Journal
JOURNAL OF CELL SCIENCE
Volume 128, Issue 21, Pages 3933-3946Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.167742
Keywords
beta-Catenin; Rac1; Wnt signaling; Proximity ligation assay
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Funding
- Cancer Institute New South Wales [12/CDF/2-12]
- Cancer Council New South Wales [RG12-04]
- National Health and Medical Research Council of Australia [570995, 1046767]
- University of Sydney
- Westmead Millennium Institute
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beta-Catenin transduces the Wnt signaling pathway and its nuclear accumulation leads to gene transactivation and cancer. Rac1 GTPase is known to stimulate beta-catenin-dependent transcription of Wnt target genes and we confirmed this activity. Here we tested the recent hypothesis that Rac1 augments Wnt signaling by enhancing beta-catenin nuclear import; however, we found that silencing/inhibition or up-regulation of Rac1 had no influence on nuclear accumulation of beta-catenin. To better define the role of Rac1, we employed proximity ligation assays (PLA) and discovered that a significant pool of Rac1-beta-catenin protein complexes redistribute from the plasma membrane to the nucleus upon Wnt or Rac1 activation. More importantly, active Rac1 was shown to stimulate the formation of nuclear beta-cateninlymphoid enhancer factor 1 (LEF-1) complexes. This regulation required Rac1-dependent phosphorylation of beta-catenin at specific serines, which when mutated (S191A and S605A) reduced beta-catenin binding to LEF-1 by up to 50%, as revealed by PLA and immunoprecipitation experiments. We propose that Rac1-mediated phosphorylation of beta-catenin stimulates Wnt-dependent gene transactivation by enhancing beta-catenin-LEF-1 complex assembly, providing new insight into the mechanism of cross-talk between Rac1 and canonical Wnt/beta-catenin signaling.
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