The posttranslational modifications of Hippo-YAP pathway in cancer.
The posttranslational modifications of Hippo-YAP pathway in cancer.
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DOI：
10.1016/j.bbagen.2019.07.006
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Fang-jie Yan;Mei-jia Qian;Qiaojun He;Hong Zhu;Bo Yang
中科院分区：
文献类型：
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作者：
Fang-jie Yan;Mei-jia Qian;Qiaojun He;Hong Zhu;Bo Yang
背景是相关蛋白(YAP)是河马途径的关键效应蛋白，在侵袭性人类癌症中经常表达失调。YAP的异常激活已成为肿瘤发生、化疗耐药和转移的重要驱动因素。由于翻译后修饰(PTM)是决定蛋白质激活或亚细胞定位的关键修饰因子，因此翻译后修饰异常导致的YAP功能障碍与多种癌症有关。总而言之，尽管YAP长期以来一直被认为是一种“无法下药”的转录辅因子，但它的PTMS可能是它的“阿喀琉斯之踵”。为了为基于PTMS的小分子抑制剂的开发提供理论支持，本文综述了PTMS在调节Hippo-YAP通路中的作用的研究现状，并进一步探讨了潜在的治疗干预措施。综述范围我们总结了已知的YAP翻译后修饰(PTM)在不同阶段决定其蛋白质稳定性、转录活性和亚细胞定位。在这里，我们清楚地总结了YAP PTMS中涉及的特定酶和位点，并将重点放在PTM调节YAP活性和转位的后果上。主要结论YAP的PTMS在控制蛋白质丰度和功能方面发挥着基础作用。因此，干扰YAP的PTM可能有助于解决YAP抑制的“不可药”问题，从而为YAP的肿瘤治疗提供新的途径。一般意义未来针对相应的PTM相关激酶/酶的研究将为癌症治疗提供新的策略，特别是在YAP调控异常的肿瘤中。
BackgroundYes-associated protein (YAP) is a key effector of the Hippo pathway and is frequently dysregulated in aggressive human cancers. Aberrant YAP activation has emerged as an important driver of tumorigenesis, chemoresistance and metastasis. Since posttranslational modifications (PTMs) are pivotal modifiers that determine protein activation or subcellular localization, the malfunction of YAP due to dysregulated PTMs has been linked to various cancers. Collectively, although YAP has long been considered an “undruggable” transcription cofactor, its PTMs may be its “Achilles' heel”. To provide theoretical support for developing small molecule inhibitors based on PTMs, in this review article, we summarize the current understanding of the impact of PTMs in regulating the Hippo-YAP pathway and further discuss potential therapeutic intervention.Scope of reviewIn our review, we summarize the known posttranslational modifications (PTMs) of YAP that dictate its protein stability, transcriptional activity and subcellular localization at different stages. Here, we clearly summarize the specific enzymes and sites involved in YAP PTMs and place additional focus on the consequences of PTM-modulated YAP activity and translocation.Main conclusionPTMs of YAP play fundamental roles in controlling the protein abundance and function. Therefore, interfering with PTMs of YAP may contribute to solving the “undruggable” problem in YAP inhibition, thus providing new approaches for YAP-based cancer therapy.General significanceFuture studies that target corresponding PTM-related kinases/enzymes will provide new strategies for cancer therapy, particularly in tumors with YAP dysregulation.