Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 2011 Feb 11;286(6):4364-70. doi: 10.1074/jbc.C110.205401. Epub 2010 Dec 27.
In both Drosophila and mammalian systems, the Hippo pathway plays an important role in controlling organ size, mainly through its ability to regulate cell proliferation and apoptosis. The key component in the Hippo pathway is the Yes-associated protein YAP1, which localizes in nucleus, functions as a transcriptional coactivator, and regulates the expression of several proliferation- and apoptosis-related genes. The Hippo pathway negatively regulates YAP1 transcriptional activity by modulating its nuclear-cytoplasmic localization in a phosphorylation-dependent manner. Here, we describe the identification of several new PY motif-containing proteins, including angiomotin-like protein 1 (AMOTL1) and 2 (AMOTL2), as YAP1-associated proteins. We demonstrate that AMOTL1 and AMOTL2 can regulate YAP1 cytoplasm-to-nucleus translocation through direct protein-protein interaction, which can occur independent of YAP1 phosphorylation status. Moreover, down-regulation of AMOTL2 in MCF10A cells promotes epithelial-mesenchymal transition, a phenotype that is also observed in MCF10A cells with YAP1 overexpression. Together, these data support a new mechanism for YAP1 regulation, which is mediated via its direct interactions with angiomotin-like proteins.
在果蝇和哺乳动物系统中，Hippo 通路通过调节细胞增殖和凋亡，在控制器官大小方面发挥着重要作用。Hippo 通路的关键组成部分是 Yes 相关蛋白 YAP1，它定位于细胞核内，作为转录共激活因子发挥作用，并调节几种增殖和凋亡相关基因的表达。Hippo 通路通过依赖于磷酸化的方式调节其核质定位，从而负向调节 YAP1 的转录活性。在这里，我们描述了几种新的含有 PY 基序的蛋白质的鉴定，包括血管生成素样蛋白 1（AMOTL1）和 2（AMOTL2），作为 YAP1 相关蛋白。我们证明 AMOTL1 和 AMOTL2 可以通过直接的蛋白-蛋白相互作用调节 YAP1 从细胞质到细胞核的易位，而无需 YAP1 的磷酸化状态。此外，在 MCF10A 细胞中下调 AMOTL2 会促进上皮-间充质转化，这一表型也发生在 YAP1 过表达的 MCF10A 细胞中。这些数据共同支持了 YAP1 调节的一种新机制，该机制通过其与血管生成素样蛋白的直接相互作用介导。
