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Human Molecular Genetics Advance Access first published online on April 20, 2005
This version published online on April 21, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi167
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received December 9, 2004
Revised February 8, 2005
Accepted April 7, 2005

Article

Alpha-actinin associates with polycystin-2 and regulates its channel activity

Qiang Li 1, Nicolás Montalbetti 2, Patrick Y. Shen 1, Xiao-Qing Dai 1, Christopher I. Cheeseman 1, Edward Karpinski 1, Guanqing Wu 3, Horacio F. Cantiello 4, and Xing-Zhen Chen 5*

1 Membrane Protein Research Group, Department of Physiology, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada
2 Laboratorio de Canales Iónicos, Departamento de Fisicoquímica y Química Analítica, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
3 Department of Medicine, Vanderbilt University, Nashville, Tennessee, 37232-0275, USA
4 Laboratorio de Canales Iónicos, Departamento de Fisicoquímica y Química Analítica, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina; Renal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
5 Membrane Protein Research Group, Department of Physiology, University of Alberta, 7-29 Medical Sciences Building, Edmonton, Alberta, T6G 2H7, Canada

* To whom correspondence should be addressed.
Xing-Zhen Chen, E-mail: xzchen{at}ualberta.ca


  Abstract

Polycystin-2 is the product of the PKD2 gene, which is mutated in 10-15% patients of autosomal dominant polycystic kidney disease (ADPKD). Polycystin-2 is an integral transmembrane protein and acts as a calcium-permeable cation channel. The functional modulation of this channel by other protein partners remains largely unknown. In the present study, using a yeast two-hybrid approach, we discovered that both intracellular N- and C-termini of polycystin-2 associate with {alpha}-actinins, actin-binding and actin-bundling proteins important in cytoskeleton organization, cell adhesion, proliferation and migration. The polycystin-2-{alpha}-actinin association was confirmed by in vitro GST pull-down and dot blot overlay assays. Furthermore, the in vivo interaction between endogenous polycystin-2 and {alpha}-actinins was demonstrated by co-immunoprecipitation in HEK293 and MDCK cells, rat kidney and heart tissues, and human syncytiotrophoblast (hST) apical membrane vesicles. Immunofluorescence experiments showed that polycystin-2 and {alpha}-actinin were partially co-localized in epithelial MDCK and IMCD cells, NIH 3T3 fibroblasts, and hST vesicles. We studied functional modulation of polycystin-2 by {alpha}-actinin in a lipid bilayer electrophysiology system using in vitro translated polycystin-2 and found that {alpha}-actinin substantially stimulated the channel activity of reconstituted polycystin-2. A similar stimulatory effect of {alpha}-actinin on polycystin-2 was also observed when hST vesicles were reconstituted in lipid bilayer. Thus, physical and functional interactions between polycystin-2 and {alpha}-actinin may play an important role in abnormal cell adhesion, proliferation and migration observed in ADPKD.

The originally published version of this paper was incorrect. Figure 9 was distorted. The publisher apologises for this error.
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