3 years ago

Downregulation of the Wnt/β-catenin signaling pathway by Cacnb4.

Lopez, Daghsni, Merle, Lefrancois, Rima, Brusés, Dunach, Mori, Fajloun, Ronjat, de Waard
The β4 isoform of the β-subunits of Voltage-Gated Calcium Channel regulates cell proliferation and cell cycle progression. Herein we show that co-expression of the β4-subunit with actors of the canonical Wnt/β-catenin signaling pathway in a hepatoma cell line inhibits Wnt responsive gene transcription and decreases cell division, in agreement with the role of the Wnt pathway in cell proliferation. β4-subunit-mediated inhibition of Wnt signaling is observed in the presence of LiCl, an inhibitor of GSK3 that promotes β-catenin translocation to the nucleus. Expression of β4-subunit mutants that lost the ability to translocate to the nucleus has no effect on Wnt signaling, suggesting that β4-subunit inhibition of Wnt signaling occurs downstream GSK3 and requires targeting of β4-subunit to the nucleus. β4-subunit co-immunoprecipitates with the TCF4 transcription factor and overexpression of TCF4 reverses the effect of β4-subunit on the Wnt pathway. We thus propose that the interaction of nuclear β4-subunit with TCF4 prevents β-catenin binding to TCF4 and leads to the inhibition of the Wnt responsive gene transcription. Thereby, our results show that β4-subunit is a TCF4 repressor and therefore appears as an interesting candidate for the regulation of this pathway in neurons where β4-subunit is specifically expressed.

Publisher URL: http://doi.org/10.1091/mbc.E17-01-0076

DOI: 10.1091/mbc.E17-01-0076

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