Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Curr Biol. 2013 Feb 4;23(3):229-35. doi: 10.1016/j.cub.2012.12.033. Epub 2013 Jan 17.
The Drosophila Yorkie (Yki) protein and its mammalian homolog Yes-associated protein (YAP) are potent growth promoters, and YAP overexpression is associated with multiple types of cancer. Yki and YAP are transcriptional coactivators and function as downstream effectors of the Hippo tumor suppressor pathway. The regulation of Yki and YAP by the Hippo signaling pathway has been extensively investigated; however, how they regulate gene expression is poorly understood. To identify additional regulators of Yki activity, we performed a genome-wide RNAi screen in Drosophila S2 cells. In this screen, we identified the conserved protein Mask (Multiple ankyrin repeats single KH domain) as a novel promoter of Yki activity in vitro and validated this function in vivo in Drosophila. We found that Mask is required downstream of the Hippo pathway for Yki to induce target-gene expression and that Mask forms complexes with Yki. The human Mask homolog MASK1 complexes with YAP and is required for the full activity of YAP. Additionally, elevated MASK1 expression is associated with worsened outcomes for breast cancer patients. We conclude that Mask is a novel cofactor for Yki/YAP required for optimal Yki/YAP activity during development and oncogenesis.
果蝇 Yorkie（Yki）蛋白及其哺乳动物同源物 Yes 相关蛋白（YAP）是强效的生长促进剂，YAP 过表达与多种类型的癌症有关。Yki 和 YAP 是转录共激活因子，是 Hippo 肿瘤抑制途径的下游效应物。Hippo 信号通路对 Yki 和 YAP 的调节已得到广泛研究，但它们如何调节基因表达仍知之甚少。为了鉴定 Yki 活性的其他调节剂，我们在果蝇 S2 细胞中进行了全基因组 RNAi 筛选。在该筛选中，我们鉴定了保守蛋白 Mask（多个锚蛋白重复序列单个 KH 结构域）作为体外 Yki 活性的新型启动子，并在体内在果蝇中验证了该功能。我们发现 Mask 是 Hippo 途径下游 Yki 诱导靶基因表达所必需的，并且 Mask 与 Yki 形成复合物。人类 Mask 同源物 MASK1 与 YAP 复合物，并为 YAP 的完全活性所必需。此外，升高的 MASK1 表达与乳腺癌患者的预后恶化相关。我们得出结论，Mask 是 Yki/YAP 的新型共激活因子，是发育和肿瘤发生过程中 Yki/YAP 活性的最佳所需。
