Ectodomains of the LDL Receptor-Related Proteins LRP1b and LRP4 Have Anchorage Independent Functions In Vivo 英文参考文献.docVIP

EctodomainsoftheLDLReceptor-RelatedProteins LRP1bandLRP4HaveAnchorageIndependentFunctions InVivo MartinF.Dietrich1.,LouisevanderWeyden2.,HaydnM.Prosser3,AllanBradley3,JoachimHerz1*, DavidJ.Adams2* 1DepartmentofMolecularGenetics,UTSouthwestern,Dallas,Texas,UnitedStatesofAmerica,2ExperimentalCancerGenetics,WellcomeTrustSangerInstitute,Hinxton, Cambs,UnitedKingdom,3MouseGenomics,WellcomeTrustSangerInstitute,Hinxton,Cambs,UnitedKingdom Abstract Background:Thelow-densitylipoprotein(LDL)receptorgenefamilyisahighlyconservedgroupofmembranereceptors withdiversefunctionsindevelopmentalprocesses,lipoproteintrafficking,andcellsignaling.Thelow-densitylipoprotein (LDL) receptor-related protein 1b (LRP1B) was reported to be deleted in several types of human malignancies, including non-smallcelllungcancer.OurgrouphaspreviouslyreportedthatadistalextracellulartruncationofmurineLrp1bthatis predictedtosecretetheentireintactextracellulardomain(ECD)isfullyviablewithnoapparentphenotype. Methods and Principal Findings: Here, we have used a gene targeting approach to create two mouse lines carrying internally rearranged exons of Lrp1b that are predicted to truncate the protein closer to the N-terminus and to prevent normaltraffickingthroughthesecretarypathway.Bothmutationsresultinearlyembryoniclethality,but,asexpectedfrom the restricted expression pattern of LRP1b in vivo, loss of Lrp1b does not cause cellular lethality as homozygous Lrp1b- deficient blastocysts can be propagated normally in culture. This is similar to findings for another LDL receptor family member, Lrp4. We provide in vitro evidence that Lrp4 undergoes regulated intramembraneous processing through metalloproteasesandc-secretasecleavage.WefurtherdemonstratenegativeregulationoftheWntsignalingpathwayby thesolubleextracellulardomain. Conclusions and Significance: Our results underline a crucial role for Lrp1b in development. The expression in mice of truncatedallelesofLrp1bandLrp4withdeletionsofthetransmembraneandintracellu