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

Mark Lal, Xuewen Song, Jennifer L. Pluznick, Valeria Di Giovanni, David M. Merrick, Norman D. Rosenblum, Veronique Chauvet, Cara J. Gottardi, York Pei, Michael J. Caplan*

*Corresponding author for this work

Research output: Contribution to journalArticle

121 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)3105-3117
Number of pages13
JournalHuman molecular genetics
Volume17
Issue number20
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Lal, M., Song, X., Pluznick, J. L., Di Giovanni, V., Merrick, D. M., Rosenblum, N. D., Chauvet, V., Gottardi, C. J., Pei, Y., & Caplan, M. J. (2008). Polycystin-1 C-terminal tail associates with β-catenin and inhibits canonical Wnt signaling. Human molecular genetics, 17(20), 3105-3117. https://doi.org/10.1093/hmg/ddn208