Vaccari Thomas, Lu Han, Kanwar Ritu, Fortini Mark E, Bilder David
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
J Cell Biol. 2008 Feb 25;180(4):755-62. doi: 10.1083/jcb.200708127.
Signaling through the transmembrane receptor Notch is widely used throughout animal development and is a major regulator of cell proliferation and differentiation. During canonical Notch signaling, internalization and recycling of Notch ligands controls signaling activity, but the involvement of endocytosis in activation of Notch itself is not well understood. To address this question, we systematically assessed Notch localization, processing, and signaling in a comprehensive set of Drosophila melanogaster mutants that block access of cargo to different endocytic compartments. We find that gamma-secretase cleavage and signaling of endogenous Notch is reduced in mutants that impair entry into the early endosome but is enhanced in mutants that increase endosomal retention. In mutants that block endosomal entry, we also uncover an alternative, low-efficiency Notch trafficking route that can contribute to signaling. Our data show that endosomal access of the Notch receptor is critical to achieve physiological levels of signaling and further suggest that altered residence in distinct endocytic compartments could underlie pathologies involving aberrant Notch pathway activation.
通过跨膜受体Notch进行的信号传导在动物发育过程中被广泛使用，并且是细胞增殖和分化的主要调节因子。在经典的Notch信号传导过程中，Notch配体的内化和再循环控制着信号传导活性，但内吞作用在Notch自身激活中的作用尚不清楚。为了解决这个问题，我们系统地评估了一组全面的果蝇突变体中Notch的定位、加工和信号传导，这些突变体阻止货物进入不同的内吞区室。我们发现，在内吞体进入受损的突变体中，内源性Notch的γ-分泌酶切割和信号传导减少，但在增加内吞体滞留的突变体中增强。在阻止内吞体进入的突变体中，我们还发现了一条替代的、低效的Notch运输途径，它可以促进信号传导。我们的数据表明，Notch受体的内吞体进入对于实现生理水平的信号传导至关重要，并且进一步表明，在不同内吞区室中停留时间的改变可能是涉及Notch途径异常激活的病理基础。
