ,CD3γ,CD3ε and CD3ζ inthe stoichiometryTCRα β - CD3εγ -
CD3εδ - CD3ζζ. Chargedresiduesinthe transmembrane domainof eachsubunitformpolarinteractions
allowingacorrect andstable assemblyof the complex.[12] The cytoplasmictail of the TCR isextremely
short,hence the CD3 adaptorproteinscontainthe signallingmotifsneededforpropagatingthe signal
fromthe triggeredTCRintothe cell.The signallingmotifsinvolvedinTCRsignallingare tyrosine residues
inthe cytoplasmictail of these adaptorproteinsthatcanbe phosphorylatedinthe eventof TCR-pMHC
binding.The tyrosine residuesreside inaspecificaminoacidsequence of the signature Yxx(L/I)x6-
8Yxx(L/I),where Y,L,I indicate tyrosine,leucine andisoleucine residues,x denotesanyaminoacids,the
subscript6-8 indicatesasequence of 6 to 8 aminoacidsinlength.Thismotif isverycommoninactivator
receptorsof the non-catalytictyrosine-phosphorylatedreceptor(NTR) familyandisreferredto as
immunoreceptortyrosine-basedactivationmotif (ITAM).[5] CD3δ,CD3γ andCD3ε eachcontaina single
ITAM, while CD3ζcontainsthree ITAMs.In total the TCR complex contains10ITAMs.[12]
PhosphorylatedITAMsact as bindingsite forSH2-domainsof additionallyrecruitedproteins.
Antigendiscrimination
T-cell receptorcomplexedwithMHCI and II
Each T cell expressesclonal TCRswhichrecognizeaspecificpeptide loadedonaMHC molecule (pMHC),
eitheronMHC classII onthe surface of antigen-presentingcellsorMHC classI on any othercell
type.[13] A unique feature of Tcellsistheirabilitytodiscriminatebetweenpeptidesderivedfrom
healthy,endogenouscellsandpeptidesfromforeignorabnormal (e.g.infectedorcancerous) cellsinthe
body.[14] Antigen-presentingcellsdonotdiscriminatebetweenself andforeignpeptidesandtypically
expressalarge numberof self-derivedpMHCsontheircell surface andonlya few copiesof anyforeign
pMHC. For example,cellsinfectedwithHIV have only8-46 HIV-specificpMHCs,comparedwith100000
total pMHCs, per cell.[15][16]
Because T cellsundergopositive selectioninthe thymus,there isanon-negligible affinitybetweenself-
pMHC andthe TCR. Nevertheless,the T-cell receptorsignallingshouldnotbe activatedbyself-pMHCso
that endogenous,healthycellsare ignoredbyTcells.However,whentheseverysame cellscontaineven
minute quantitiesof pathogen-derivedpMHC,Tcellsmustgetactivatedand initiate immune responses.

7. The abilityof T cells toignore healthycellsbutrespondwhenthese same cellsexpressasmall number
of foreignpMHCsisknownas antigendiscrimination.[17][18]
To do so,T cellshave a veryhighdegree of antigenspecificity,despite the factthatthe affinitytothe
peptide/MHCligandisratherlowincomparisontootherreceptortypes.[19] The affinity,givenasthe
dissociationconstant(Kd),betweenaTCR and a pMHC wasdeterminedbysurface plasmonresonance
(SPR) tobe inthe range of 1-100 μM, withanassociationrate (kon) of 1000 -10000 M−1 s−1 and a
dissociationrate (koff) of 0.01 -0.1 s−1.[20] In comparison,cytokineshave anaffinityof KD= 10-600 pM
to theirreceptor.[21] Ithas beenshownthatevenasingle aminoacidchange inthe presentedpeptide
that affectsthe affinityof the pMHCto the TCR reducesthe T cell response andcannotbe compensated
by a higherpMHC concentration.[22] A negative correlationbetweenthe dissociationrate of the pMHC-
TCR complex andthe strengthof the T cell response has beenobserved.[23] Thatmeans,pMHCthat
bindthe TCR for a longertime initiate astrongeractivationof the Tcell.Furthermore,Tcellsare highly
sensitive;interactionwithasingle pMHCisenoughtotriggeractivation.[24] Tcellsmove onquickly
fromantigensthatdo not triggerresponses,rapidlyscanningpMHCon an antigen-presentingcell (APC)
to increase the chance of findingaspecificpMHC.On average,a T cell encounters20 APCsperhour.[25]
Differentmodelsforthe molecularmechanismsthat underlie thishighlyspecificandhighlysensitive
processof antigendiscriminationhave beenproposed.The occupational model simplysuggeststhatthe
