The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila
The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila
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DOI：
10.1073/pnas.1004060107
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发表时间：
2010-09-07
影响因子：
11.1
通讯作者：
Halder, Georg
中科院分区：
文献类型：
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作者：
Chen, Chiao-Lin;Gajewski, Kathleen M.;Halder, Georg
在脊椎动物中，顶基细胞极性缺陷和细胞极性决定子的异常表达通常与癌症有关。在果蝇中，顶基决定簇的异常表达可导致肿瘤表型，包括细胞极性丧失和过度增殖。然而，顶基极性决定因素影响生长的途径知之甚少。在这里，我们研究了顶端决定因素Crumbs（Crb）影响果蝇成虫盘生长的机制。Crb的过度表达导致严重的过度增殖，我们发现Crb的丢失同样会导致成虫盘的过度生长。Crb的获得和功能丧失导致Hippo信号传导的缺陷，Hippo信号传导是控制果蝇和哺乳动物组织生长的关键信号传导途径。Crb水平的操纵引起Hippo靶基因的上调，与已知的Hippo途径组分在遗传上相互作用，并且需要Yorkie，一种在Hippo途径下游起作用的转录共激活因子，用于靶基因诱导和过度生长。有趣的是，Crb通过其胞内结构域中的不同基序调节生长和细胞极性。一个质膜FERM结构域结合基序负责生长调节和诱导Hippo靶基因表达，而Crb使用PDZ结合基序与其他极性因子形成复合物。Hippo途径组分Expanded是一种位于顶端的衔接蛋白，在crb突变细胞和Crb过表达组织中均错误定位，而其他Hippo途径组分Fat和Merlin则不受影响。总之，我们的数据表明，Crb通过Hippo信号调节生长，从而确定Crb作为以前未描述的Hippo通路的上游输入。
Defects in apical-basal cell polarity and abnormal expression of cell polarity determinants are often associated with cancer in vertebrates. In Drosophila, abnormal expression of apical-basal determinants can cause neoplastic phenotypes, including loss of cell polarity and overproliferation. However, the pathways through which apical-basal polarity determinants affect growth are poorly understood. Here, we investigated the mechanism by which the apical determinant Crumbs (Crb) affects growth in Drosophila imaginal discs. Overexpression of Crb causes severe overproliferation, and we found that loss of Crb similarly results in overgrowth of imaginal discs. Crb gain and loss of function caused defects in Hippo signaling, a key signaling pathway that controls tissue growth in Drosophila and mammals. Manipulation of Crb levels caused the up-regulation of Hippo target genes, genetically interacted with known Hippo pathway components, and required Yorkie, a transcriptional coactivator that acts downstream in the Hippo pathway, for target gene induction and overgrowth. Interestingly, Crb regulates growth and cell polarity through different motifs in its intracellular domain. A juxtamembrane FERM domain-binding motif is responsible for growth regulation and induction of Hippo target gene expression, whereas Crb uses a PDZ-binding motif to form a complex with other polarity factors. The Hippo pathway component Expanded, an apically localized adaptor protein, is mislocalized in both crb mutant cells and Crb overexpressing tissues, whereas the other Hippo pathway components, Fat and Merlin, are unaffected. Taken together, our data show that Crb regulates growth through Hippo signaling, and thus identify Crb as a previously undescribed upstream input into the Hippo pathway.