Vaccari Thomas, Bilder David
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA.
Dev Cell. 2005 Nov;9(5):687-98. doi: 10.1016/j.devcel.2005.09.019.
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.
细胞间信号传导在发育过程中协调后生动物组织的增殖，其改变可诱导恶性转化。内吞作用通过控制跨膜受体在配体结合之前和之后的水平及活性来调节信号传导。在此，我们鉴定出Vps25，它是ESCRT机制的一个组成部分，调节信号受体的内吞分选，是一种非传统类型的果蝇肿瘤抑制因子。vps25突变细胞会发生自主性肿瘤样转化，但它们也会刺激非自主性细胞增殖。vps25细胞中的内吞运输缺陷导致信号受体Notch在内体中积累并增强Notch信号传导。Notch活性增加导致有丝分裂原性JAK-STAT途径配体Unpaired的异位产生，该配体从突变细胞中分泌出来，诱导周围上皮细胞过度增殖。我们的数据表明，内吞分选缺陷既能使细胞发生转化，又能通过异型信号传导改变邻近野生型组织的行为。
