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Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling.

Cell | Apr 18, 2008

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.

Pubmed ID: 18423204 RIS Download

Mesh terms: Animals | Cell Line | Cell Nucleus | Embryo, Mammalian | Extremities | Intercellular Signaling Peptides and Proteins | Mice | Mitogen-Activated Protein Kinase 9 | Neuropeptides | Phosphatidylinositol 3-Kinases | Phosphorylation | Signal Transduction | Wnt Proteins | Wnt3 Protein | beta Catenin | rac GTP-Binding Proteins | rac1 GTP-Binding Protein | rho GTP-Binding Proteins

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK 065789
  • Agency: NIAMS NIH HHS, Id: T32 AR007033
  • Agency: NIAMS NIH HHS, Id: 5T32AR07033
  • Agency: NIDDK NIH HHS, Id: R01 DK065789
  • Agency: NIDDK NIH HHS, Id: R01 DK065789-03
  • Agency: NIDDK NIH HHS, Id: R01 DK062757
  • Agency: NIDDK NIH HHS, Id: R01 DK 62757
  • Agency: NIDDK NIH HHS, Id: R01 DK065789-04
  • Agency: NICHD NIH HHS, Id: P01 HD070394

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