Evidence for discrete modes of YAP1 signaling via mRNA splice isoforms in development and diseases
Evidence for discrete modes of YAP1 signaling via mRNA splice isoforms in development and diseases
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DOI：
10.1016/j.ygeno.2021.03.009
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发表时间：
2021-03-20
期刊：
影响因子：
4.4
通讯作者：
Forte, Giancarlo
中科院分区：
文献类型：
--
作者：
Vrbsky, Jan;Vinarsky, Vladimir;Forte, Giancarlo
Yes 相关蛋白 1 (YAP1) 是 Hippo 通路下游的转录共激活因子。该通路在器官发生中发挥着至关重要的作用，其失调与不同癌症类型的扩散有关。 YAP1基因编码多种蛋白质异构体，其具体功能尚不清楚。我们证明了异构体特异性 mRNA 的剪接是以阶段和组织特异性方式控制的。我们设计了编码最具代表性的 YAP1 亚型的表达载体，具有一个或两个 WW 结构域，并研究了它们在 YAP1 敲除细胞系中的特定信号传导活性。由于其独特的蛋白质相互作用组，YAP1 亚型表现出常见和独特的功能，并激活不同的转录程序。通过生成基于 TEAD 的转录报告细胞系，我们证明单个 YAP1 亚型对细胞增殖和分化显示出独特的作用。最后，我们说明了 Hippo-YAP1 效应器在心脏生理和病理条件下调节的复杂性。
Yes-associated protein 1 (YAP1) is a transcriptional co-activator downstream of Hippo pathway. The pathway exerts crucial roles in organogenesis and its dysregulation is associated with the spreading of different cancer types. YAP1 gene encodes for multiple protein isoforms, whose specific functions are not well defined. We demonstrate the splicing of isoform-specific mRNAs is controlled in a stage- and tissue-specific fashion. We designed expression vectors encoding for the most-represented isoforms of YAP1 with either one or two WW domains and studied their specific signaling activities in YAP1 knock-out cell lines. YAP1 isoforms display both common and unique functions and activate distinct transcriptional programs, as the result of their unique protein interactomes. By generating TEAD-based transcriptional reporter cell lines, we demonstrate individual YAP1 isoforms display unique effects on cell proliferation and differentiation. Finally, we illustrate the complexity of the regulation of Hippo-YAP1 effector in physiological and in pathological conditions of the heart.