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Abstract
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.