Journal of Biological Chemistry
Volume 290, Issue 50, 11 December 2015, Pages 29808-29819
Journal home page for Journal of Biological Chemistry

Developmental Biology
Tumor Suppressor Lzap Suppresses Wnt/β-Catenin Signaling to Promote Zebrafish Embryonic Ventral Cell Fates via the Suppression of Inhibitory Phosphorylation of Glycogen Synthase Kinase 3*

https://doi.org/10.1074/jbc.M115.669309Get rights and content
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Wnt/β-catenin signaling controls various cell fates in metazoan development, and its dysregulation is often associated with cancer formation. However, regulations of this signaling pathway are not completely understood. Here, we report that Lzap, a tumor suppressor, controls nuclear translocation of β-catenin. In zebrafish embryos disruption of lzap increases the expression of chordin (chd), which encodes a bone morphogenetic protein (BMP) antagonist that is localized in prospective dorsal cells and promotes dorsal fates. Consistently, lzap-deficient embryos with attenuated BMP signaling are dorsalized, which can be rescued by overexpression of zebrafish lzap or bmp2b or human LZAP. The expansion of chd expression in embryos lacking lzap is due to the accumulation of nuclear β-catenin in ventral cells, in which β-catenin is usually degraded. Furthermore, the activity of GSK3, a master regulator of β-catenin degradation, is suppressed in lzap-deficient embryos via inhibitory phosphorylation. Finally, we also report that a similar regulatory axis is also likely to be present in a human tongue carcinoma cell line, SAS. Our results reveal that Lzap is a novel regulator of GSK3 for the maintenance of ventral cell properties and may prevent carcinogenesis via the regulation of β-catenin degradation.

β-catenin (B-catenin)
bone morphogenetic protein (BMP)
glycogen synthase kinase 3 (GSK-3)
tumor suppressor gene
Wnt signaling
Cdk5rap3
Chordin
dorsal-ventral patterning

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*

This work was supported by intramural funding from the Institute of Cellular and Organismic Biology, Academia Sinica, Taiwan. The authors declare that they have no conflicts of interest with the contents of this article.

This article contains supplemental Table S1 and Figs. S1–S14.

1

Present address: Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, National Chung-Hsing University and Academia Sinica, Taipei 11529.

2

Present address: Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu 30013, Taiwan.