Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation
Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation
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DOI：
10.1016/j.cub.2004.12.028
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发表时间：
2004-12-29
期刊：
影响因子：
9.2
通讯作者：
Hayashi, S
中科院分区：
文献类型：
--
作者：
Sakata, T;Sakaguchi, H;Hayashi, S
背景：配体诱导的质膜受体Notch的蛋白水解切割和内化导致其活化。然而，Notch的配体非依赖性稳态内化不会导致激活。下游效应子区分Notch内化的这些二分模式的机制尚不清楚。Nedd4是含有HECT结构域的E3泛素连接酶，其靶向含有PPSY基序的跨膜受体用于内吞作用。Deltex是一个积极的Notch信号调节器，编码一个假定的泛素连接酶的环finger type.Results：我们使用的果蝇系统显示，Notch是泛素化和不稳定的Nedd4的方式需要在Notch细胞内域的PPSY基序。Nedd4功能的丧失主要抑制Notch和Deltex突变体表型，并且其超活化减弱Notch活性。在组织培养细胞中，显性负性形式的Nedd4阻断稳态Notch内化并独立于配体结合激活Notch信号传导。Deltex进一步增强了这种效果。结论：Nedd4通过促进Notch和Deltex的降解来拮抗Notch信号通路。这种Nedd4功能对于保护未受刺激的细胞免受Notch信号传导的偶发性激活可能是重要的。
Background: Ligand-induced proteolytic cleavage and internalization of the plasma membrane receptor Notch leads to its activation. Ligand-independent, steadystate internalization of Notch, however, does not lead to activation. The mechanism by which downstream effectors discriminate between these bipartite modes of Notch internalization is not understood. Nedd4 is a HECT domain-containing E3 ubiquitin ligase that targets transmembrane receptors containing the PPSY motif for endocytosis. Deltex is a positive Notch signaling regulator that encodes a putative ubiquitin ligase of the ring finger type.Results: We used the Drosophila system to show that Notch is ubiquitinated and destabilized by Nedd4 in a manner requiring the PPSY motif in the Notch intracellular domain. Loss of Nedd4 function dominantly suppresses the Notch and Deltex mutant phenotypes, and its hyperactivation attenuates Notch activity. In tissue culture cells, the dominant-negative form of Nedd4 blocks steady-state Notch internalization and activates Notch signaling independently of ligand binding. This effect was further potentiated by Deltex. Nedd4 destines Deltex for degradation in a Notch-dependent manner.Conclusions: Nedd4 antagonizes Notch signaling by promoting degradation of Notch and Deltex. This Nedd4function may be important for protecting unstimulated cells from sporadic activation of Notch signaling.