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Originally published as MBC in Press, 10.1091/mbc.E07-02-0142 on August 8, 2007 Originally published as MBC in Press, 10.1091/mbc.E07-02-0142 on August 1, 2007

Vol. 18, Issue 10, 4050-4061, October 2007

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Polycystin-1 Induces Cell Migration by Regulating Phosphatidylinositol 3-kinase-dependent Cytoskeletal Rearrangements and GSK3beta-dependent Cell–Cell Mechanical AdhesionFormula Formula

Manila Boca*, Lisa D'Amato*, Gianfranco Distefano*, Roman S. Polishchuk{dagger}, Gregory G. Germino{ddagger}, and Alessandra Boletta*

*Dulbecco Telethon Institute (DTI) at Dibit, San Raffaele Scientific Institute, 20132 Milan, Italy; {dagger}Department of Cell Biology and Oncology, Consorzio "Mario Negri Sud," 66030 Santa Maria Imbaro, Chieti, Italy; and {ddagger}The Johns Hopkins University School of Medicine, Baltimore, MD 21205

Submitted February 20, 2007; Revised July 18, 2007; Accepted July 23, 2007
Monitoring Editor: Keith Mostov

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.


This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-02-0142) on August 8, 2007.

Formula Formula The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Alessandra Boletta (aboletta{at}dti.telethon.it)




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