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

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

Authors

  • Wu X
  • Tu X
  • Joeng KS
  • Hilton MJ
  • Williams DA
  • Long F

Journal

Cell

Publication Data

April 18, 2008

Associated Grants

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

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