Chemical compound screening and development for Hippo signaling pathway

哺乳动物Hippo通路由哺乳动物Ste20样（MST）激酶和大肿瘤抑制因子（LATS）激酶组成。在该途径激活后，具有PDZ结合基序（TAZ）和yes相关蛋白（雅普）的转录共激活因子被磷酸化并从细胞核募集到胞质溶胶，基因转录被关闭。TAZ与多种转录因子协同作用，发挥多种作用。我们开发了一种基于细胞的测定，使用表达TAZ的MCF 10A细胞形成的球体作为读数，以筛选18，458种化合物的TAZ激活剂。在这项研究中，我们专注于一种化合物IBS008738。IBS008738促进心脏毒素诱导的肌肉损伤中的肌肉修复，并预防地塞米松诱导的肌肉萎缩。因此，这种基于细胞的测定可用于鉴定具有多种细胞输出的TAZ激活剂。我们的研究结果也支持TAZ是肌肉萎缩的潜在治疗靶点的观点。

The mammalian Hippo pathway is composed of mammalian Ste20-like (MST) kinases and large tumor suppressor (LATS) kinases. Upon the activation of the pathway, transcriptional co-activator with PDZ-binding motif (TAZ) and yes-associated protein (YAP) are phosphorylated and recruited to the cytosol from the nucleus, and gene transcription is turned off. TAZ cooperates with various transcriptional factors and plays various roles. We developed a cell-based assay using sphere formation by TAZ-expressing MCF10A cells as a readout to screen 18,458 chemical compounds for TAZ activators. In this study, we focused on one compound, IBS008738. IBS008738 facilitates muscle repair in cardiotoxin-induced muscle injury and prevents dexamethasone-induced muscle atrophy. Thus, this cell-based assay is useful to identify TAZ activators with a variety of cellular outputs. Our findings also support the idea that TAZ is a potential therapeutic target for muscle atrophy.