Human Molecular Genetics Advance Access published online on July 16, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn208
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Polycystin-1 C-terminal Tail Associates with β-catenin and Inhibits Canonical Wnt Signaling
1 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA 2 Divisions of Nephrology and Genomic Medicine, Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada 3 Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada 4 Division of Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada 5 Institut Curie-UMR 144, Section de recherché, Paris, France 6 Departments of Pulmonary and Critical Care Medicine and Cell & Molecular Biology, Northwestern University, Chicago, IL, USA
* Address correspondence to: Michael J. Caplan, Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510, USA, Tel: (203) 785-7316, Fax: (203) 785-4951, michael.caplan{at}yale.edu
Received March 29, 2008; Revised July 14, 2008; Accepted July 14, 2008
Polycystin-1 (PC1), the product of the PKD1 gene mutated in the majority of ADPKD cases, undergoes a cleavage resulting in the intracellular release of its C-terminal tail (CTT). Here, we demonstrate that the PC1 CTT co-localizes with and binds to β-catenin in the nucleus. This interaction requires a nuclear localization motif present in the PC1 CTT as well as the N-terminal portion of β-catenin. The PC1 CTT inhibits the ability of both β-catenin and Wnt ligands to activate TCF-dependent gene transcription, a major effector of the canonical Wnt signaling pathway. The PC1 CTT may produce this effect by reducing the apparent affinity of the interaction between β-catenin and the TCF protein. DNA microarray analysis reveals that the canonical Wnt signaling pathway is activated in ADPKD patient cysts. Our results suggest a novel mechanism through which PC1 cleavage may impact upon Wnt-dependent signaling and thereby modulate both developmental processes and cystogenesis.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors and the last two authors should be regarded as joint Last Authors.
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