The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating Notch trafficking
The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating Notch trafficking
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DOI：
10.1016/j.devcel.2005.09.019
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发表时间：
2005-11-01
影响因子：
11.8
通讯作者：
Bilder, D
中科院分区：
文献类型：
--
作者：
Vaccari, T;Bilder, D
细胞-细胞信号在后生动物组织发育过程中协调增殖，其改变可诱发恶性转化。内吞作用通过控制配体结合前后跨膜受体的水平和活性来调节信号传导。在这里，我们发现Vps25是一种非常规类型的果蝇肿瘤抑制因子，它是ESCRT机制的一个组成部分，调节信号受体的内吞分选。Vps25突变细胞经历自主的肿瘤样转化，但它们也刺激非自主细胞增殖。vps25细胞的内吞运输缺陷导致信号受体Notch的内体积累和Notch信号的增强。Notch活性的增加导致有丝分裂JAK-STAT通路配体Unpaired异位产生，该配体由突变细胞分泌，诱导周围上皮过度增殖。我们的数据表明，内噬分选中的缺陷既可以转化细胞，也可以通过异型信号传导改变邻近野生型组织的行为。
Cell-cell signaling coordinates proliferation of metazoan tissues during development, and its alteration can induce malignant transformation. Endocytosis regulates signaling by controlling the levels and activity of transmembrane receptors, both prior to and following ligand engagement. Here, we identify Vps25, a component of the ESCRT machinery that regulates endocytic sorting of signaling receptors, as an unconventional type of Drosophila tumor suppressor. vps25 mutant cells undergo autonomous neoplastic-like transformation, but they also stimulate nonautonomous cell proliferation. Endocytic trafficking defects in vps25 cells cause endosomal accumulation of the signaling receptor Notch and enhanced Notch signaling. Increased Notch activity leads to ectopic production of the mitogenic JAK-STAT pathway ligand Unpaired, which is secreted from mutant cells to induce overproliferation of the surrounding epithelium. Our data show that defects in endocytic sorting can both transform cells and, through heterotypic signaling, alter the behavior of neighboring wild-type tissue.