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A more recent version of this article appeared on March 1, 2004
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Submitted on May 13, 2003
Revised on October 7, 2003
Accepted on November 20, 2003
1 Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131
2 Division of Nephrology, Mayo Clinic, Rochester, MN 55905
3 Department of Medicine, Indiana University Medical Center, Indianapolis, IN 46202
4 Department of Molecular Genetics and Microbiology, University of New Mexico Health, Sciences Center, Albuquerque, NM 87131
* Corresponding author. E-mail address: wness{at}unm.edu.
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/
-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 -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.
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