A polycystin-1 multiprotein complex is disrupted in polycystic kidney disease cells

Mol Biol Cell. 2004 Mar;15(3):1334-46. doi: 10.1091/mbc.e03-05-0296. Epub 2004 Jan 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adherens Junctions / metabolism
  • Cadherins / metabolism
  • Cell Membrane / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Epithelial Cells / metabolism*
  • Gene Expression Profiling
  • Humans
  • Kidney / metabolism*
  • Phosphorylation
  • Polycystic Kidney Diseases / metabolism*
  • Proteins / metabolism*
  • TRPP Cation Channels
  • Trans-Activators / metabolism
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • Proteins
  • TRPP Cation Channels
  • Trans-Activators
  • beta Catenin
  • polycystic kidney disease 1 protein