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.

Abstract

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.

• Authors: Kun-Yang Lin, Shih-Han Kao, Chun-Ming Lai, Ciao-Ting Chen, Chang-Yi Wu, Hwei-Jan Hsu, Wen-Der Wang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 50 Pg. 29808-19 (Dec 11 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26475862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• CDK5Rap3 protein, zebrafish
• Tumor Suppressor Proteins
• Wnt Proteins
• Zebrafish Proteins
• beta Catenin
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cell Lineage
• Genes, Tumor Suppressor
• Glycogen Synthase Kinase 3 (metabolism)
• Phosphorylation
• Signal Transduction
• Tumor Suppressor Proteins (physiology)
• Wnt Proteins (metabolism)
• Zebrafish (embryology)
• Zebrafish Proteins (physiology)
• beta Catenin (metabolism)