Elucidation of a universal size-control mechanism in Drosophila and mammals
Elucidation of a universal size-control mechanism in Drosophila and mammals
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DOI：
10.1016/j.cell.2007.07.019
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发表时间：
2007-09-21
期刊：
影响因子：
64.5
通讯作者：
Pan, Duojia
中科院分区：
文献类型：
--
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
细胞增殖和细胞死亡的协调对于在发育期间获得适当的器官大小和维持整个出生后生命的组织稳态是必不可少的。在果蝇中，这两个过程由Hippo激酶级联反应协调，Hippo激酶级联反应是一种生长抑制途径，最终拮抗转录辅激活因子Yorkie（Yki）。在这里，我们证明了一个单一的磷酸化位点在Yki介导的生长抑制输出的河马途径。Hippo介导的磷酸化通过将Yki从细胞核中排除而使Yki失活，而Hippo信号传导的丧失导致细胞核积累并因此增加Yki活性。我们进一步描绘了哺乳动物海马信号通路，最终在磷酸化的雅普，哺乳动物同源的Yki。使用条件性雅普转基因小鼠模型，我们证明了哺乳动物Hippo通路是器官大小的有效调节器，并且其失调导致肿瘤发生。这些结果揭示了后生动物普遍的大小控制机制.
Coordination of cell proliferation and cell death is essential to attain proper organ size during development and for maintaining tissue homeostasis throughout postnatal life. In Drosophila, these two processes are orchestrated by the Hippo kinase cascade, a growth- suppressive pathway that ultimately antagonizes the transcriptional coactivator Yorkie ( Yki). Here we demonstrate that a single phosphorylation site in Yki mediates the growth suppressive output of the Hippo pathway. Hippo- mediated phosphorylation inactivates Yki by excluding it from the nucleus, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased Yki activity. We further delineate a mammalian Hippo signaling pathway that culminates in the phosphorylation of YAP, the mammalian homolog of Yki. Using a conditional YAP transgenic mouse model, we demonstrate that the mammalian Hippo pathway is a potent regulator of organ size, and that its dysregulation leads to tumorigenesis. These results uncover a universal size- control mechanism in metazoan.