Aswithmanycell-surfacereceptors,activationoftheEGFreceptorcanresultinreceptorinternalizationthroughreceptor-mediatedendocytosis,desensitizingfurtherreceptorsignaling.Thisprocessrequiresclathrinandoccursinclathrin-coatedpits,whichpinchofffromtheplasmamembranetoformvesiclesthatmovetotheearlyendosome.Fromtheearlyendosome,receptorscaneitherberecycledbacktothecellsurface,ortheycanmovethroughthelateendosometothelysosomeforproteolyticdegradation.Thesortingofreceptorsintheearlyendosomefordegradationrequiresthetyrosinekinaseactivityofactivatedgrowthfactorreceptor,andinvolvesubiquitinationofthereceptor.TargetingofreceptorsfordegradationrequiresmembersoftheCblgenefamily.CblproteinsbindtotyrosinephosphorylatedEGFreceptor,andareE3ubiquitinationligasesthatlabelreceptorfordegradation.CblalsorecruitsCin85tothereceptorcomplex,andblockingCin85interactionblocksreceptorinternalizationanddegradation.Endophilinsarealsoamemberofthisreceptor-boundproteincomplex.Initsroleasaubiquitinligaseanddockingprotein,CbldesensitizesEGFsignalingandalsoopposescellularproliferationinducedbyEGF.EGFactivationalsoappearstoactivatethetyrosinekinaseSrc,whichphosphorylatesCbl,andhelpstoactivatetheubiquitinationanddegradationofEGFreceptor.PKCactivationandthreoninephosphorylationoftheEGFreceptorcaninduceheterologousreceptorinternalization,butopposesCbl-mediatedreceptordegradation.PKCphosphorylatedreceptorsaresortedforrecyclingtothecellsurface,anddirectedawayfromthelateendosomeandproteosome.Othergrowthfactorreceptorsareregulatedinasimilarmanner,includingthePDGFreceptor,HGFreceptorandtheCSF-1receptor,indicatingthatthisisafairlygeneralregulatorymechanism.TheimportanceofCblinthedown-regulationofgrowthfactorsignalingmeansthatitwillhaveanimportantroleincellulartransformationandthedevelopmentandtreatmentofcancer.

Contributor:KosiGramatikoff,PhD

REFERENCES:BaoJ,AlroyI,WatermanH,SchejterED,BrodieC,GruenbergJ,YardenY.Threoninephosphorylationdivertsinternalizedepidermalgrowthfactorreceptorsfromadegradativepathwaytotherecyclingendosome.JBiolChem.2000Aug25;275(34):26178-86.BurkeP,SchoolerK,WileyHS.Regulationofepidermalgrowthfactorreceptorsignalingbyendocytosisandintracellulartrafficking.MolBiolCell.2001Jun;12(6):1897-910.ClagueMJ,UrbeS.Theinterfaceofreceptortraffickingandsignalling.JCellSci.2001Sep;114(Pt17):3075-81.Review.deMelkerAA,vanderHorstG,CalafatJ,JansenH,BorstJ.c-CblubiquitinatestheEGFreceptorattheplasmamembraneandremainsreceptorassociatedthroughouttheendocyticroute.JCellSci.2001Jun;114(Pt11):2167-78.EttenbergSA,MagnificoA,CuelloM,NauMM,RubinsteinYR,YardenY,WeissmanAM,LipkowitzS.Cbl-b-dependentcoordinateddegradationoftheepidermalgrowthfactorreceptorsignalingcomplex.JBiolChem.2001Jul20;276(29):27677-84.FreywaldA,SharfeN,RoifmanCM.Thekinase-nullEphB6receptorundergoestransphosphorylationinacomplexwithEphB1.JBiolChem.2002Feb8;277(6):3823-8.KirchhausenT.Clathrinadaptorsreallyadapt.Cell.2002May17;109(4):413-6.Review.LevkowitzG,OvedS,KlapperLN,HarariD,LaviS,SelaM,YardenY.c-Cblisasuppressoroftheneuoncogene.JBiolChem.2000Nov10;275(45):35532-9.PeschardP,FournierTM,LamorteL,NaujokasMA,BandH,LangdonWY,ParkM.Mutationofthec-CblTKBdomainbindingsiteontheMetreceptortyrosinekinaseconvertsitintoatransformingprotein.MolCell.2001Nov;8(5):995-1004.PetrelliA,GilestroGF,LanzardoS,ComoglioPM,MigoneN,GiordanoS.Theendophilin-CIN85-Cblcomplexmediatesligand-dependentdownregulationofc-Met.Nature.2002Mar14;416(6877):187-90.RaoN,DodgeI,BandH.TheCblfamilyofubiquitinligases:criticalnegativeregulatorsoftyrosinekinasesignalingintheimmunesystem.JLeukocBiol.2002May;71(5):753-63.Review.RosenkranzS,IkunoY,LeongFL,KlinghofferRA,MiyakeS,BandH,KazlauskasA.Srcfamilykinasesnegativelyregulateplatelet-derivedgrowthfactoralphareceptor-dependentsignalinganddiseaseprogression.JBiolChem.2000Mar31;275(13):9620-7.SoubeyranP,KowanetzK,SzymkiewiczI,LangdonWY,DikicI.Cbl-CIN85-endophilincomplexmediatesligand-induceddownregulationofEGFreceptors.Nature.2002Mar14;416(6877):183-7.SteenH,KusterB,FernandezM,PandeyA,MannM.Tyrosinephosphorylationmappingoftheepidermalgrowthfactorreceptorsignalingpathway.JBiolChem.2002Jan11;277(2):1031-9.TsygankovAY,TeckchandaniAM,FeshchenkoEA,SwaminathanG.BeyondtheRING:CBLproteinsasmultivalentadapters.Oncogene.2001Oct1;20(44):6382-402.Review.WatermanH,KatzM,RubinC,ShtiegmanK,LaviS,ElsonA,JovinT,YardenY.AmutantEGF-receptordefectiveinubiquitylationandendocytosisunveilsaroleforGrb2innegativesignaling.EMBOJ.2002Feb1;21(3):303-13.WilhelmsenK,BurkhalterS,vanderGeerP.C-CblbindstheCSF-1receptorattyrosine973,anovelphosphorylationsiteinthereceptorscarboxy-terminus.Oncogene.2002Feb7;21(7):1079-89.WongA,LamotheB,LiA,SchlessingerJ,LaxI.FRS2alphaattenuatesFGFreceptorsignalingbyGrb2-mediatedrecruitmentoftheubiquitinligaseCbl.ProcNatlAcadSciUSA.2002May14;99(10):6684-9.WongES,LimJ,LowBC,ChenQ,GuyGR.EvidencefordirectinteractionbetweenSproutyandCbl.JBiolChem.2001Feb23;276(8):5866-75.YokouchiM,KondoT,HoughtonA,BartkiewiczM,HorneWC,ZhangH,YoshimuraA,BaronR.Ligand-inducedubiquitinationoftheepidermalgrowthfactorreceptorinvolvestheinteractionofthec-CblRINGfingerandUbcH7.JBiolChem.1999Oct29;274(44):31707-12.