Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP.
Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP.
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DOI：
10.1101/gad.264234.115
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发表时间：
2015-06-15
影响因子：
10.5
通讯作者：
Pan D
中科院分区：
文献类型：
--
作者：
Chen Q;Zhang N;Xie R;Wang W;Cai J;Choi KS;David KK;Huang B;Yabuta N;Nojima H;Anders RA;Pan D
在本研究中，Chen等人研究了YAP磷酸化在调节内源性YAP活性中的生理重要性。使用突变的YapS112A敲入小鼠，他们发现由于哺乳动物特异性的YAP磷酸化位点磷酸化增加，小鼠的YAP蛋白水平出现代偿性下降。这些结果为维持YAP活性的生理水平的稳态机制提供了新的见解，这可能有助于防止YAP的致癌激活。Hippo信号通路聚集在YAP上调控生长、分化和再生。先前对过表达蛋白的研究表明，YAP被其上游激酶Lats1/2在多个位点磷酸化，包括一个进化上保守的14-3-3结合位点，其磷酸化被认为通过将YAP排除在细胞核外来抑制YAP。事实上，在目前的文献中，YAP的核定位或YAP在该位点磷酸化水平的降低（果蝇为S168，人类为S127，小鼠为S112）被广泛用作YAP激活的替代指标，尽管这种磷酸化事件在调节内源性YAP活性中的生理重要性尚未明确。在这里，我们通过在内源性Yap基因座中引入YapS112A敲入突变来解决这个问题。尽管YapS112A突变体在体内的核定位和体外细胞质易位的严重缺陷，但YapS112A小鼠却令人惊讶地正常。有趣的是，突变型YapS112A小鼠显示出YAP蛋白水平的代偿性下降，这是由于哺乳动物特异性的YAP磷酸化位点磷酸化增加。这些发现揭示了一个强大的内稳态机制，维持YAP活性的生理水平，并警告不要将YAP定位单独作为YAP活性的替代。
In this study, Chen et al. investigate the physiological importance of YAP phosphorylation in regulating endogenous YAP activity. Using mutant YapS112A knock-in mice, they found that the mice show a compensatory decrease in YAP protein levels due to increased phosphorylation at a mammalian-specific phosphodegron site on YAP. The results provide novel insight into a homeostatic mechanism that maintains physiological levels of YAP activity, which could work to prevent oncogenic activation of YAP. The Hippo signaling pathway converges on YAP to regulate growth, differentiation, and regeneration. Previous studies with overexpressed proteins have shown that YAP is phosphorylated by its upstream kinase, Lats1/2, on multiple sites, including an evolutionarily conserved 14-3-3-binding site whose phosphorylation is believed to inhibit YAP by excluding it from the nucleus. Indeed, nuclear localization of YAP or decreased YAP phosphorylation at this site (S168 in Drosophila, S127 in humans, and S112 in mice) is widely used in current literature as a surrogate of YAP activation even though the physiological importance of this phosphorylation event in regulating endogenous YAP activity has not been defined. Here we address this question by introducing a YapS112A knock-in mutation in the endogenous Yap locus. The YapS112A mice are surprisingly normal despite nuclear localization of the mutant YAP protein in vivo and profound defects in cytoplasmic translocation in vitro. Interestingly, the mutant YapS112A mice show a compensatory decrease in YAP protein levels due to increased phosphorylation at a mammalian-specific phosphodegron site on YAP. These findings reveal a robust homeostatic mechanism that maintains physiological levels of YAP activity and caution against the assumptive use of YAP localization alone as a surrogate of YAP activity.
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影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
11.8
作者：
Genevet A;Wehr MC;Brain R;Thompson BJ;Tapon N
通讯作者：
Tapon N
影响因子：
64.5
作者：
Harvey, KF;Pfleger, CM;Hariharan, IK
通讯作者：
Hariharan, IK
影响因子：
21.3
作者：
Sorrentino, Giovanni;Ruggeri, Naomi;Del Sal, Giannino
通讯作者：
Del Sal, Giannino
DOI：
10.1073/pnas.0911409107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Song, Hai;Mak, Kinglun Kingston;Yang, Yingzi
通讯作者：
Yang, Yingzi