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

Oncogene volume 23, pages 8260–8271 (2004)Cite this article

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 β-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 β-catenin. This induction was completely blocked by the expression of dominant-negative TCF-4, suggesting that β-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 β-catenin/TCF-dependent manner. We observed that Rac1 co-immunoprecipitates with β-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 expression of β-catenin. Interestingly, mutation of the polybasic region of Rac1, which prevents its nuclear localization, also caused an appreciable decrease in nuclear localization of β-catenin, and effectively abolished its β-catenin-dependent transcription co-activator function. Taken together, our data demonstrate a novel mechanism of Wnt pathway regulation whereby activation of Rac1 amplifies the signaling activity of stabilized/mutated β-catenin by promoting its accumulation in the nucleus, and synergizing with β-catenin to augment TCF/LEF-dependent gene transcription.

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Acknowledgements

We thank S Kulkarni and L Dixon for their expert technical assistance, and our colleagues mentioned in Materials and methods for kindly providing reagents. This work was supported by the National Cancer Institute of Canada, Grant No. 010277 (BB), Canadian Institute For Health Research, Grant No. MOP_64225 (BB), Ontario Graduate Scholarship (SE), and the Ontario Student Opportunity Trust Funds (SE).

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  1. Department of Pathology and Laboratory Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada

    S Esufali & B Bapat

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

    S Esufali & B Bapat

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  1. S Esufali
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Correspondence to B Bapat.

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Esufali, S., Bapat, B. Cross-talk between Rac1 GTPase and dysregulated Wnt signaling pathway leads to cellular redistribution of β-catenin and TCF/LEF-mediated transcriptional activation. Oncogene 23, 8260–8271 (2004). https://doi.org/10.1038/sj.onc.1208007

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