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Originally published as MBC in Press, 10.1091/mbc.E03-05-0296 on January 12, 2004

Vol. 15, Issue 3, 1334-1346, March 2004

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A Polycystin-1 Multiprotein Complex Is Disrupted in Polycystic Kidney Disease Cells

Tamara Roitbak *, Christopher J. Ward {dagger}, Peter C. Harris {dagger}, Robert Bacallao {ddagger}, Scott A. Ness §, and Angela Wandinger-Ness * ¶

{dagger} Division of Nephrology, Mayo Clinic, Rochester, Minnesota 55905; {ddagger} Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana 46202; § Department of Molecular Genetics and Microbiology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico 87131; and * Department of Pathology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico 87131

Submitted May 13, 2003; Revised October 7, 2003; Accepted November 20, 2003
Monitoring Editor: Keith Mostov

Autosomal dominant polycystic kidney disease (ADPKD) is typified by the accumulation of fluid-filled cysts and abnormalities in renal epithelial cell function. The disease is principally caused by mutations in the gene encoding polycystin-1, a large basolateral plasma membrane protein expressed in kidney epithelial cells. Our studies reveal that, in normal kidney cells, polycystin-1 forms a complex with the adherens junction protein E-cadherin and its associated catenins, suggesting a role in cell adhesion or polarity. In primary cells from ADPKD patients, the polycystin-1/polycystin-2/E-cadherin/{beta}-catenin complex was disrupted and both polycystin-1 and E-cadherin were depleted from the plasma membrane as a result of the increased phosphorylation of polycystin-1. The loss of E-cadherin was compensated by the transcriptional upregulation of the normally mesenchymal N-cadherin. Increased cell surface N-cadherin in the disease cells in turn stabilized the continued plasma membrane localization of {beta}-catenin in the absence of E-cadherin. The results suggest that enhanced phosphorylation of polycystin-1 in ADPKD cells precipitates changes in its localization and its ability to form protein complexes that are critical for the stabilization of adherens junctions and the maintenance of a fully differentiated polarized renal epithelium.

Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E03-05-0296. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E03-05-0296.

Abbreviations used: ADPKD, autosomal polycystic kidney disease; NK, normal kidney; PKD1, polycystic kidney disease locus 1.

Online version of this article contains supplementary materials. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: wness{at}unm.edu.




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