ImmunologicalReviews.2019;291:123–133.wileyonlinelibrary.com/journal/imr|123©2019JohnWiley&SonsA/S.PublishedbyJohnWiley&SonsLtd1|INTRODUCTIONTheCasitasB‐lineagelymphoma(Cbl)proteinsbelongtothesu‐perfamilyoftheRINGfinger‐containingE3ubiquitinligasesthatregulatemanyreceptorandtranscriptionsignals.1‐5Inmammalsthisfamilyhasthreemembers,Cbl,Cbl‐b,andCbl‐3.6‐9ThethreememberssharehighlyconservedstructuresintheirN‐terminalregions,whichcontainintandemaTKB(tyrosinekinasebinding),linkerandRINGfingerdomain.Incontrast,theC‐terminalportionsofCblproteinsaremorediverse.TheC‐terminusofCbl‐3istrun‐cated,whereasthatofbothCblandCbl‐bcontainsmultiplepro‐line‐richmotifs,tyrosineresiduesthatcanbephosphorylateduponreceptorsignaling,andaUBAdomain,allofwhichmayserveasprotein‐proteininteractionmotifs(Figure1).10‐12TheRINGfingerdomainplaysacriticalrolethatenablesCblproteinstofunctionasE3ubiquitinligasesforvarioussubstrates,becauseitformsstableinteractionwiththeactivatedE2ubiquitinconjugatingenzymesandfacilitatestheubiquitintransferfromE2tothefinalsubstratesthatassociatedwithoneoftheCblprotein‐proteininteractiondo‐mains.13,14CblandCbl‐baretwomembersoftheCblfamilyex‐pressedinhematopoieticcells.9Sinceitsdiscoverythreedecadesago,theCblfamilyofproteinshasemergedasacentralplayerintheimmuneregulationrangingfromtheearlydevelopmentofmul‐tiplelineagesoflymphoidandnon‐lymphoidhematopoieticpre‐cursorstotheeffectorfunctionsofT,B,andmyeloidcells.15‐17ThisreviewmainlyfocusesontheprogressfromourlaboratorywithanemphasisonrecentlydiscoveredcompoundeffectsofCblandCbl‐b(Cbls)inT,B,anddendriticcells.2|THEFUNCTIONOFCBLANDCBL‐BINTLINEAGECELLS2.1|CblscontrolearlyTcelldevelopmentDevelopmentofconventionalTcellsisasequentialprocessandisstrictlycontrolledbyTcellantigenreceptor(TCR)signaling.18ItReceived:10May2019|Accepted:30May2019DOI:10.1111/imr.12789INVITEDREVIEWRegulationofimmunesystemdevelopmentandfunctionbyCbl‐mediatedubiquitinationXinLi1|LiyingGong2,3|HuaGu2,3,4Thisarticleispartofas...
