The Hippo pathway is a conserved and critical regulator of tissue growth. The FERM protein Expanded is a key signaling hub that promotes activation of the Hippo pathway, thereby inhibiting the transcriptional co-activator Yorkie. Previous work identified the polarity determinant Crumbs as a primary regulator of Expanded. Here, we show that the giant cadherin Fat also regulates Expanded directly and independently of Crumbs. We show that direct binding between Expanded and a highly conserved region of the Fat cytoplasmic domain recruits Expanded to the apicolateral junctional zone and stabilizes Expanded. In vivo deletion of Expanded binding regions in Fat causes loss of apical Expanded and promotes tissue overgrowth. Unexpectedly, we find Fat can bind its ligand Dachsous via interactions of their cytoplasmic domains, in addition to the known extracellular interactions. Importantly, Expanded is stabilized by Fat independently of Dachsous binding. These data provide new mechanistic insights into how Fat regulates Expanded, and how Hippo signaling is regulated during organ growth.

中文翻译：

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Expanded 直接结合脂肪的保守区域，通过 Hippo 途径抑制生长


Hippo 途径是组织生长的保守且关键的调节因子。 FERM 蛋白 Expanded 是促进 Hippo 通路激活的关键信号传导中枢，从而抑制转录共激活因子 Yorkie。先前的工作将极性决定因素 Crumbs 确定为 Expanded 的主要调节因子。在这里，我们表明巨型钙粘蛋白脂肪也直接且独立于面包屑调节扩展。我们表明，Expanded 和脂肪细胞质结构域的高度保守区域之间的直接结合将 Expanded 招募到顶端外侧连接区并稳定 Expanded。体内脂肪中 Expanded 结合区域的缺失会导致顶端 Expanded 的损失并促进组织过度生长。出乎意料的是，我们发现除了已知的细胞外相互作用外，Fat 还可以通过其细胞质结构域的相互作用结合其配体 Dachsous。重要的是，Expanded 被 Fat 稳定，独立于 Dachsous 结合。这些数据为了解 Fat 如何调节 Expanded 以及 Hippo 信号在器官生长过程中如何调节提供了新的机制见解。