Department of Developmental Biology, Washington University School of Medicine, St. Louis, USA.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
J Cell Biol. 2023 May 1;222(5). doi: 10.1083/jcb.202204059. Epub 2023 Apr 18.
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.
Hippo 通路是组织生长的保守和关键调节因子。FERM 蛋白 Expanded 是一个关键的信号枢纽，它促进 Hippo 通路的激活，从而抑制转录共激活因子 Yorkie。以前的工作确定了极性决定因子 Crumbs 是 Expanded 的主要调节因子。在这里，我们表明巨型钙粘蛋白 Fat 也直接调节 Expanded，而不依赖于 Crumbs。我们表明，Expanded 和 Fat 细胞质结构域的一个高度保守区域之间的直接结合将 Expanded 招募到顶侧连接区，并稳定 Expanded。体内删除 Fat 中 Expanded 结合区域会导致顶侧 Expanded 的丢失，并促进组织过度生长。出乎意料的是，我们发现 Fat 可以通过其细胞质结构域的相互作用与其配体 Dachsous 结合，除了已知的细胞外相互作用。重要的是，Fat 独立于 Dachsous 结合稳定 Expanded。这些数据为 Fat 如何调节 Expanded 以及 Hippo 信号在器官生长过程中如何被调节提供了新的机制见解。
