Polycystin-1 induces cell migration by regulating phosphatidylinositol 3-kinase-dependent cytoskeletal rearrangements and GSK3beta-dependent cell cell mechanical adhesion.

Abstract

Polycystin-1 (PC-1) is a large plasma-membrane receptor encoded by the PKD1 gene mutated in autosomal dominant polycystic kidney disease (ADPKD). Although the disease is thought to be recessive on a molecular level, the precise mechanism of cystogenesis is unclear, although cytoarchitecture defects seem to be the most likely initiating events. Here we show that PC-1 regulates the actin cytoskeleton in renal epithelial cells (MDCK) and induces cell scattering and cell migration. All of these effects require phosphatidylinositol 3-kinase (PI3-K) activity. Consistent with these observations Pkd1-/- mouse embryonic fibroblasts (MEFs) have reduced capabilities to migrate compared with controls. PC-1 overexpressing MDCK cells are able to polarize normally with proper adherens and tight junctions formation, but show quick reabsorption of ZO-1, E-cadherin, and beta-catenin upon wounding of a monolayer and a transient epithelial-to-mesenchymal transition (EMT) that favors a rapid closure of the wound and repolarization. Finally, we show that PC-1 is able to control the turnover of cytoskeletal-associated beta-catenin through activation of GSK3beta. Expression of a nondegradable form of beta-catenin in PC-1 MDCK cells restores strong cell-cell mechanical adhesion. We propose that PC-1 might be a central regulator of epithelial plasticity and its loss results in impaired normal epithelial homeostasis.

• Authors: Manila Boca, Lisa D'Amato, Gianfranco Distefano, Roman S Polishchuk, Gregory G Germino, Alessandra Boletta
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 18 Issue 10 Pg. 4050-61 (Oct 2007) ISSN: 1059-1524 [Print] United States
• PMID: 17671167 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• TRPP Cation Channels
• beta Catenin
• polycystic kidney disease 1 protein
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Adherens Junctions (drug effects, metabolism)
• Animals
• Biomechanical Phenomena
• Cell Adhesion (drug effects)
• Cell Line
• Cell Movement (drug effects)
• Cell Polarity (drug effects)
• Cytoskeleton (drug effects, enzymology)
• Dogs
• Enzyme Activation (drug effects)
• Epithelial Cells (cytology, drug effects, enzymology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• TRPP Cation Channels (metabolism)
• Tight Junctions (drug effects, metabolism)
• beta Catenin (metabolism)