Institute of Molecular Systems Biology, ETH Zürich, Wolfgang-Pauli-Strasse 16, 8093 Zürich, Switzerland.
Curr Biol. 2012 Mar 6;22(5):389-96. doi: 10.1016/j.cub.2012.01.019. Epub 2012 Feb 2.
The conserved Hippo signaling pathway acts in growth control and is fundamental to animal development and oncogenesis. Hippo signaling has also been implicated in adult midgut homeostasis in Drosophila. Regulated divisions of intestinal stem cells (ISCs), giving rise to an ISC and an enteroblast (EB) that differentiates into an enterocyte (EC) or an enteroendocrine (EE) cell, enable rapid tissue turnover in response to intestinal stress. The damage-related increase in ISC proliferation requires deactivation of the Hippo pathway and consequential activation of the transcriptional coactivator Yorkie (Yki) in both ECs and ISCs. Here, we identify Pez, an evolutionarily conserved FERM domain protein containing a protein tyrosine phosphatase (PTP) domain, as a novel binding partner of the upstream Hippo signaling component Kibra. Pez function--but not its PTP domain--is essential for Hippo pathway activity specifically in the fly midgut epithelium. Thus, Pez displays a tissue-specific requirement and functions as a negative upstream regulator of Yki in the regulation of ISC proliferation.
保守的 Hippo 信号通路在生长控制中起作用，是动物发育和肿瘤发生的基础。Hippo 信号通路也与果蝇成年中肠稳态有关。肠干细胞 (ISCs) 的有调节的分裂，产生一个 ISC 和一个 enteroblast (EB)，后者分化为肠细胞 (EC) 或肠内分泌细胞 (EE)，使组织在受到肠道应激时能够快速更新。ISC 增殖的损伤相关增加需要 Hippo 途径的失活，以及随后在 EC 和 ISC 中转录共激活因子 Yorkie (Yki) 的激活。在这里，我们鉴定出 Pez，一种进化上保守的 FERM 结构域蛋白，含有一个蛋白酪氨酸磷酸酶 (PTP) 结构域，作为上游 Hippo 信号组分 Kibra 的一个新的结合伴侣。Pez 的功能——而不是其 PTP 结构域——对于 Hippo 途径在果蝇中肠上皮细胞中的活性是必需的。因此，Pez 表现出组织特异性的要求，并作为 Yki 在调节 ISC 增殖中的负上游调节剂发挥作用。
