Human Molecular Genetics Advance Access originally published online on July 16, 2008
Human Molecular Genetics 2008 17(20):3105-3117; 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 Division of Nephrology 3 Division of Genomic Medicine, Toronto General Hospital, University of Toronto, Toronto, ON, Canada 4 Program in Developmental and Stem Cell Biology, Toronto, ON, Canada 5 Division of Nephrology, Hospital for Sick Children, Toronto, ON, Canada 6 Institut Curie-UMR 144, Section de recherché, Paris, France 7 Department of Pulmonary and Critical Care Medicine 8 Department of Cell and Molecular Biology, Northwestern University, Chicago, IL, USA
* To whom correspondence should be addressed at: Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510, USA. Tel: +1 2037857316; Fax: +1 2037854951; Email: michael.caplan{at}yale.edu
Received March 29, 2008; Accepted July 14, 2008
Polycystin-1 (PC1), the product of the PKD1 gene mutated in the majority of autosomal dominant polycystic kidney disease (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 T-cell factor (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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