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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation
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Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation

机译：钙黏着蛋白活性的边界调节河马信号通路诱导细胞增殖

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The conserved Hippo tumor suppressor pathway is a key signaling pathway that controls organ size in Drosophila. To date a signal transduction cascade from the Cadherin Fat at the plasma membrane into the nucleus has been discovered. However, how the Hippo pathway is regulated by extracellular signals is poorly understood. Fat not only regulates growth but also planar cell polarity, for which it interacts with the Dachsous (Ds) Cadherin, and Four-jointed (Fj), a transmembrane kinase that modulates the interaction between Ds and Fat. Ds and Fj are expressed in gradients and manipulation of their expression causes abnormal growth. However, how Ds and Fj regulate growth and whether they act through the Hippo pathway is not known. Here, we report that Ds and Fj regulate Hippo signaling to control growth. Interestingly, we found that Ds/Fj regulate the Hippo pathway through a remarkable logic. Induction of Hippo target genes is not proportional to the amount of Ds or Fj presented to a cell, as would be expected if Ds and Fj acted as traditional ligands. Rather, Hippo target genes are up-regulated when neighboring cells express different amounts of Ds or Fj. Consistent with a model that differences in Ds/Fj levels between cells regulate the Hippo pathway, we found that artificial Ds/Fj boundaries induce extra cell proliferation, whereas flattening the endogenous Ds and Fj gradients results in growth defects. The Ds/Fj signaling system thus defines a cell-to-cell signaling mechanism that regulates the Hippo pathway, thereby contributing to the control of organ size.
机译：保守的河马抑癌途径是控制果蝇器官大小的关键信号传导途径。迄今为止，已经发现了从质膜上的钙黏着蛋白脂肪到细胞核的信号转导级联反应。但是，人们对如何通过细胞外信号调节河马途径的了解却很少。脂肪不仅调节生长，而且还调节平面细胞极性，为此它与Dachsous（Ds）钙粘蛋白和四联（Fj）（一种调节Ds与脂肪之间的相互作用的跨膜激酶）相互作用。 Ds和Fj以梯度表示，对其表达的操纵会导致异常生长。然而，尚不清楚Ds和Fj如何调节生长以及它们是否通过河马途径起作用。在这里，我们报道Ds和Fj调节河马信号来控制生长。有趣的是，我们发现Ds / Fj通过非凡的逻辑调节Hippo途径。 Hippo目标基因的诱导与呈递给细胞的Ds或Fj的数量不成正比，如果Ds和Fj充当传统的配体，这是可以预期的。相反，当邻近细胞表达不同量的Ds或Fj时，河马靶基因被上调。与细胞之间Ds / Fj水平差异调节Hippo通路的模型一致，我们发现人工Ds / Fj边界诱导额外的细胞增殖，而扁平化内源Ds和Fj梯度会导致生长缺陷。因此，Ds / Fj信号系统定义了一种调控Hippo途径的细胞间信号机制，从而有助于控制器官的大小。

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