Human Molecular Genetics Advance Access originally published online on September 28, 2006
Human Molecular Genetics 2006 15(22):3280-3292; doi:10.1093/hmg/ddl404
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Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin
1 Membrane Protein Research Group, Department of Physiology and 2 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada, 3 School of Mechanical Engineering, Jimei University, Xiamen, Fujian, China, 4 Department of Medicine, Vanderbilt University, Nashville, TN, USA, 5 Laboratorio de Canales Iónicos, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina, 6 Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA and 7 Renal Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
* To whom correspondence should be addressed at: Department of Physiology, University of Alberta, 7-29 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7. Tel: +1 7804922294; Fax: +1 7804928915; Email: xzchen{at}ualberta.ca
Received July 25, 2006; Accepted September 21, 2006
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1, encoding polycystin-1 (PC1), or PKD2 (polycystin-2, PC2). Autosomal recessive PKD (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). No molecular link between ADPKD and ARPKD has been determined. Here, we demonstrated, by yeast two-hybrid and biochemical assays, that KIF3B, a motor subunit of kinesin-2, associates with PC2 and FPC. Co-immunoprecipitation experiments using Madin-Darby canine kidney (MDCK) and inner medullary collecting duct (IMCD) cells and human kidney revealed that PC2 and KIF3B, FPC and KIF3B and, furthermore, PC2 and FPC are endogenously in the same complex(es), though no direct association between the PC2 and FPC intracellular termini was detected. In vitro binding and Far Western blot experiments demonstrated that PC2 and FPC are in the same complex only if KIF3B is present, presumably by forming a PC2–KIF3B–FPC complex. This was supported by our observation that altering KIF3B level in IMCD cells by over-expression or siRNA significantly affected complexing between PC2 and FPC. Immunofluorescence experiments showed that PC2, FPC and KIF3B partially co-localized in primary cilia of over-confluent and perinuclear regions of sub-confluent cells. Furthermore, KIF3B mediated functional modulation of purified PC2 channels by FPC in a planer lipid bilayer electrophysiology system. The FPC C-terminus substantially stimulated PC2 channel activity in the presence of KIF3B, whereas FPC or KIF3B alone had no effect. Taken together, we discovered that kinesin-2 is a linker between PC2 and FPC and mediates the regulation of PC2 channel function by FPC. Our study may be important for elucidating common molecular pathways for PKD of different genotypes.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint first authors.
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