Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation
Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation
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DOI：
10.1073/pnas.0805201105
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发表时间：
2008-09-30
影响因子：
11.1
通讯作者：
Halder, Georg
中科院分区：
文献类型：
--
作者：
Willecke, Maria;Hamaratoglu, Fisun;Halder, Georg
保守的Hippo肿瘤抑制通路是控制果蝇器官大小的关键信号通路。迄今为止，已经发现了从质膜上的钙粘蛋白脂肪级联到细胞核的信号转导。然而，Hippo通路是如何被细胞外信号调节的，人们知之甚少。脂肪不仅调节生长，而且还调节平面细胞极性，因此它与Dachsous (Ds) Cadherin和Four-jointed （Fj）相互作用，这是一种调节Ds和脂肪之间相互作用的跨膜激酶。Ds和Fj呈梯度表达，操纵其表达可导致生长异常。然而，Ds和Fj如何调节生长以及它们是否通过Hippo通路起作用尚不清楚。在这里，我们报道了Ds和Fj调节Hippo信号来控制生长。有趣的是，我们发现Ds/Fj通过一种非凡的逻辑调节Hippo通路。如果Ds和Fj作为传统的配体，则预期Hippo靶基因的诱导与呈现给细胞的Ds或Fj的数量不成比例。相反，当邻近细胞表达不同数量的Ds或Fj时，Hippo靶基因被上调。与细胞间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，而平坦的内源性Ds和Fj梯度导致生长缺陷。因此，Ds/Fj信号系统定义了一种细胞间信号传导机制，调节Hippo通路，从而有助于控制器官大小。
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.