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

Abstract:

:The β4 isoform of the β-subunits of voltage-gated calcium channel regulates cell proliferation and cell cycle progression. Herein we show that coexpression 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 glycogen synthase kinase (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 from GSK3 and requires targeting of β4-subunit to the nucleus. β4-subunit coimmunoprecipitates 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.

journal_name

Mol Biol Cell

authors

Rima M,Daghsni M,Lopez A,Fajloun Z,Lefrancois L,Dunach M,Mori Y,Merle P,Brusés JL,De Waard M,Ronjat M

doi

10.1091/mbc.E17-01-0076

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

3699-3708

issue

25

eissn

1059-1524

issn

1939-4586

pii

mbc.E17-01-0076

journal_volume

28

pub_type

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