Dachsous钙黏蛋白活性的边界调节Hippo信号通路以诱导细胞增殖。

Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation.

作者信息

Willecke Maria, Hamaratoglu Fisun, Sansores-Garcia Leticia, Tao Chunyao, Halder Georg

机构信息

Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

出版信息

Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14897-902. doi: 10.1073/pnas.0805201105. Epub 2008 Sep 22.

Abstract

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.

摘要

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,已发现从质膜上的钙黏蛋白Fat到细胞核的信号转导级联反应。然而,人们对Hippo通路如何受细胞外信号调节知之甚少。Fat不仅调节生长,还调节平面细胞极性,为此它与Dachsous(Ds)钙黏蛋白以及Four-jointed(Fj,一种调节Ds与Fat之间相互作用的跨膜激酶)相互作用。Ds和Fj呈梯度表达,对其表达的操纵会导致异常生长。然而,Ds和Fj如何调节生长以及它们是否通过Hippo通路发挥作用尚不清楚。在此,我们报道Ds和Fj调节Hippo信号以控制生长。有趣的是,我们发现Ds/Fj通过一种显著的逻辑调节Hippo通路。Hippo靶基因的诱导与呈现给细胞的Ds或Fj的量不成正比,而如果Ds和Fj作为传统配体发挥作用则会是预期的那样。相反,当相邻细胞表达不同量的Ds或Fj时,Hippo靶基因会上调。与细胞间Ds/Fj水平差异调节Hippo通路的模型一致,我们发现人工的Ds/Fj边界会诱导额外的细胞增殖,而使内源性Ds和Fj梯度变平则会导致生长缺陷。因此,Ds/Fj信号系统定义了一种调节Hippo通路的细胞间信号机制,从而有助于控制器官大小。

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