Chemical compound screening and development for Hippo signaling pathway

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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.