An emerging role for Hippo-YAP signaling in cardiovascular development.
An emerging role for Hippo-YAP signaling in cardiovascular development.
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DOI：
10.7555/jbr.28.20140020
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发表时间：
2014-07
影响因子：
2.3
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Zhou J
Hippo信号通路最初是在果蝇中发现的，并被证明对器官大小控制和肿瘤发生至关重要。这一途径由一系列激酶和几个接头组成，这些接头通过核排斥导致果蝇的转录辅助因子Yorkie或哺乳动物的yes相关蛋白YAP的磷酸化和抑制。最近的研究表明，小鼠心脏特异性缺失Hippo通路激酶Mst （ste20样蛋白激酶）共激活子WW45 （WW结构域含适配子45）、Mst1、Mst2或Lats2（大肿瘤抑制同源物2）会导致心脏过度生长，心肌细胞增殖升高。与这些观察结果一致，小鼠胚胎心脏中YAP的过表达通过诱导心肌细胞增殖，增加心肌梗死后心脏大小，促进心脏再生和收缩性，而小鼠心脏中YAP的缺失则阻碍心肌细胞增殖，导致心肌发育不全和胚胎或过早死亡。YAP也被证明在血管系统中发挥重要作用。小鼠血管平滑肌细胞中YAP的特异性缺失导致动脉壁发育不全表型的大动脉异常发育。希波- yap信号与其他信号通路如IGF（胰岛素样生长因子）和Wnt信号交叉对话，通过增加细胞周期基因的表达来促进心脏生长。本综述的目的是总结这些最新发现，并讨论基于操纵Hippo-YAP信号的心血管系统潜在的诊断或治疗策略。
The Hippo signaling pathway was originally discovered in Drosophila and shown to be critical for organ size control and tumorigenesis. This pathway consists of a cascade of kinases and several adaptors that lead to the phosphorylation and inhibition, through nuclear exclusion, of the transcriptional cofactor Yorkie in Drosophila or YAP (yes associated protein) in mammals. Recent studies demonstrate that cardiac-specific deletion of the Hippo pathway kinase Mst (STE20-like protein kinases) co-activator WW45 (WW domain-containing adaptor 45), Mst1, Mst2, or Lats2 (large tumor suppressor homologue 2) in mice result in over-grown hearts with elevated cardiomyocyte proliferation. Consistent with these observations, over-expression of YAP in the mouse embryonic heart increases heart size and promotes cardiac regeneration and contractility after myocardial infarction by inducing cardiomyocyte proliferation, whereas deletion of YAP in the mouse heart impedes cardiomyocyte proliferation, causing myocardial hypoplasia and embryonic or premature lethality. YAP has also been shown to play an important role in the vascular system. Specific-deletion of YAP from vascular smooth muscle cells in mice results in aberrant development of large arteries with a hypoplastic arterial wall phenotype. Hippo-YAP signaling cross-talks with other signaling pathways such as IGF (insulin-like growth factor) and Wnt signaling to promote heart growth by increasing expression of cell cycle genes. The purpose of this review is to summarize these recent findings and discuss potential diagnostic or therapeutic strategies in cardiovascular system based on manipulating the Hippo-YAP signaling.