An Essential Role of the Universal Polarity Protein, aPKCλ, on the Maintenance of Podocyte Slit Diaphragms 英文参考文献.docVIP

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An Essential Role of the Universal Polarity Protein, aPKCλ, on the Maintenance of Podocyte Slit Diaphragms 英文参考文献.doc

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An Essential Role of the Universal Polarity Protein, aPKCλ, on the Maintenance of Podocyte Slit Diaphragms 英文参考文献

AnEssentialRoleoftheUniversalPolarityProtein, aPKCl,ontheMaintenanceofPodocyteSlitDiaphragms TomonoriHirose1,DaisukeSatoh1,HidetakeKurihara2,ChihoKusaka1,HirokoHirose1 ,Kazunori Akimoto1,TaijiMatsusaka3,IekuniIchikawa4,TetsuoNoda5,ShigeoOhno1,6* 1DepartmentofMolecularBiology,YokohamaCityUniversityGraduateSchoolofMedicalScience,Yokohama,Kanagawa,Japan,2DepartmentofAnatomy,Juntendo UniversitySchoolofMedicine,Bunkyo-ku,Tokyo,Japan,3InstituteofMedicalSciences,TokaiUniversitySchoolofMedicine,Isehara,Kanagawa,Japan,4Departmentof Bioethics,TokaiUniversitySchoolofMedicine,Isehara,Kanagawa,Japan,5DepartmentofCellBiology,CancerInstitute,JapaneseFoundationforCancerResearch,Koto- ku,Tokyo,Japan,6AdvancedMedicalResearchCenter,YokohamaCityUniversity,Yokohama,Kanagawa,Japan Abstract Glomerularvisceralepithelialcells(podocytes)containinterdigitatedprocessesthatformspecializedintercellularjunctions, termed slit diaphragms, which provide a selective filtration barrier in the renal glomerulus. Analyses of disease-causing mutationsinfamilialnephroticsyndromesandtargetedmutagenesisinmicehaverevealedcriticalrolesofseveralproteins intheassemblyofslitdiaphragms.Thenephrin–podocincomplexisthemainconstituentofslitdiaphragms.However,the molecular mechanisms regulating these proteins to maintain the slit diaphragms are still largely unknown. Here, we demonstratethatthePAR3–atypicalproteinkinaseC(aPKC)–PAR6bcellpolarityproteinsco-localizetotheslitdiaphragms withnephrin.Furthermore,selectivedepletionofaPKClinmousepodocytesresultsinthedisassemblyofslitdiaphragms,a disturbanceinapico-basalcellpolarity,andfocalsegmentalglomerulosclerosis(FSGS).TheaPKC–PAR3complexassociates with the nephrin–podocin complex in podocytes through direct interaction between PAR3 and nephrin, and the kinase activityofaPKCisrequiredfortheappropriatedistributionofnephrinandpodocininpodocytes.Theseobservationsnot onlyestablishacriticalfunctionofthepolarityproteinsinthemaintenanceofslitdiaphragms,butalsoimplytheirpotential