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
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
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DOI：
10.1074/jbc.m115.669309
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发表时间：
2015-12-11
影响因子：
4.8
通讯作者：
Wang, Wen-Der
中科院分区：
文献类型：
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作者：
Lin, Kun-Yang;Kao, Shih-Han;Wang, Wen-Der
Wnt/ β -连环蛋白信号控制着后生动物发育中的各种细胞命运，其失调通常与癌症的形成有关。然而，这一信号通路的调控尚不完全清楚。在这里，我们报道Lzap，一种肿瘤抑制因子，控制β -连环蛋白的核易位。在斑马鱼胚胎中，lzap的破坏增加了脊索蛋白（chd）的表达，脊索蛋白编码一种骨形态发生蛋白（BMP）拮抗剂，该拮抗剂定位于未来的背细胞并促进背命运。与此一致的是，缺乏lzap且BMP信号减弱的胚胎是背化的，这可以通过斑马鱼lzap或bmp2b或人类lzap的过表达来拯救。在缺乏lzap的胚胎中，chd表达的增加是由于核β -连环蛋白在腹侧细胞中积累，在腹侧细胞中β -连环蛋白通常被降解。此外，GSK3 （β -连环蛋白降解的主要调节因子）的活性在缺乏lzap的胚胎中通过抑制性磷酸化受到抑制。最后，我们还报道了类似的调控轴也可能存在于人类舌癌细胞系SAS中。我们的研究结果表明，Lzap是GSK3维持腹侧细胞特性的一种新的调节剂，可能通过调节β -连环蛋白的降解来防止癌变。
Wnt/beta-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 beta-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 beta-catenin in ventral cells, in which beta-catenin is usually degraded. Furthermore, the activity of GSK3, a master regulator of beta-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 beta-catenin degradation.