Mammalian Numb protein antagonizes Notch by controlling postendocytic trafficking of the Notch ligand Delta-like 4.
J Biol Chem
; 292(50): 20628-20643, 2017 12 15.
Article
em En
| MEDLINE
| ID: mdl-29042443
ABSTRACT
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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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Endotélio Vascular
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Transdução de Sinais
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Peptídeos e Proteínas de Sinalização Intercelular
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Proteínas Adaptadoras de Transporte Vesicular
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Endocitose
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Receptor Notch1
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Proteínas de Membrana
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Proteínas do Tecido Nervoso
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
China