期刊
JOURNAL OF CELL BIOLOGY
卷 210, 期 2, 页码 303-318出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201411001
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资金
- Medical Research Council [G0800034]
- Bio-technology and Biological Sciences Research Council
- Deutsche Forschungsgemeinschaft [Sachbeihilfe KL 1028/5-1]
- MRC [MR/L007177/1, G0800034] Funding Source: UKRI
- Medical Research Council [MR/L007177/1, G0800034] Funding Source: researchfish
Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.
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