A Novel Signaling Pathway Mediated by the Nuclear Targeting of C-Terminal Fragments of Mammalian Patched 1 英文参考文献.docVIP

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A Novel Signaling Pathway Mediated by the Nuclear Targeting of C-Terminal Fragments of Mammalian Patched 1 英文参考文献.doc

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A Novel Signaling Pathway Mediated by the Nuclear Targeting of C-Terminal Fragments of Mammalian Patched 1 英文参考文献

ANovelSignalingPathwayMediatedbytheNuclear TargetingofC-TerminalFragmentsofMammalian Patched1 HirokiKagawa1,2,YukaShino2,DaigoKobayashi2,SyunsukeDemizu2,MasumiShimada2 ,Hiroyoshi Ariga1,HiroyukiKawahara2* 1Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan, 2Department of Biological Sciences, Tokyo MetropolitanUniversity,Tokyo,Japan Abstract Background:Patched1(Ptc1)isapolytopicreceptorproteinthatisessentialforgrowthanddifferentiation.Itsextracellular domainsacceptitsligand,SonicHedgehog,whilethefunctionofitsC-terminalintracellulardomainislargelyobscure. PrincipalFindings:Inthisstudy,westablyexpressedhumanPtc1proteininHeLacellsandfoundthatitissubjectedto proteolytic cleavage at the C-terminus, resulting in the generation of soluble C-terminal fragments. These fragments accumulatedinthenucleus,whiletheN-terminalregionofPtc1remainedinthecytoplasmicmembranefractions.Usingan anti-Ptc1 C-terminal domain antibody, we provide conclusive evidence that C-terminal fragments of endogenous Ptc1 accumulate in the nucleus of C3H10T1/2 cells. Similar nuclear accumulation of endogenous C-terminal fragments was observednotonlyinC3H10T1/2cellsbutalsoinmouseembryonicprimarycells.Importantly,theC-terminalfragmentsof Ptc1modulatetranscriptionalactivityofGli1. Conclusions:AlthoughPtc1proteinwasoriginallythoughttoberestrictedtocellmembranefractions,ourfindingssuggest thatitsC-terminalfragmentscanfunctionasanalternativesignaltransducerthatisdirectlytransportedtothecellnucleus. Citation: Kagawa H, Shino Y, Kobayashi D,DemizuS, ShimadaM, et al.(2011) ANovel Signaling Pathway Mediated by the Nuclear Targeting of C-Terminal FragmentsofMammalianPatched1.PLoSONE6(4):e18638.doi:10.1371/journal.pone.0018638 Editor:IrinaAgoulnik,FloridaInternationalUniversity,UnitedStatesofAmerica ReceivedOctober11,2010;AcceptedMarch14,2011;PublishedApril13,2011 Copyright: ? 2011 Kagawa et al. This is an open-access article distributed under the terms