POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation
POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation
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POSH 通过泛素介导的扩展降解调节 Hippo 信号传导
DOI：
10.1073/pnas.1715165115
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发表时间：
2018-02-27
影响因子：
11.1
通讯作者：
Xue, Lei
中科院分区：
文献类型：
--
作者：
Ma, Xianjue;Guo, Xiaowei;Xue, Lei
Hippo信号通路是器官生长、组织稳态和肿瘤发生的主要调控者。Hippo通路的活性受多种上游组分控制，包括Expanded（Ex），但Ex具体的分子调控机制仍不甚明了。在此，我们鉴定出富含SH3结构域蛋白（POSH）——一种E3泛素连接酶，是果蝇Hippo信号传导中的关键组分。POSH过表达与Kibra缺失协同作用，可诱导过度生长以及Hippo通路靶基因的上调。此外，敲低POSH会阻碍硫酸葡聚糖钠诱导的、依赖于Yorkie的肠道干细胞更新，这表明POSH在调节Hippo信号传导中具有生理作用。从机制上讲，POSH与Ex的C端结合，对于Crumbs诱导的Ex泛素化和降解至关重要。我们的研究结果表明，POSH是一个关键的调节因子，它整合来自细胞表面的信号，对果蝇中Ex介导的Hippo激活起负调控作用。
Significance Here we performed a genetic screen in Drosophila and identified POSH (Plenty of SH3s), an E3 ubiquitin ligase, as a regulator of Hippo pathway. We found POSH ubiquitinates and degrades Ex (Expanded) to inactivate Hippo signaling. Intriguingly, POSH is particularly crucial for damage-induced intestinal stem cell renewal in a Yorki-dependent manner, highlighting the essential physiological role of POSH as a stress sensor in gut epithelia. Given the conservation of the Hippo signaling pathway between Drosophila and human, our findings here suggest that POSH might play a similar role in mammalian growth control. The Hippo signaling pathway is a master regulator of organ growth, tissue homeostasis, and tumorigenesis. The activity of the Hippo pathway is controlled by various upstream components, including Expanded (Ex), but the precise molecular mechanism of how Ex is regulated remains poorly understood. Here we identify Plenty of SH3s (POSH), an E3 ubiquitin ligase, as a key component of Hippo signaling in Drosophila. POSH overexpression synergizes with loss of Kibra to induce overgrowth and up-regulation of Hippo pathway target genes. Furthermore, knockdown of POSH impedes dextran sulfate sodium-induced Yorkie-dependent intestinal stem cell renewal, suggesting a physiological role of POSH in modulating Hippo signaling. Mechanistically, POSH binds to the C-terminal of Ex and is essential for the Crumbs-induced ubiquitination and degradation of Ex. Our findings establish POSH as a crucial regulator that integrates the signal from the cell surface to negatively regulate Ex-mediated Hippo activation in Drosophila.