TCR response isproportional tothe numberof pMHC boundto the receptor.Giventhismodel,ashorter
lifetimeof apeptide canbe compensatedbyhigherconcentrationsuchthatthe maximumresponse of
the T cell staysthe same.However,thiscannotbe seeninexperimentsandthe model hasbeenwidely
rejected.[23] The mostacceptedviewisthatthe TCR engagesinkineticproofreading.The kinetic
proofreadingmodelproposesthata signal isnotdirectlyproduceduponbindingbuta seriesof
intermediate stepsensure atime delaybetweenbindingandsignal output.Suchintermediate
"proofreading"stepscanbe multiple roundsof tyrosine phosphorylation.These stepsrequire energy
and therefore donothappenspontaneously,onlywhenthe receptorisboundtoitsligand.Thisway
onlyligandswithhighaffinitythatbindthe TCRfor a longenoughtime can initiate asignal.All
intermediate stepsare reversible,suchthatuponliganddissociationthe receptorrevertstoitsoriginal
unphosphorylatedstate before anewligandbinds.[26] Thismodel predictsthatmaximumresponse of T
cellsdecreasesforpMHCwithshorterlifetime.Experimentshave confirmedthismodel.[23] However,
the basic kineticproofreadingmodel hasatrade-off betweensensitivityandspecificity.Increasingthe
numberof proofreadingstepsincreasesthe specificitybutlowersthe sensitivity of the receptor.The
model istherefore notsufficienttoexplainthe highsensitivityandspecificityof TCRsthathave been
observed.(AltanBonnet2005) Multiple modelsthatextendthe kineticproofreadingmodel have been
proposed,butevidence forthe modelsisstill controversial.[14][27][28]
The antigensensitivityishigherinantigen-experiencedTcellsthaninnaive T cells.Naive Tcellspass
throughthe processof functional aviditymaturationwithnochange inaffinity.Itisbasedonthe fact
that effectorandmemory(antigen-experienced) Tcell are lessdependentoncostimulatorysignalsand
higherantigenconcentrationthannaive Tcell.[29]

8. Signalingpathway
The essential functionof the TCRcomplex isto identifyspecificboundantigenderivedfromapotentially
harmful pathogenandelicitadistinctandcritical response.Atthe same time ithasto ignore anyself-
antigenandtolerate harmlessantigenssuchasfoodantigens.The signal transductionmechanismby
whicha T cell elicitsthisresponseuponcontactwithitsunique antigenistermedT-cell activation.Upon
bindingtopMHC, the TCR initiatesasignallingcascade,involvingtranscriptionfactoractivationand
cytoskeletal remodellingresultinginTcell activation.ActiveTcellssecrete cytokines,undergorapid
proliferation,have cytotoxicactivityanddifferentiate intoeffectorandmemorycells.Whenthe TCRis
triggered,Tcellsforman immunological synapseallowingthemtostayin contact withthe antigen
presentingcell forseveral hours.[30] Ona populationlevel,Tcell activationdependsonthe strengthof
TCR stimulation,the dose–response curve of ligandtocytokine productionissigmoidal.However,Tcell
activationona single cell level canbe characterisedbya digital switch-likeresponse,meaningthe Tcell
isfullyactivatedif the stimulusishigherthana giventhreshold,otherwise the Tcell stayinits non-
activatedstate.There isnointermediateactivationstate.The robustsigmoiddose-response curve on
populationlevel resultsfromindividualTcellshavingslightlydifferentthresholds.[22]
T cellsneedthree signalstobecome fullyactivated.Signal 1isprovidedbythe T-cell receptorwhen
recognisingaspecificantigenonaMHC molecule.Signal 2comesfromco-stimulatoryreceptorssuchas
CD28, presentedonthe surface of otherimmune cells.Itisexpressedonlywhenaninfectionwas
detectedbythe innate immune system,itisa"Dangerindicatingsignal".Thistwo-signalsystemmakes
sure that T cellsonlyrespondtoharmful pathogensandnotto self-antigens.Anadditional thirdsignalis
providedbycytokines,whichregulatethe differentiationof Tcellsintodifferentsubsetsof effectorT
cells.[30] There are myriadmoleculesinvolvedinthe complex biochemical process(calledtrans-
membrane signaling) bywhichT-cellactivationoccurs.Below,the signallingcascade isdescribedin
detail.
