The Drosophila F-box protein Fbxl7 binds to the protocadherin fat and regulates Dachs localization and Hippo signaling.
The Drosophila F-box protein Fbxl7 binds to the protocadherin fat and regulates Dachs localization and Hippo signaling.
复制标题
果蝇F-box蛋白FBXL7与原粘蛋白脂肪结合，并调节DACHS定位和河马信号传导。
DOI：
10.7554/elife.03383
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发表时间：
2014-08-08
期刊：
影响因子：
7.7
通讯作者：
Hariharan IK
中科院分区：
文献类型：
--
作者：
Bosch JA;Sumabat TM;Hafezi Y;Pellock BJ;Gandhi KD;Hariharan IK
果蝇原钙粘附素脂肪(Ft)调节生长、平面细胞极性(PCP)和近端模式。Ft信号的一个关键下游成分是非典型的肌球蛋白Dachs(D)。Ft胞内区的多个区域参与调节生长和PCP，但Ft如何调节D尚不清楚。Fbx17编码F-box蛋白，它的突变导致组织过度生长和近端图案的异常，这种表型复制删除了Ft细胞内域(ICD)的特定部分，该部分既调节生长又调节PCP。Fbx17与Ft ICD的这一部分结合，与Ft共同定位于细胞的近端边缘，并调节顶膜D的水平和不对称性。Fbx17还可以调节蛋白质在顶膜和细胞内小泡之间的运输。因此，Fbxl7在Ft下游的通路子集中起作用，并将Ft与D定位联系起来。DOI：http://dx.doi.org/10.7554/eLife.03383.001多细胞生物是由组织成组织和器官的细胞组成的，这些组织和器官在发育结束时达到可预测的大小和形状。要做到这一点，细胞必须能够感知它们在体内的位置和方向，并知道何时停止生长。上皮细胞构成动物身体的外表面，并排列在其内部器官的腔内，它们相互连接形成平板。这些单元格的板材包含沿板材平面定向的结构。然而，这种所谓的平面细胞极性如何与细胞生长相协调，以构建复杂的组织和器官仍有待发现。一种名为脂肪的蛋白质是平面细胞极性和河马信号通路的主要参与者，河马信号通路控制细胞生长。因此，脂肪蛋白似乎对控制器官的大小和形状至关重要。脂肪蛋白的突变会导致大量组织过度生长，阻止平面细胞极性的正确建立，并阻止果蝇的腿和翅膀正常发育。脂肪蛋白还在分配另一种名为Dachs的蛋白质方面发挥作用，这种蛋白质也是河马信号通路的一部分。在发育中的翅上皮细胞中，达赫斯大多位于最靠近发育翼顶端的细胞一侧(即所谓的“远端表面”)。胖子和达克斯是如何一起工作的还不清楚，但我们知道它们并不直接绑定在一起。现在，博世等人。研究表明，果蝇体内的脂肪蛋白与另一种名为Fbxl7的蛋白质结合。不能产生工作Fbx17的果蝇在平面细胞极性的某些方面存在缺陷，组织生长略有增加。Fbx17似乎解释了脂肪限制组织生长的部分(但不是全部)能力。此外，缺乏Fbxl7蛋白会导致达克斯蛋白在上皮细胞的顶端表面--面向上皮层外--扩散。另一方面，如果Fbxl7过度表达，Dach就会被驱使到每个细胞的内部。因此，正常水平的Fbxl7蛋白会将DACHES蛋白限制在细胞表面的正确部分。博世等人的发现加在一起。表明Fbxl7蛋白是脂肪和达克斯蛋白之间的关键纽带。这些结果还提供了对生长和平面细胞极性--对所有多细胞生物体的正常发育至关重要的两个过程--如何协调的理解。DOI：http://dx.doi.org/10.7554/eLife.03383.002
The Drosophila protocadherin Fat (Ft) regulates growth, planar cell polarity (PCP) and proximodistal patterning. A key downstream component of Ft signaling is the atypical myosin Dachs (D). Multiple regions of the intracellular domain of Ft have been implicated in regulating growth and PCP but how Ft regulates D is not known. Mutations in Fbxl7, which encodes an F-box protein, result in tissue overgrowth and abnormalities in proximodistal patterning that phenocopy deleting a specific portion of the intracellular domain (ICD) of Ft that regulates both growth and PCP. Fbxl7 binds to this same portion of the Ft ICD, co-localizes with Ft to the proximal edge of cells and regulates the levels and asymmetry of D at the apical membrane. Fbxl7 can also regulate the trafficking of proteins between the apical membrane and intracellular vesicles. Thus Fbxl7 functions in a subset of pathways downstream of Ft and links Ft to D localization. DOI: http://dx.doi.org/10.7554/eLife.03383.001 Multi-cellular organisms are made up of cells that are organized into tissues and organs that reach a predictable size and shape at the end of their development. To do this, cells must be able to sense their position and orientation within the body and know when to stop growing. Epithelial cells—which make up the outer surface of an animal's body and line the cavities of its internal organs—connect to each other to form flat sheets. These sheets of cells contain structures that are oriented along the plane of the sheet. However, how this so-called ‘planar cell polarity’ coordinates with cell growth in order to build complex tissues and organs remains to be discovered. A protein called Fat is a major player in both planar cell polarity and the Hippo signaling pathway, which controls cell growth. As such, the Fat protein appears to be crucial for controlling the size and shape of organs. Mutations in the Fat protein cause massive tissue overgrowth, prevent planar cell polarity being established correctly, and stop the legs and wings of fruit flies developing normally. The Fat protein also plays a role in distributing another protein called Dachs—which is also part of the Hippo signaling pathway. In epithelial cells of the developing wing, Dachs is mostly located on the side of the cell that is closest to the tip of the developing wing (the so-called ‘distal surface’). How Fat and Dachs work together is not understood, but it is known that they do not bind to each other directly. Now, Bosch et al. show that in the fruit fly Drosophila, the Fat protein binds to another protein called Fbxl7. Flies that cannot produce working Fbxl7 have defects in some aspects of planar cell polarity and a modest increase in tissue growth. Fbxl7 seems to account for part, but not all, of the ability of Fat to restrict tissue growth. Furthermore, a lack of the Fbxl7 protein results in a spreading of Dachs protein across the apical surface—which faces out of the epithelial sheet—of epithelial cells. On the other hand, if Fbxl7 is over-expressed, Dachs is driven to the interior of each cell. Hence, a normal level of Fbxl7 protein restricts the Dachs protein to the correct parts of the cell surface. Together, the findings of Bosch et al. show that the Fbxl7 protein is a key link between the Fat and Dachs proteins. These results also provide an understanding of how growth and planar cell polarity—two processes that are essential for normal development of all multi-cellular organisms—are coordinated. DOI: http://dx.doi.org/10.7554/eLife.03383.002