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[[Ficheiro:Raf-activation-cycle-sketch.png|miniatura|Exemplo do traballo das MAP3 quinases: o ciclo de activación das poteínas Raf de mamíferos (diagrama moi simplificado).<ref name="pmid21779496">{{cite journal |vauthors=Matallanas D, Birtwistle M, Romano D, etal |title=Raf family kinases: old dogs have learned new tricks |journal=Genes Cancer |volume=2 |issue=3 |pages=232–60 |date=March 2011 |pmid=21779496 |pmc=3128629 |doi=10.1177/1947601911407323 }}</ref><ref name="pmid20883493">{{cite journal |vauthors=Alexa A, Varga J, Reményi A |title=Scaffolds are 'active' regulators of signaling modules |journal=FEBS J. |volume=277 |issue=21 |pages=4376–82 |date=November 2010 |pmid=20883493 |doi=10.1111/j.1742-4658.2010.07867.x }}</ref>]]
As mentionedMAPK above,forman MAPKsnormalmente typicallyvías formde multi-tieredmoitos pathwayspasos, receivingque inputreciben severalsinais levelsa abovevarios theniveis por actualencima da MAP kinasequinase. InA contrastdiferenza todo the relativelyrelativamente simple, phosphorylation-dependentmecanismo activationde mechanismactivación ofdependente MAPKsda andfosforilación [[Mitogen-activateddas proteinMAPK kinasee kinase|[[MAP2K]]s, MAP3Ksas haveMAP3K stunninglyteñen complexunha regulation.regulación Manysorprendentemente ofmís thecomplexa. better-knownMoitas das [[Mitogen-activatedMAP3K]] proteinmellor kinase kinase kinase|MAP3Ks]]coñecidas, such ascomo [[c-Raf]], [[MEKK4]] orou [[MLK3]] requirerequiren multiplemúltiples stepspasos forpara theira activationsúa activación. TheseSon areencimas typicallynormalmente allosterically-controlledcontrolados enzymes[[encima alostérico|alostericamente]], tighlymoi lockedestabilizados intoen anestado inactiveinactivo statepor bymoitos multiple mechanismsmecanismos. TheO firstprimeiro steppaso enna routeruta toda theirsúa activationactivación consisté ofliberalos relievingda theirsúa autoinhibitionautoinhibición bypor aun [[ligando]] smallermáis ligandpequeno (such ascomo [[subfamilia Ras subfamily|Ras]] forpara a quinase [[c-Raf]], ou [[GADD45]] forpara a [[MAP3K4|MEKK4]]<ref name="pmid17242196">{{cite journal | vauthors = Miyake Z, Takekawa M, Ge Q, Saito H | title = Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain | journal = Molecular and Cellular Biology | volume = 27 | issue = 7 | pages = 2765–76 | date = Apr 2007 | pmid = 17242196 | pmc = 1899887 | doi = 10.1128/MCB.01435-06 }}</ref> orou [[CDC42|Cdc42]] forpara a [[MAP3K11|MLK3]].<ref name="pmid16253996">{{cite journal | vauthors = Du Y, Böck BC, Schachter KA, Chao M, Gallo KA | title = Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3 | journal = The Journal of Biological Chemistry | volume = 280 | issue = 52 | pages = 42984–93 | date = Dec 2005 | pmid = 16253996 | doi = 10.1074/jbc.M502671200 }}</ref>). ThisIsto ocorre commonlyxeralmente (butpero notnon alwayssempre) happensna atmembrana theda cell membranecélula, whereonde mostse ofunen theira activatorsmaioría aredos boundseus activaores (notenótese thatque [[Smallpequena GTPase|smallpequenas G-proteinsproteínas]] areestán constitutivelyasociadas membrane-associatedá duemembrna toconstitutivamente debido á súa [[prenylationprenilación]]). ThatEste steppaso isvai followedseguido bypor side-to-sideunha homo- ande heterodimerisationheterodimerización ofdos theirseus nowagora accessibleaccesibles kinasedominios domainsquinase. RecentlyEstruturas determinedcomplexas complexdeterminadas structuresrecentemente revealrevelaron thatque theos dimersdímeros arefórmanse formedcunha inorientación anque orientationdeixa thatlibres leavesambas bothas theirrexións substrate-bindingde unión regionsao freesubstrato.<ref name="pmid19727074">{{cite journal | vauthors = Rajakulendran T, Sahmi M, Lefrançois M, Sicheri F, Therrien M | title = A dimerization-dependent mechanism drives RAF catalytic activation | journal = Nature | volume = 461 | issue = 7263 | pages = 542–5 | date = Sep 2009 | pmid = 19727074 | doi = 10.1038/nature08314 }}</ref> Importantly,Outro thisdatoimportante dimerisationé eventque alsoesta forcesdimerización thetamén MAP3forza kinasea domainsque toestes adoptdominios ada partiallyMAP3K activeadopten conformationunha conformación parcialmente activa. FullSó activitychegan isa onlyter achievedunha onceactividade thesecompleta dimersunha transphosphorylatevez eachque otherestes ondímeros theirse activationtransfosforilan entre si nos seus bucles de loopsactivación. TheO latterúltimo steppaso canpode alsotamén beconseguirse achievedou orser aidedfavorecido bypor auxiliaryproteína proteinquinases kinasesauxiliares (MAP4 kinasesquinses, membersmembros ofda thefamilia Ste20 family). OnceUnha avez que unha MAP3 kinasequinase isestá fullytotalmente activeactiva, itpode mayfosforilar phosphorylateo itsseu substratesubstrato, que é unha MAP2 kinasesquinase, whichque iná turnsúa willvez phosphorylatefosforilará theirao seu substrato, que é unha MAP kinasequinase. substratesPor tanto, nesta fervenza de activación actúan en cadea unha ''quinase da quinase da quinase'' (MAP3K), seguida dunha ''quinase da quinase'' (MAP2K), e finalmente a ''quinase'' activada (MAPK).
=== En animais ===
[[FileFicheiro:MAPK-pathway-mammalian.png|thumbminiatura|ADiagrama simplifiedglobal overviewsimplificado ofdas vías MAPK pathwaysen in mammalsmamíferos, organisedorganizada en intotres threemódulos mainprincipais signalingde modulessinalización (ERK1/2, JNK/p38 ande ERK5).]]
The [[Extracellular signal-regulated kinases|ERK1/2]] pathway of mammals is probably the best-characterized MAPK system. The most important upstream activators of this pathway are the Raf proteins ([[ARAF|A-Raf]], [[BRAF (gene)|B-Raf]] or [[c-Raf]]), the key mediators of response to growth factors ([[epidermal growth factor|EGF]], [[fibroblast growth factor|FGF]], [[PDGF]], etc.); but other MAP3Ks such as c-Mos and [[MAP3K8|Tpl2/Cot]] can also play the same role. All these enzymes phosphorylate and thus activate the [[MAP2K1|MKK1]] and/or [[MAP2K2|MKK2]] kinases, that are highly specific activators for [[MAPK3|ERK1]] and [[MAPK1|ERK2]]. The latter phosphorylate a number of substrates important for [[Cell growth|cell proliferation]], [[Cell cycle|cell cycle progression]], [[Mitosis|cell division]] and [[Cellular differentiation|differentiation]] ([[ribosomal s6 kinase|RSK kinases]], [[ELK1|Elk-1]] [[transcription factor]], etc.)
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