Rho1-Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila
Rho1-Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila
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Rho1-Wnd 信号调节果蝇细胞极性丧失诱导的细胞侵袭
DOI：
10.1038/onc.2015.137
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发表时间：
2016-02-18
期刊：
影响因子：
8
通讯作者：
Xue, L.
中科院分区：
文献类型：
--
作者：
Ma, X.;Chen, Y.;Xue, L.
细胞极性和 c-Jun N 末端激酶 (JNK) 活性对于维持组织稳态至关重要，其中任一者的破坏在癌症进展中很常见。尽管细胞极性丧失和 JNK 激活之间存在联系，但人们对异常细胞极性诱导 JNK 介导的细胞迁移和肿瘤侵袭的分子机制知之甚少。在这里，我们展示了通过敲低果蝇翼盘中细胞极性基因的体内侵袭模型进行遗传筛选的结果，并确定 Rho1-Wnd 信号传导是介导细胞极性丧失触发的 JNK 激活和细胞侵袭的重要分子环节。我们发现 Wallenda (Wnd) 是丝裂原激活蛋白激酶激酶家族的一种蛋白激酶，通过与 GTPase Rho1 形成复合物，对于 Rho1 诱导的 JNK 依赖性细胞侵袭、MMP1 激活和上皮间质转化来说既是必要的也是充分的。此外，当细胞凋亡被 p35 抑制时，Wnd 通过无翼产生促进细胞增殖和组织生长。最后，Wnd 显示出与 Ras(V12) 的致癌协同作用，触发眼盘中的肿瘤生长并导致腹神经索的侵袭。总之，我们的数据不仅提供了关于细胞极性丧失如何促进细胞侵袭的新颖机制见解，而且还强调了果蝇模型系统在探索人类癌症生物学方面的价值。
Both cell polarity and c-Jun N-terminal kinase (JNK) activity are essential to the maintenance of tissue homeostasis, and disruption of either is commonly seen in cancer progression. Despite the established connection between loss-of-cell polarity and JNK activation, much less is known about the molecular mechanism by which aberrant cell polarity induces JNK-mediated cell migration and tumor invasion. Here we show results from a genetic screen using an in vivo invasion model via knocking down cell polarity gene in Drosophila wing discs, and identify Rho1-Wnd signaling as an important molecular link that mediates loss-of-cell polarity-triggered JNK activation and cell invasion. We show that Wallenda (Wnd), a protein kinase of the mitogen-activated protein kinase kinase kinase family, by forming a complex with the GTPase Rho1, is both necessary and sufficient for Rho1-induced JNK-dependent cell invasion, MMP1 activation and epithelial-mesenchymal transition. Furthermore, Wnd promotes cell proliferation and tissue growth through wingless production when apoptosis is inhibited by p35. Finally, Wnd shows oncogenic cooperation with Ras(V12) to trigger tumor growth in eye discs and causes invasion into the ventral nerve cord. Together, our data not only provides a novel mechanistic insight on how cell polarity loss contributes to cell invasion, but also highlights the value of the Drosophila model system to explore human cancer biology.