Endosomal regulation of contact inhibition through the AMOT:YAP pathway.
Endosomal regulation of contact inhibition through the AMOT:YAP pathway.
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DOI：
10.1091/mbc.e15-04-0224
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发表时间：
2015-07-15
影响因子：
3.3
通讯作者：
Wilson JM
中科院分区：
文献类型：
--
作者：
Cox CM;Mandell EK;Stewart L;Lu R;Johnson DL;McCarter SD;Tavares A;Runyan R;Ghosh S;Wilson JM
之前已经表明，内管蛋白（内体的一种完整膜蛋白）调节内体和紧密连接之间紧密连接蛋白的运输。在这里，它表明，内管蛋白调节雅普定位的内涵体通过其与AMOT的相互作用，因此可能发挥作用的接触抑制。接触介导的细胞增殖抑制是器官生长控制的重要组成部分，转录辅激活因子Yes相关蛋白（雅普）在这一过程中起着关键作用。除了雅普的磷酸化依赖性调节之外，整合膜蛋白血管动蛋白（AMOT）和AMOT家族成员通过直接结合来控制雅普。在这里，我们报告说，雅普活性的调节发生在内体膜通过动态相互作用的AMOT与内体膜蛋白，内管蛋白（EDTB）。EDTB与AMOT和occludin相互作用，并且在融合细胞中优先与occludin结合，但在亚融合细胞中与AMOT家族成员结合。EDTB与雅普竞争结合亚融合细胞中的AMOT蛋白。胞质结构域或全长EDTB的过表达诱导雅普易位到细胞核，过度生长表型，并在软琼脂中生长。这种增殖的增加依赖于雅普活性，并通过p130-AMOT的过表达来补充。此外，EDTB的过表达抑制AMOT：雅普相互作用。与融合细胞相比，EDTB和AMOT在亚融合细胞中具有更大的关联，并且这种关联在内体膜处受到调节。这些数据提供了紧密连接蛋白通过内体的运输和接触抑制调节的细胞生长之间的联系。
It was shown previously that endotubin, an integral membrane protein of endosomes, regulates the trafficking of tight junction proteins between endosomes and the tight junctions. Here it is shown that endotubin regulates YAP localization on endosomes through its interaction with AMOT and thus may play a role in contact inhibition. Contact-mediated inhibition of cell proliferation is an essential part of organ growth control; the transcription coactivator Yes-associated protein (YAP) plays a pivotal role in this process. In addition to phosphorylation-dependent regulation of YAP, the integral membrane protein angiomotin (AMOT) and AMOT family members control YAP through direct binding. Here we report that regulation of YAP activity occurs at the endosomal membrane through a dynamic interaction of AMOT with an endosomal integral membrane protein, endotubin (EDTB). EDTB interacts with both AMOT and occludin and preferentially associates with occludin in confluent cells but with AMOT family members in subconfluent cells. EDTB competes with YAP for binding to AMOT proteins in subconfluent cells. Overexpression of the cytoplasmic domain or full-length EDTB induces translocation of YAP to the nucleus, an overgrowth phenotype, and growth in soft agar. This increase in proliferation is dependent upon YAP activity and is complemented by overexpression of p130-AMOT. Furthermore, overexpression of EDTB inhibits the AMOT:YAP interaction. EDTB and AMOT have a greater association in subconfluent cells compared with confluent cells, and this association is regulated at the endosomal membrane. These data provide a link between the trafficking of tight junction proteins through endosomes and contact-inhibition-regulated cell growth.