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.
Wu
Ximei
X
Department of Medicine, Washington University Medical School, St. Louis, MO 63110, USA.
Tu
Xiaolin
X
Joeng
Kyu Sang
KS
Hilton
Matthew J
MJ
Williams
David A
DA
Long
Fanxin
F
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005121:Extremities / Q000196:embryology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein; D051176:beta Catenin / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D048056:Mitogen-Activated Protein Kinase 9; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins