Role of the Drosophila Non-Visual ？-Arrestin Kurtz in Hedgehog Signalling 英文参考文献.docVIP

RoleoftheDrosophilaNon-Visual?-ArrestinKurtzin HedgehogSignalling CristinaMolnar,AnaRuiz-Go′mez,MercedesMart?′n,SusanaRojo-Berciano,FedericoMayor Jr., JoseF.deCelis* CentrodeBiolog?′aMolecular‘‘SeveroOchoa,’’ConsejoSuperiordeInvestigacionesCient?′ficasandUniversidadAuto′nomadeMadridCantoblanco,Madrid,Spain Abstract Thenon-visual?-arrestinsarecytosolicproteinshighlyconservedacrossspeciesthatparticipateinavarietyofsignalling events,includingplasmamembranereceptordegradation,recycling,andsignalling,andthatcanalsoactasscaffoldingfor kinases such as MAPK and Akt/PI3K. In Drosophila melanogaster, there is only a single non-visual ?-arrestin, encoded by kurtz,whosefunctionisessentialforneuronalactivity.WehaveaddressedtheparticipationofKurtzinsignallingduringthe developmentoftheimaginaldiscs,epithelialtissuesrequiringtheactivityoftheHedgehog,Wingless,EGFR,Notch,Insulin, and TGFb pathways. Surprisingly, we found that the complete elimination of kurtz by genetic techniques has no major consequencesinimaginalcells.Incontrast,theover-expressionofKurtzinthewingdisccausesaphenotypeidenticaltothe loss of Hedgehog signalling and prevents the expression of Hedgehog targets in the corresponding wing discs. The mechanismbywhichKurtzantagonisesHedgehogsignallingistopromoteSmoothenedinternalizationanddegradationin aclathrin-andproteosomal-dependentmanner.Intriguingly,theeffectsofKurtzonSmoothenedareindependentofGprk2 activity and of the activation state of the receptor. Our results suggest fundamental differences in the molecular mechanismsregulatingreceptorturnoverandsignallinginvertebratesandinvertebrates,andtheycouldprovideimportant insightsintodivergentevolutionofHedgehogsignallingintheseorganisms. Citation: Molnar C, Ruiz-Go′mez A, Mart?′n M, Rojo-Berciano S, Mayor F Jr, et al. (2011) Role of the Drosophila Non-Visual ?-Arrestin Kurtz in Hedgehog Signalling.PLoSGenet7(3):e1001335.doi:10.1371/journal.pgen.1001335 Editor:EricRulifson,UniversityofCaliforniaSanFrancisco,UnitedSt