NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
复制标题
DOI：
10.1038/ncomms7314
复制
发表时间：
2015-02-01
影响因子：
16.6
通讯作者：
Seol, Jae Hong
中科院分区：
文献类型：
--
作者：
Bae, Sung Jun;Kim, Myungjin;Seol, Jae Hong
河马途径在调节器官大小和干细胞动态平衡方面起着至关重要的作用。虽然对核心河马蛋白激酶的信号级联相对了解较多，但对调节河马信号通路活性的机制知之甚少。在这里，我们报告了NEDD4，一种Hect类型的E3泛素连接酶，作为河马途径的调节成分。我们证明了NEDD4泛素化和破坏WW45和LATS激酶的稳定，这两个蛋白都是激活河马信号所必需的。有趣的是，MST1可以保护WW45而不是LATS2免受NEDD4的侵袭。我们还提供了证据表明，NEDD4在高细胞密度下的失活是与接触抑制相关的高河马活性的先决条件。此外，NEDD4通过抑制河马信号来促进果蝇肠道干细胞的更新。综上所述，我们提出了一种调控机制，NEDD4通过该机制控制河马通路，从而协调细胞增殖和凋亡。
The Hippo pathway plays crucial roles in regulating organ size and stem cell homeostasis. Although the signalling cascade of the core Hippo kinases is relatively well understood, little is known about the mechanisms that modulate the activity of the Hippo pathway. Here, we report identification of NEDD4, a HECT-type E3 ubiquitin ligase, as a regulatory component of the Hippo pathway. We demonstrate that NEDD4 ubiquitylates and destabilizes WW45 and LATS kinase, both of which are required for active Hippo signalling. Interestingly, MST1 protects WW45, but not LATS2, against NEDD4. We also provide evidence indicating that NEDD4 inactivation at high cell density is a prerequisite for the elevated Hippo activity linked to contact inhibition. Moreover, NEDD4 promotes intestinal stem cell renewal in Drosophila by suppressing Hippo signalling. Collectively, we present a regulatory mechanism by which NEDD4 controls the Hippo pathway leading to coordinated cell proliferation and apoptosis.