Receptoractivation
The initial triggeringfollowsthe mechanismcommonforall NTRreceptorfamilymembers.Once the
TCR bindsa specificpMHC,the tyrosine residuesof the Immunoreceptortyrosine-basedactivation
motifs(ITAMs) initsCD3 adaptor proteinsare phosphorylated.The residuesserve asdockingsitesfor
downstreamsignallingmolecules,whichcanpropagate the signal.[31][32] Phosphorylationof ITAMsis
mediatedbythe Src kinase Lck.Lck is anchoredtothe plasmamembrane byassociatingwiththe co-
receptorCD4 or CD8, dependingonthe T cell subtype.CD4isexpressedonhelperTcellsandregulatory
T cells,andis specificforMHC classII. CD8, on the otherhand,specificforMHC class I,is expressedon
cytotoxicT cells.Bindingof the co-receptortothe MHC bringsLck in close proximitytothe CD3 ITAMs. It
has beenshownthat40% of Lck is active evenbefore the TCRbindspMHCand therefore hasthe ability
to constantlyphosphorylate the TCR.[33] TonicTCR signallingisavoidedbythe presenceof phosphatase
CD45 that removesphosphorylationfromtyrosineresiduesandinhibitssignal initiation.Uponbinding
the balance of kinase activitytophosphatase activityisperturbed,leadingtoa surplusof

9. phosphorylationandinitiationof the signal.How suchperturbationisaccomplishedbyTCRbindingis
still debated.Mechanismsinvolvingconformational change of TCR,TCR aggregationandkinetic
segregationhave beensuggested.[31] Tyrosine kinase Fynmightbe involvedinITAMphosphorylation
but isnot essential forTCRsignalling.[34][35]
Proximal TCRsignaling
PhosphorylatedITAMsinthe cytoplasmic tailsof CD3 recruitproteintyrosine kinase Zap70that can bind
to the phosphorylatedtyrosine residueswithitsSH2domain.ThisbringsZap70 intoclose proximityto
Lck whichresultstoits phosphorylationandactivationbyLck.[36] Lck phosphorylatesa numberof
differentproteinsinthe TCRpathway.[37] Once activated,Zap70isable to phosphorylate multiple
tyrosine residuesof the transmembraneproteinLAT.LATisa scaffoldproteinassociatedwiththe
membrane.Ititself doesnothave anycatalytic activitybutitprovidesbindingsitesforsignalling
moleculesviaphosphorylatedtyrosineresidues.LATassociateswithanotherscaffoldingproteinSlp-76
viathe Grap2 adaptor protein,whichprovidesadditional bindingsites.TogetherLATand Slp-76provide
a platformforthe recruitmentof manydownstreamsignallingmolecules.Bybringingthese signalling
moleculesintocloseproximity,theycanthenbe activatedbyLck, Zap70 andotherskinases.Therefore,
the LAT/Slp76 complex actas a highlycooperative signalosome.[36]
Moleculesthatbindthe LAT/Slp76complex include:Phospholipase Cγ1(PLCγ1),SOSviaa Grb2 adaptor,
Itk,Vav,Nck1 and Fyb.[36]
Signal transductiontothe nucleus
PLCγ is a veryimportantenzyme inthe pathwayasit generatessecondmessengermolecules.Itis
activatedbythe tyrosine kinase Itkwhichisrecruitedtothe cell membrane bybindingto
Phosphatidylinositol(3,4,5)-trisphosphate (PIP3).PIP3isproducedbythe actionof Phosphoinositide3-
kinase(PI-3K),whichphosphorylatesPhosphatidylinositol4,5-bisphosphate (PIP2) toproduce PIP3.It is
not knownthatPI-3Kis activatedbythe T cell receptoritself,butthere isevidence thatCD28,a co-
stimulatoryreceptorprovidingthe secondsignal,isable toactivate PI-3K.The interactionbetweenPLCγ,
Itk andPI-3K couldbe the pointinthe pathwaywhere the firstandthe secondsignal are integrated.
Onlyif bothsignalsare present,PLCγ isactivated.[30] Once PLCγ isactivatedbyphosphorylation,it
hydrolysesPIP2intotwo secondarymessengermolecules,namelythe membrane-bounddiacyl
glycerol(DAG) andthe soluble inositol 1,4,5-trisphosphate(IP3).[38]
These secondmessengermoleculesamplifythe TCRsignal anddistribute the priorlocalisedactivationto
the entire cell andactivate proteincascadesthatfinallyleadtothe activationof transcriptionfactors.
