Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos.
Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos.
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DOI：
10.1016/j.cub.2013.05.014
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发表时间：
2013-07-08
期刊：
影响因子：
9.2
通讯作者：
Sasaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Hirate, Yoshikazu;Hirahara, Shino;Inoue, Ken-ichi;Suzuki, Atsushi;Alarcon, Vernadeth B.;Akimoto, Kazunori;Hirai, Takaaki;Hara, Takeshi;Adachi, Makoto;Chida, Kazuhiro;Ohno, Shigeo;Marikawa, Yusuke;Nakao, Kazuki;Shimono, Akihiko;Sasaki, Hiroshi
在植入前的小鼠胚胎中，滋养外胚层或内细胞团的第一个细胞命运发生在早期囊胚期。细胞命运由细胞位置依赖的河马信号控制，尽管位置依赖的河马信号的机制尚不清楚。我们发现，细胞极性和细胞间黏附的结合建立了位置依赖的河马信号，其中外层细胞和内部细胞分别是极性和非极性的。连接相关蛋白Angiomotin(AMOT)和Amotl2对于河马通路的激活和适当的细胞命运指定是必不可少的。在非极性内细胞中，AMOT定位于黏附连接(AJs)，细胞与细胞间的黏附激活了HIPPO途径。在外部细胞中，细胞的极性从基底外侧的AJ到顶端区域，从而抑制HIPPO信号转导。AMOT的N-末端结构域是肌动蛋白结合、Nf2/Merlin介导的与E-钙粘蛋白复合体结合以及与LATS蛋白激酶相互作用所必需的。在AJS中，AMOT N-末端结构域的Ser176被LATS磷酸化，这抑制了肌动蛋白的结合活性，从而稳定了AMOT-LATS的相互作用，激活了河马通路。我们认为在AJ中，S176的磷酸化是激活Hippo通路的关键步骤，细胞极性通过隔离AJ中的AMOT而使Hippo通路与细胞间的黏附断开。这种机制将位置信息转换为差异河马信号，从而导致不同的细胞命运。
In preimplantation mouse embryos, the first cell fate specification to the trophectoderm or inner cell mass occurs by the early blastocyst stage. The cell fate is controlled by cell position-dependent Hippo signaling, although the mechanisms underlying position-dependent Hippo signaling are unknown. We showed that a combination of cell polarity and cell–cell adhesion establishes position-dependent Hippo signaling, where the outer and inner cells are polar and nonpolar, respectively. The junction-associated proteins angiomotin (Amot) and Amotl2 are essential for Hippo pathway activation and appropriate cell fate specification. In the nonpolar inner cells, Amot localizes to adherens junctions (AJs) and cell–cell adhesion activates the Hippo pathway. In the outer cells, the cell polarity sequesters Amot from basolateral AJs to apical domains, thereby suppressing Hippo signaling. The N-terminal domain of Amot is required for actin binding, Nf2/Merlin-mediated association with the E-cadherin complex, and interaction with Lats protein kinase. In AJs, Ser176 in the N-terminal domain of Amot is phosphorylated by Lats, which inhibits the actin-binding activity, thereby stabilizing the Amot–Lats interaction to activate the Hippo pathway. We propose that the phosphorylation of S176 in Amot is a critical step for activation of the Hippo pathway in AJs and that cell polarity disconnects the Hippo pathway from cell–cell adhesion by sequestering Amot from AJ. This mechanism converts positional information into differential Hippo signaling, thereby leading to differential cell fates.
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影响因子：
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作者：
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