Nuclear localization is required for Dishevelled function in Wnt/beta-catenin signaling.
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/beta-catenin signaling pathway. We discuss the relevance of these findings to existing models of Wnt signal transduction to the nucleus.
Itoh
Keiji
K
Department of Microbiology and Molecular Genetics, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Brott
Barbara K
BK
Bae
Gyu-Un
GU
Ratcliffe
Marianne J
MJ
Sokol
Sergei Y
SY
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001757:Blastomeres / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000502:physiology; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D023061:Gene Order / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D049790:Nuclear Export Signals / Q000235:genetics / Q000502:physiology; D009842:Oligopeptides / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D016415:Sequence Alignment; D051153:Wnt Proteins / Q000502:physiology*; D014981:Xenopus / Q000196:embryology / Q000502:physiology*; D029867:Xenopus Proteins; D051176:beta Catenin / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D049790:Nuclear Export Signals; D009842:Oligopeptides; D010750:Phosphoproteins; C402304:SV40 nuclear localization peptide; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; D049452:Green Fluorescent Proteins
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