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1: Cell. 2008 Apr 18;133(2):340-53.
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Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling.

Wu X, Tu X, Joeng KS, Hilton MJ, Williams DA, Long F.

Department of Medicine, Washington University Medical School, St. Louis, MO 63110, USA.

Canonical Wnt signaling critically regulates cell fate and proliferation in development and disease. Nuclear localization of beta-catenin is indispensable for canonical Wnt signaling; however, the mechanisms governing beta-catenin nuclear localization are not well understood. Here we demonstrate that nuclear accumulation of beta-catenin in response to Wnt requires Rac1 activation. The role of Rac1 depends on phosphorylation of beta-catenin at Ser191 and Ser605, which is mediated by JNK2 kinase. Mutations of these residues significantly affect Wnt-induced beta-catenin nuclear accumulation. Genetic ablation of Rac1 in the mouse embryonic limb bud ectoderm disrupts canonical Wnt signaling and phenocopies deletion of beta-catenin in causing severe truncations of the limb. Finally, Rac1 interacts genetically with beta-catenin and Dkk1 in controlling limb outgrowth. Together these results uncover Rac1 activation and subsequent beta-catenin phosphorylation as a hitherto uncharacterized mechanism controlling canonical Wnt signaling and may provide additional targets for therapeutic intervention of this important pathway.

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PMID: 18423204 [PubMed - indexed for MEDLINE]

PMCID: PMC2390926 [Available on 04/18/09]