Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
Sci China Life Sci. 2022 Nov;65(11):2131-2144. doi: 10.1007/s11427-022-2156-2. Epub 2022 Sep 1.
The evolutionarily conserved Hippo pathway coordinates cell proliferation, differentiation and apoptosis to regulate organ growth and tumorigenesis. Hippo signaling activity is tightly controlled by various upstream signals including growth factors and cell polarity, but the full extent to which the pathway is regulated during development remains to be resolved. Here, we report the identification of Shaggy, the homolog of mammalian Gsk3β, as a novel regulator of the Hippo pathway in Drosophila. Our results show that Shaggy promotes the expression of Hippo target genes in a manner that is dependent on its kinase activity. Loss of Shaggy leads to Yorkie inhibition and downregulation of Hippo pathway target genes. Mechanistically, Shaggy acts upstream of the Hippo pathway and negatively regulates the abundance of the FERM domain containing adaptor protein Expanded. Our results reveal that Shaggy is functionally required for Crumbs/Slmb-mediated downregulation of Expanded in vivo, providing a potential molecular link between cellular architecture and the Hippo signaling pathway.
进化保守的 Hippo 通路协调细胞增殖、分化和凋亡，以调节器官生长和肿瘤发生。Hippo 信号活性受到各种上游信号的严格控制，包括生长因子和细胞极性，但通路在发育过程中的调控程度仍有待解决。在这里，我们报道了 Shaggy 的鉴定，它是果蝇中 Hippo 通路的一个新的调节因子。我们的结果表明，Shaggy 以依赖其激酶活性的方式促进 Hippo 靶基因的表达。Shaggy 的缺失导致 Yorkie 的抑制和 Hippo 通路靶基因的下调。在机制上，Shaggy 作用于 Hippo 通路的上游，负调控 FERM 结构域包含衔接蛋白 Expanded 的丰度。我们的结果表明，Shaggy 在体内 Crumbs/Slmb 介导的 Expanded 下调中具有功能上的必要性，为细胞结构和 Hippo 信号通路之间提供了一个潜在的分子联系。
