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Open Access Highly Accessed Research article

Nuclear localization is required for Dishevelled function in Wnt/β-catenin signaling

Keiji Itoh1, Barbara K Brott1, Gyu-Un Bae1, Marianne J Ratcliffe1 and Sergei Y Sokol12*

Author affiliations

1 Department of Microbiology and Molecular Genetics, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA

2 Current address: Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, Box 1020, One Gustave L. Levy Place, New York, NY 10029, USA

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Citation and License

Journal of Biology 2005, 4:3  doi:10.1186/jbiol20

Published: 15 February 2005

Abstract

Background

Dishevelled (Dsh) is a key component of multiple signaling pathways that are initiated by Wnt secreted ligands and Frizzled receptors during embryonic development. Although Dsh has been detected in a number of cellular compartments, the importance of its subcellular distribution for signaling remains to be determined.

Results

We report that Dsh protein accumulates in cell nuclei when Xenopus embryonic explants or mammalian cells are incubated with inhibitors of nuclear export or when a specific nuclear-export signal (NES) in Dsh is disrupted by mutagenesis. Dsh protein with a mutated NES, while predominantly nuclear, remains fully active in its ability to stimulate canonical Wnt signaling. Conversely, point mutations in conserved amino-acid residues that are essential for the nuclear localization of Dsh impair the ability of Dsh to activate downstream targets of Wnt signaling. When these conserved residues of Dsh are replaced with an unrelated SV40 nuclear localization signal, full Dsh activity is restored. Consistent with a signaling function for Dsh in the nucleus, treatment of cultured mammalian cells with medium containing Wnt3a results in nuclear accumulation of endogenous Dsh protein.

Conclusions

These findings suggest that nuclear localization of Dsh is required for its function in the canonical Wnt/β-catenin signaling pathway. We discuss the relevance of these findings to existing models of Wnt signal transduction to the nucleus.