Cross-talk between Rac1 GTPase and dysregulated Wnt signaling pathway leads to cellular redistribution of beta-catenin and TCF/LEF-mediated transcriptional activation

Oncogene
Susmita Esufali, Bharati Bapat

Abstract

Aberrant activation of the Wnt pathway is observed in numerous cancers, and is particularly important in colon cancer. We demonstrate that Rac1 GTPase can significantly increase the signaling activity of beta-catenin in cells with inherent dysregulation of the canonical Wnt signaling pathway. Expression of dominant-negative (N17)Rac1 mutant in colon cancer cells caused a marked inhibition of Wnt signaling, as determined by the TCF/LEF-responsive (TOPFLASH) transcription assay. Expression of a constitutively active (V12)Rac1 mutant caused up to 40-fold induction from the TOPFLASH promoter, and this was dependent on the presence of stabilized beta-catenin. This induction was completely blocked by the expression of dominant-negative TCF-4, suggesting that beta-catenin and TCF-4 complex formation is required for Rac1-mediated transcription. Furthermore, we show that Cyclin D1, an important biological Wnt target gene, is regulated by Rac1 in a beta-catenin/TCF-dependent manner. We observed that Rac1 co-immunoprecipitates with beta-catenin and TCF-4 only in its active GTP-bound form. Both cell fractionation studies and fluorescence microscopy indicate that overexpression of V12Rac1 results in increased cytosolic and nuclear expressio...Continue Reading

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