The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth
The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth
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DOI：
10.1038/nature14298
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发表时间：
2015-06-25
期刊：
影响因子：
64.8
通讯作者：
Leopold, Pierre
中科院分区：
文献类型：
--
作者：
Andersen, Ditte S.;Colombani, Julien;Leopold, Pierre
上皮极性的破坏是肿瘤生长的关键事件。已知JNK信号传导在驱动许多上皮肿瘤的恶性进展中起重要作用，尽管极性丧失与JNK信号传导之间的联系仍然难以捉摸。在果蝇全基因组遗传筛选中，我们发现了grindelwald（grnd），这是一种编码与肿瘤坏死因子受体（TNFR）超家族成员同源的跨膜蛋白的基因。在这里，我们表明，Grnd介导的Eiger（Egr），独特的果蝇TNF的促凋亡功能，并在体内激活JNK信号转导的Grnd缺乏细胞外结构域的活性形式的过表达是足够的。Grnd还通过Egr依赖性基质金属蛋白酶-1（Mmp 1）表达促进Ras（V12）/scrib（-/-）肿瘤的侵袭性。Grnd定位于具有细胞极性决定子Crumbs（Crb）的亚顶端膜结构域，并通过与Veli（也称为Lin-7）的物理相互作用将Crb诱导的极性丧失与JNK活化和肿瘤生长偶联。因此，Grnd代表了TNFR的第一个例子，它整合了来自Egr和顶端极性决定簇的信号，以诱导JNK依赖性细胞死亡或肿瘤生长。
Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth(1), we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. Grnd also promotes the invasiveness of Ras(V12)/scrib(-/-) tumours through Egr-dependent Matrix metallo-protease-1 (Mmp1) expression. Grnd localizes to the subapical membrane domain with the cell polarity determinant Crumbs (Crb) and couples Crb-induced loss of polarity with JNK activation and neoplastic growth through physical interaction with Veli (also known as Lin-7). Therefore, Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth.