Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP
Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP
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DOI：
10.1038/onc.2011.216
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发表时间：
2012-01-01
期刊：
影响因子：
8
通讯作者：
Sudol, M.
中科院分区：
文献类型：
--
作者：
Oka, T.;Schmitt, A. P.;Sudol, M.
YAP （Yes-associated protein）癌基因已被发现与血管运动素（Angiomotin, Amot）蛋白家族成员形成稳定的复合物，其结合YAP的WW结构域并将该蛋白隔离在细胞质和连接复合物中。量介导的YAP在细胞质中的滞留导致其增殖功能的抑制。通过对HEK293细胞中YAP的凋亡“读出”，我们证实了Amot调控YAP的分子模式。我们发现Amot家族的一个代表成员AmotL1 （Angiomotin-like-1）利用其PPxY基序结合YAP的WW结构域并抑制YAP的核易位和促凋亡功能。最近我们还发现，YAP利用其pdz结合基序与ZO-2蛋白相互作用，从而促进YAP向细胞核的易位。我们还询问了AmotL1、YAP和ZO-2是否同时发出信号。我们在这里报道了AmotL1和ZO-2与YAP形成一个三方复合物，并在HEK293细胞中以相反的方向调节其功能。AmotL1抑制YAP的促凋亡功能，而ZO-2增强YAP的促凋亡功能。由于YAP是一种强效致癌基因，其调控因子的鉴定和表征非常重要。AmotL1和ZO-2是两个可能被利用来控制YAP的致癌功能的候选基因。中华肿瘤杂志，2012,31,128-134；doi: 10.1038 / onc.2011.216;2011年6月20日在线发布
YAP (Yes-associated protein) oncogene has been found to form a stable complex with members of the Angiomotin (Amot) family of proteins, which bind WW domains of YAP and sequester the protein in the cytoplasm and junctional complexes. The Amot-mediated retention of YAP in the cytoplasm results in the inhibition of its proliferative function. Using apoptotic 'read-out' of YAP in HEK293 cells, we confirmed the molecular mode by which Amot regulates YAP. We showed that a representative member of the Amot family, AmotL1 (Angiomotin-like-1), uses its PPxY motifs to bind WW domains of YAP and inhibit YAP's nuclear translocation and pro-apoptotic function. Recently we also showed that YAP uses its PDZ-binding motif to interact with zona occludens-2 (ZO-2) protein, which promotes YAP's translocation to the nucleus. We also asked if AmotL1, YAP and ZO-2 signal together. We report here that AmotL1 and ZO-2 form a tripartite complex with YAP and regulate its function in HEK293 cells in opposite directions. AmotL1 inhibits proapoptotic function of YAP, whereas ZO-2 enhances it. As YAP is a potent oncogene, the identification and characterization of its regulators is important. AmotL1 and ZO-2 are two candidates that could be harnessed to control the oncogenic function of YAP. Oncogene (2012) 31, 128-134; doi: 10.1038/onc.2011.216; published online 20 June 2011