Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway
Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway
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DOI：
10.1158/0008-5472.can-07-6205
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发表时间：
2008-04-15
期刊：
影响因子：
11.2
通讯作者：
Haber, Daniel A.
中科院分区：
文献类型：
--
作者：
Zhang, Jianmin;Smolen, Gromoslaw A.;Haber, Daniel A.
Hippo 通路定义了一种调节果蝇细胞增殖和存活的新型信号级联，其中涉及激酶 Hippo 和 Warts 对转录共激活因子 Yorkie 的负调节。我们最近表明，Yorkie 的人类直系同源物 YAP 在小鼠和人类癌症中定位到最小扩增位点，并且它介导 MCF10A 原代乳腺上皮细胞中的显着转化活性。在这里，我们发现 LATS 蛋白（疣的哺乳动物直系同源物）直接与哺乳动物细胞中的 YAP 相互作用，并且 LATS1（而非 LATS2）的异位表达可有效抑制 YAP 表型。此外，shRNA 介导的 LATS1 敲低可导致 YAP 过度表达。由于这种效应可以通过同时敲除 YAP 来抑制，因此表明 YAP 是哺乳动物细胞中 LATS1 的主要靶标。由 YAP 异位表达或 LATS I 敲低诱导的基因表达谱揭示了与上皮间质转化有关的潜在 Hippo 通路靶标的子集，表明这是哺乳动物细胞中 YAP 信号传导的关键特征。
The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here, we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Because this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS I reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition, suggesting that this is a key feature of YAP signaling in mammalian cells.