Self-refinement of Notch activity through the transmembrane protein Crumbs:: modulation of γ-secretase activity
Self-refinement of Notch activity through the transmembrane protein Crumbs:: modulation of γ-secretase activity
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DOI：
10.1038/sj.embor.7400617
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发表时间：
2006-03-01
期刊：
影响因子：
7.7
通讯作者：
Milán, M
中科院分区：
文献类型：
--
作者：
Herranz, H;Stamataki, E;Milán, M
Notch家族受体介导的细胞相互作用与组织边界的特化有关。Notch的紧密局部激活对于尖锐边界的形成至关重要。在果蝇翅盘中，Notch受体在所有细胞中表达。然而，Notch活性仅限于沿背-腹隔室边界沿着的窄条细胞，在那里它诱导靶基因的表达。目前还不完全清楚广泛表达的蛋白质如何在果蝇翅膀的背腹边界受到严格调节。在这里，我们表明，跨膜蛋白Crumbs参与反馈机制所使用的Notch完善自己的激活域在果蝇翅缘。面包屑降低γ-分泌酶复合物的活性，该复合物介导Notch的蛋白水解细胞内加工。这些结果表明Notch信号调节的新分子机制，并且Crumbs中的缺陷可能涉及在阿尔茨海默病中观察到的类似异常γ-分泌酶复合物活性。
Cell interactions mediated by Notch family receptors have been implicated in the specification of tissue boundaries. Tightly localized activation of Notch is crucial for the formation of sharp boundaries. In the Drosophila wing imaginal disc, the Notch receptor is expressed in all cells. However, Notch activity is limited to a narrow stripe of cells along the dorsal-ventral compartment boundary, where it induces the expression of target genes. How a widely expressed protein becomes tightly regulated at the dorsal-ventral boundary in the Drosophila wing is not completely understood. Here, we show that the transmembrane protein Crumbs is involved in a feedback mechanism used by Notch to refine its own activation domain at the Drosophila wing margin. Crumbs reduces the activity of the gamma-Secretase complex, which mediates the proteolytic intracellular processing of Notch. These results indicate a novel molecular mechanism of the regulation of Notch signal, and also that defects in Crumbs might be involved in similar abnormal gamma-Secretase complex activity observed in Alzheimer's disease.