A polycystin-1 multiprotein complex is disrupted in polycystic kidney disease cells.
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.
Roitbak
Tamara
T
Department of Pathology, University of New Mexico, Health Science Center, Albuquerque, New Mexico 87131, USA.
Ward
Christopher J
CJ
Harris
Peter C
PC
Bacallao
Robert
R
Ness
Scott A
SA
Wandinger-Ness
Angela
A
D022005:Adherens Junctions / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D010766:Phosphorylation; D007690:Polycystic Kidney Diseases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D050396:TRPP Cation Channels; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D011506:Proteins; D050396:TRPP Cation Channels; D015534:Trans-Activators; D051176:beta Catenin; C495270:CTNNB1 protein, human