Shi Xianle, Yin Zixi, Ling Bin, Wang Lingling, Liu Chang, Ruan Xianhui, Zhang Weiyu, Chen Lingyi
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center for Biotherapy, Tianjin Key Laboratory of Protein Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics and College of Life Sciences, Nankai University, Tianjin 300071, China.
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China.
Development. 2017 Nov 1;144(21):3957-3967. doi: 10.1242/dev.157917. Epub 2017 Sep 25.
The Hippo pathway modulates the transcriptional activity of Yap to regulate the differentiation of the inner cell mass (ICM) and the trophectoderm (TE) in blastocysts. Yet how Hippo signaling is differentially regulated in ICM and TE cells is poorly understood. Through an inhibitor/activator screen, we have identified Rho as a negative regulator of Hippo in TE cells, and PKA as a positive regulator of Hippo in ICM cells. We further elucidated a novel mechanism by which Rho suppresses Hippo, distinct from the prevailing view that Rho inhibits Hippo signaling through modulating cytoskeleton remodeling and/or cell polarity. Active Rho prevents the phosphorylation of Amot Ser176, thus stabilizing the interaction between Amot and F-actin, and restricting the binding between Amot and Nf2. Moreover, Rho attenuates the interaction between Amot and Nf2 by binding to the coiled-coil domain of Amot. By blocking the association of Nf2 and Amot, Rho suppresses Hippo in TE cells.
河马通路调节Yap的转录活性，以调控囊胚中内细胞团（ICM）和滋养外胚层（TE）的分化。然而，目前对河马信号在ICM和TE细胞中如何受到差异调节的了解还很少。通过抑制剂/激活剂筛选，我们确定Rho是TE细胞中河马信号的负调节因子，而蛋白激酶A（PKA）是ICM细胞中河马信号的正调节因子。我们进一步阐明了一种新机制，即Rho抑制河马信号，这与普遍认为的Rho通过调节细胞骨架重塑和/或细胞极性来抑制河马信号的观点不同。活性Rho可阻止Amot第176位丝氨酸的磷酸化，从而稳定Amot与F-肌动蛋白之间的相互作用，并限制Amot与Nf2之间的结合。此外，Rho通过与Amot的卷曲螺旋结构域结合，减弱了Amot与Nf2之间的相互作用。通过阻断Nf2与Amot的结合，Rho在TE细胞中抑制了河马信号。
