Tumor Suppressor Lzap Suppresses Wnt/β-catenin signaling to Promote Zebrafish Embryonic Ventral Cell Fates via the Suppression of Inhibitory Phosphorylation of GSK3

Wnt/β-catenin signaling controls various cell fates in metazoan development, and its dysregulation is often associated with cancer formation. However, regulation of this signaling pathway remains unclear. Here, we report that Lzap, a tumor suppressor, suppresses inhibitory phosphorylation of GSK3 to prevent the nuclear translocation of β-catenin. In zebrafish embryos, disruption of lzap increases the expression of chordin (chd), which encodes a 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. Further, 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 promotion of β-catenin degradation.