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Hum Mol Genet. 2008 Oct 15;17(20):3105-17. doi: 10.1093/hmg/ddn208. Epub 2008 Jul 16.

Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling.

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1
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.

Abstract

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 beta-catenin in the nucleus. This interaction requires a nuclear localization motif present in the PC1 CTT as well as the N-terminal portion of beta-catenin. The PC1 CTT inhibits the ability of both beta-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 beta-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.

PMID:
18632682
PMCID:
PMC2722884
DOI:
10.1093/hmg/ddn208
[Indexed for MEDLINE]
Free PMC Article
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