Numb Regulates Post-endocytic Trafficking and Degradation of Notch1
Numb Regulates Post-endocytic Trafficking and Degradation of Notch1
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DOI：
10.1074/jbc.m109.014845
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发表时间：
2009-09-25
影响因子：
4.8
通讯作者：
McGlade, C. Jane
中科院分区：
文献类型：
--
作者：
McGill, Melanie A.;Dho, Sascha E.;McGlade, C. Jane
Noch是一种跨膜受体，在发育和组织内稳态过程中控制细胞命运的决定。Notch信号的激活和衰减都受到内吞作用的严格调控。接头蛋白Numb作为Notch的抑制因子，在细胞内转运途径中发挥作用。然而，Numb在规范缺口贩运中的作用尚未确定。在这里，我们表明哺乳动物Notch1被结构性内化并被贩运到再循环和晚期内体隔室，我们还证明了Numb表达的变化改变了Notch1运输的动力学。Numb的过表达促进了Notch1通过晚期内体进行降解，而Numb的耗尽促进了Notch1的循环。许多不与泛素蛋白异肽连接酶Itch相互作用的突变体，或者缺乏与内吞蛋白相互作用的重要基序的突变体，都无法促进Notch1的降解。我们的数据表明，Numb通过调节导致Notch1降解的内吞后分选事件来抑制Notch1的活性。
Notch is a transmembrane receptor that controls cell fate decisions during development and tissue homeostasis. Both activation and attenuation of the Notch signal are tightly regulated by endocytosis. The adaptor protein Numb acts as an inhibitor of Notch and is known to function within the intracellular trafficking pathways. However, a role for Numb in regulating Notch trafficking has not been defined. Here we show that mammalian Notch1 is constitutively internalized and trafficked to both recycling and late endosomal compartments, and we demonstrate that changes in Numb expression alter the dynamics of Notch1 trafficking. Overexpression of Numb promotes sorting of Notch1 through late endosomes for degradation, whereas depletion of Numb facilitates Notch1 recycling. Numb mutants that do not interact with the ubiquitin-protein isopeptide ligase, Itch, or that lack motifs important for interaction with endocytic proteins fail to promote Notch1 degradation. Our data suggest that Numb inhibits Notch1 activity by regulating post-endocytic sorting events that lead to Notch1 degradation.