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A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization

Oncogene volume 26, pages 7628–7636 (2007)Cite this article

Abstract

Wnt signaling follows canonical and non-canonical pathways to regulate a variety of processes during cellular homeostasis and development. The large T-antigen (T-Ag) of the human neurotropic JC virus, has been shown to modulate the Wnt-signaling pathway via interaction with β-catenin, one of the most important components of the canonical Wnt pathway. Here, we have identified an alternative non-canonical pathway that allows T-Ag to recruit Rac1 for stabilizing β-catenin by inhibiting its ubiquitin-dependent proteasomal degradation. We demonstrate that inhibition of Rac1 by its dominant negative mutant, RacN17, abrogates T-Ag-mediated stabilization of β-catenin yet exhibits no impact on the transcriptional activity of β-catenin. Results from immunocytochemistry revealed that together with T-Ag, a pool of β-catenin appears at the cell surface, particularly at the membrane ruffles where active Rac1 is positioned. Interestingly, cooperativity between T-Ag and β-catenin leads to activation of Rac1, which in turn, stimulates its association with β-catenin. These observations unravel the interplay between β-catenin and Rac1 that is initiated by T-Ag and results in stabilization of β-catenin and its presence in cell membrane ruffles.

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Abbreviations

ALLN:

acetyle-L-leucyl-L-norleucinal

DMSO:

dimethyl sulfoxide

GSK:

glycogen synthase kinase

IB:

immunoblotting

IP:

immunoprecipitation

LiCl:

lithium chloride

Rho:

Ras homology

SRE:

serum response element

T-Ag:

Large T-antigen of JC virus

Ub:

ubiquitin

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Acknowledgements

We thank past and present members of the Department of Neuroscience and the Center for Neurovirology for their support, and sharing of reagents and ideas. We also thank Dr Wedegaertner, Dr Grosscheld, Dr Sheikhattar, Dr Woodgett, Dr Tuszynski and Dr Marchese for providing the various plasmids and antibodies. We thank Dr Banerjee, Dr White and Dr Gordon for suggestions during manuscript preparation. This work was supported by NIH grants to KK.

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  1. Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA

    R Bhattacharyya, E K Noch & K Khalili

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  1. R Bhattacharyya
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  2. E K Noch
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  3. K Khalili
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Correspondence to K Khalili.

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Bhattacharyya, R., Noch, E. & Khalili, K. A novel role of Rac1 GTPase in JCV T-antigen-mediated β-catenin stabilization. Oncogene 26, 7628–7636 (2007). https://doi.org/10.1038/sj.onc.1210576

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