Polycystin-1 induces cell migration by regulating phosphatidylinositol 3-kinase-dependent cytoskeletal rearrangements and GSK3β-dependent cell-cell mechanical adhesion

Manila Boca, Lisa D'Amato, Gianfranco Distefano, Roman S. Polishchuk, Gregory G. Germino, Alessandra Boletta

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 β-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 β-catenin through activation of GSK3β. Expression of a nondegradable form of β-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.

Original languageEnglish
Pages (from-to)4050-4061
Number of pages12
JournalMolecular Biology of the Cell
Volume18
Issue number10
DOIs
Publication statusPublished - Oct 2007

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Phosphatidylinositol 3-Kinase
Cell Adhesion
Cell Movement
Catenins
Madin Darby Canine Kidney Cells
Adherens Junctions
Autosomal Dominant Polycystic Kidney
Epithelial-Mesenchymal Transition
Tight Junctions
Cadherins
Actin Cytoskeleton
polycystic kidney disease 1 protein
Homeostasis
Fibroblasts
Epithelial Cells
Cell Membrane
Kidney
Wounds and Injuries
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Polycystin-1 induces cell migration by regulating phosphatidylinositol 3-kinase-dependent cytoskeletal rearrangements and GSK3β-dependent cell-cell mechanical adhesion. / Boca, Manila; D'Amato, Lisa; Distefano, Gianfranco; Polishchuk, Roman S.; Germino, Gregory G.; Boletta, Alessandra.

In: Molecular Biology of the Cell, Vol. 18, No. 10, 10.2007, p. 4050-4061.

Research output: Contribution to journalArticle

Boca, Manila ; D'Amato, Lisa ; Distefano, Gianfranco ; Polishchuk, Roman S. ; Germino, Gregory G. ; Boletta, Alessandra. / Polycystin-1 induces cell migration by regulating phosphatidylinositol 3-kinase-dependent cytoskeletal rearrangements and GSK3β-dependent cell-cell mechanical adhesion. In: Molecular Biology of the Cell. 2007 ; Vol. 18, No. 10. pp. 4050-4061.
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