Mammalian Numb protein antagonizes Notch by controlling postendocytic trafficking of the Notch ligand Delta-like 4
Mammalian Numb protein antagonizes Notch by controlling postendocytic trafficking of the Notch ligand Delta-like 4
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哺乳动物 Numb 蛋白通过控制 Notch 配体 Delta-like 4 的内吞后运输来拮抗 Notch
DOI：
10.1074/jbc.m117.800946
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发表时间：
2017-10
影响因子：
4.8
通讯作者：
Li Hongchang
中科院分区：
文献类型：
--
作者：
Shao Ximing;Ding Zhihao;Zhao Ming;Liu Ke;Sun Haiyan;Chen Juntao;Liu Xianming;Zhang Yuzhen;Hong Yang;Li Huashun;Li Hongchang
信号蛋白Numb和Notch之间的生物拮抗作用涉及许多发育过程的调节，特别是在不对称细胞分裂中。机制研究表明，Numb通过内吞作用和蛋白酶体降解使Notch失活，直接降低细胞表面的Notch蛋白水平。然而，Numb如何对抗Notch的某些方面仍不清楚。在这里，我们报告了一种新的机制，其中Numb作为一个Notch拮抗剂通过控制细胞内的目的地和稳定性的Notch配体Delta样4（Dll4）通过postendocytic-sorting过程。我们观察到Numb/Numblike敲低增加了Dll4的稳定性和细胞表面积累。进一步的研究表明，Numb作为一个分选开关，以控制Dll4的胞内后运输。值得注意的是，Numb/Numb样敲低减少了Dll 4向溶酶体的递送，同时增加了Dll 4向质膜的再循环。此外，我们证明了在Numb/Numb样敲低细胞内的细胞表面处的Dll4的这种富集可以激活邻近细胞中的Notch信号传导。我们还提供了证据表明，Numb负控制Dll4质膜再循环通过一个有据可查的再循环调节蛋白AP 1。总之，我们的研究揭示了Numb调节Notch配体Dll4内吞运输的分子机制。我们的研究结果为Numb如何抵消Notch信号传导提供了一个新的视角，并对Numb和Notch信号传导之间的拮抗关系提供了额外的重要见解。
The biological antagonism between the signaling proteins Numb and Notch has been implicated in the regulation of many developmental processes, especially in asymmetric cell division. Mechanistic studies show that Numb inactivates Notch via endocytosis and proteasomal degradation that directly reduce Notch protein levels at the cell surface. However, some aspects of how Numb antagonizes Notch remain unclear. Here, we report a novel mechanism in which Numb acts as a Notch antagonist by controlling the intracellular destination and stability of the Notch ligand Delta-like 4 (Dll4) through a postendocytic-sorting process. We observed that Numb/Numblike knockdown increases the stability and cell-surface accumulation of Dll4. Further study indicated that Numb acts as a sorting switch to control the postendocytic trafficking of Dll4. Of note, the Numb/Numblike knockdown decreased Dll4 delivery to the lysosome, while increasing the recycling of Dll4 to the plasma membrane. Moreover, we demonstrate that this enrichment of Dll4 at the cell surface within Numb/Numblike knockdown cells could activate Notch signaling in neighboring cells. We also provide evidence that Numb negatively controls the Dll4 plasma membrane recycling through a well-documented recycling regulator protein AP1. In conclusion, our study has uncovered a molecular mechanism whereby Numb regulates the endocytic trafficking of the Notch ligand Dll4. Our findings provide a new perspective on how Numb counteracts Notch signaling and sheds additional critical insights into the antagonistic relationship between Numb and Notch signaling.
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影响因子：
16.2
作者：
Spana, EP;Doe, CQ
通讯作者：
Doe, CQ
Numb 通过 Mon1b 的膜募集调节早期内体同型融合的囊泡对接
影响因子：
44.1
作者：
Shao Ximing;Liu Yi;Yu Qian;Ding Zhihao;Qian Wenyu;Zhang Lei;Zhang Jianchao;Jiang Nan;Gui Linfei;Xu Zhiheng;Hong Yang;Ma Yifan;Wei Yanjie;Liu Xiaoqing;Jiang Changan;Zhu Minyan;Li Hongchang;Li Huashun
通讯作者：
Li Huashun
影响因子：
64.5
作者：
Emery, G;Hutterer, A;Knoblich, JA
通讯作者：
Knoblich, JA
影响因子：
11.8
作者：
Nishimura, Takashi;Kaibuchi, Kozo
通讯作者：
Kaibuchi, Kozo
影响因子：
3.3
作者：
Christian A. Smith;S. Dho;J. Donaldson;U. Tepass;C. McGlade
通讯作者：
Christian A. Smith;S. Dho;J. Donaldson;U. Tepass;C. McGlade