TranscriptionfactorsinvolvedinTcell signallingpathwayare the NFAT,NF-κBandAP1,a heterodimerof
proteinsFosandJun.All three transcriptionfactorsare neededtoactivate the transcriptionof
interleukin-2(IL2) gene.[30]

10. NFAT
NFATactivationdependsoncalciumsignaling.IP3producedbyPLC-γ isnolongerboundtothe
membrane anddiffusesrapidlyinthe cell.Bindingof IP3tocalciumchannel receptors onthe
endoplasmicreticulum(ER) inducesthe release of calcium(Ca2+) intothe cytosol.The resultinglow
Ca2+ concentrationinthe ER causesSTIM1 clusteringonthe ER membrane,whichinturnleadsto
activationof cell membrane CRACchannelsthatallowsadditional calciumtoflow intothe cytosol from
the extracellularspace.Therefore,levelsof Ca2+are stronglyincreasedinthe T cell.Thiscytosolic
calciumbindscalmodulin,inducingaconformational change of the proteinsuchthatitcan thenbind
and activate calcineurin.Calcineurin,inturn,dephosphorylatesNFAT.Initsdeactivatedstate,NFAT
cannot enterthe nucleusasitsnuclearlocalisationsequence (NLS) cannotbe recognisedbynuclear
transportersdue tophosphorylationbyGSK-3.WhendephosphorylatedbyCalcineurintranslocationof
NFATintothe nucleusispossible.[30] Additionally,there isevidence thatPI-3Kviasignal molecules
recruitsthe proteinkinase AKTtothe cell membrane.AKTisable todeactivate GSK3and thereby
inhibitingthe phosphorylationof NFAT,whichcouldcontributetoNFATactivation.[36]
NF-κB
NF-κBactivationisinitiatedbyDAG,the second,membrane boundproductof PLCγ hydrolysationof
PIP2.DAG bindsand recruitsProteinkinase Cθ(PKCθ) tothe membrane where itcanactivatedthe
membrane boundscaffoldproteinCARMA1.CARMA1thenundergoesaconformational change which
allowitto oligomerise andbindthe adapterproteinsBCL10,CARDdomainand MALT1. This
multisubunitcomplex bindsthe Ubiquitinligase TRAF6.Ubiquitinationof TRAF6servesasscaffoldto
recruitNEMO, IκB kinase (IKK) andTAK1.[30] TAK1 phosphorylatesIKK,whichinturnphosphorylates
the NF-κBinhibitorI-κB,leadingtothe ubiquitinationandsubsequentdegradationof I-κB.I-κBblocks
the NLS of NF-κBtherefore preventingitstranslocationtothe nucleus.Once I-κBisdegraded,itcannot
bindto NF-κBandthe NLS of NF-κBbecomesaccessible fornucleartranslocation.[30]
AP1
Activationof AP1involvesthreeMAPKsignallingpathways.These pathwayuse aphosphorylation
cascade of three successive actingproteinkinasestotransmita signal.The three MAPKpathwaysinT
cellsinvolvekinasesof differentspecificitiesbelongingtoeachof the MAP3K, MAP2K,MAPK families.
Initial activationisdone bythe GTPase Ras or Rac whichphosphorylate the MAP3K.[30] A cascade
involvingthe enzymesRaf,MEK1, ERK resultsinthe phosphorylationof Jun,conformational change
allowsJuntobindto Fos and hence AP-1toform.AP-1 thenacts as transcriptionfactor.Raf is activated
viathe secondmessengerDAG,SOS,andRas. DAG recruitsamongotherproteinsthe RASguanyl
nucleotide-releasingprotein(RasGRP),aguanine nucleotide exchangefactor(GEF),tothe membrane.
RasGRP activatesthe small GTPase Ras byexchangingGuanosine diphosphate (GDP) boundtoRas
againstGuanosine triphosphate(GTP).Rascanalso be activatedbythe guanine nucleotide exchange
factor SOSwhichbindsto the LAT signalosom.Rastheninitiatesthe MAPKcascade.[36] The second
MAPK cascade withMEKK1, JNKK,JNKinducesproteinexpressionof Jun.Anothercascade,alsoinvolving

11. MEKK1 as MAPK3,but thenactivatingMKK3 /6 and p38 inducesFostranscription.Activationof MEKK1,
additionallytobeingactivatedbyRas,involvesSlp-76recruitingthe GEFVav to the LAT signalosom,
whichthenactivatesthe GTPase Rac. Rac andRas activate MEKK1 and therebyinitiate the MAPK
cascade.[36]
See also
B-cell receptor
Co-stimulation
ImmTAC
MHC multimer
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