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

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