The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis.
The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis.
复制标题
DOI：
10.7554/elife.05996
复制
发表时间：
2015-07-29
期刊：
影响因子：
7.7
通讯作者：
Artavanis-Tsakonas S
中科院分区：
文献类型：
--
作者：
Ho DM;Pallavi SK;Artavanis-Tsakonas S
Notch信号通过与其他信号通路的协同相互作用，在发育和疾病期间控制广泛的细胞命运决定。在这里，通过果蝇全基因组遗传筛选，我们发现了一个高度复杂的Notch依赖的遗传电路，深刻影响增殖，从而增生。我们报告了Notch与非受体酪氨酸激酶Src 42 A和Src 64 B中的任一种之间的新型协同关系，以促进增生和组织解体，这导致细胞周期扰动、JAK/STAT信号激活和Notch靶点的差异调节。值得注意的是，JNK途径负责Notch-Src协同作用下游的大多数表型和转录变化。我们先前报道Notch-Mef 2也激活JNK，表明Notch依赖性增殖电路中存在共性;然而，目前的数据表明Notch-Src以与Notch-Mef 2显著不同的方式访问JNK。DOI：http://dx.doi.org/10.7554/eLife.05996.001动物体内的细胞被组织成执行特定角色的组织和器官。为了发展和维持这些结构，单个细胞分裂和生长的能力受到许多蛋白质的活动的严格控制，其中包括一种称为Notch的蛋白质。这种蛋白质存在于所有多细胞生物中，并允许细胞相互交流。编码Notch的基因突变会导致细胞过度分裂，导致癌症和其他疾病。Notch通过与许多其他蛋白质相互作用来调节细胞的生长和分裂。例如，Mef 2与Notch一起激活一个称为JNK通路的通信系统。该通路参与控制细胞分裂、细胞死亡和细胞运动。然而，人们认为Notch也可能与其他尚未鉴定的蛋白质相互作用。现在，Ho等人在果蝇中进行了全基因组筛选，以寻找与Notch相互作用的蛋白质。这些实验使用的苍蝇会长出异常大的眼睛，因为它们有一种过度活跃的Notch蛋白。Ho等人鉴定了数百种果蝇基因，这些基因可以在Notch活性存在的情况下增加或减少果蝇眼睛的大小。已知这些基因中的许多参与发育、细胞分裂或控制其他基因的活性。Ho等人发现，其中两个基因编码类似的蛋白质，称为Src 42 A和Src 64 B，它们与参与许多类型人类癌症的Src蛋白相似。实验表明，这两种蛋白质与Notch相互作用，促进不受控制的细胞分裂，并导致果蝇的组织变得更加混乱。JNK通路也被Notch与Src 42 A或Src 64 B一起激活，但与Mef 2和Notch激活的方式不同，对细胞的影响也不同。这项研究为基因如何共同作用以影响细胞分裂和发育中的其他事件提供了新的见解。此外，它表明Notch活性可能调节与Src蛋白缺陷相关的癌症的生长。DOI：http://dx.doi.org/10.7554/eLife.05996.002网站
Notch signaling controls a wide range of cell fate decisions during development and disease via synergistic interactions with other signaling pathways. Here, through a genome-wide genetic screen in Drosophila, we uncover a highly complex Notch-dependent genetic circuitry that profoundly affects proliferation and consequently hyperplasia. We report a novel synergistic relationship between Notch and either of the non-receptor tyrosine kinases Src42A and Src64B to promote hyperplasia and tissue disorganization, which results in cell cycle perturbation, JAK/STAT signal activation, and differential regulation of Notch targets. Significantly, the JNK pathway is responsible for the majority of the phenotypes and transcriptional changes downstream of Notch-Src synergy. We previously reported that Notch-Mef2 also activates JNK, indicating that there are commonalities within the Notch-dependent proliferation circuitry; however, the current data indicate that Notch-Src accesses JNK in a significantly different fashion than Notch-Mef2. DOI: http://dx.doi.org/10.7554/eLife.05996.001 The cells within animals are organized into tissues and organs that perform particular roles. To develop and maintain these structures, the ability of individual cells to divide and grow is strictly controlled by the activities of many proteins, including one called Notch. This protein is found in all multicellular organisms and allows cells to communicate with each other. Mutations in the gene that encodes Notch can cause cells to divide excessively and lead to cancer and other diseases. Notch regulates the growth and division of cells by interacting with many other proteins. For example, Mef2 works with Notch to activate a communication system called the JNK pathway. This pathway is involved in controlling cell division, cell death, and cell movement. However, it is thought that Notch may also interact with other proteins that have not yet been identified. Now, Ho et al. have conducted a genome-wide screen in fruit flies to find proteins that interact with Notch. The experiments used flies that develop abnormally large eyes because they have an over-active Notch protein. Ho et al. identified hundreds of fruit fly genes that could increase or decrease the size of the flies' eyes in the presence of Notch activity. Many of these genes are known to be involved in development, cell division, or in controlling the activity of other genes. Ho et al. found that two of these genes encode similar proteins called Src42A and Src64B, which are similar to the Src proteins that are involved in many types of human cancers. The experiments show that both proteins interact with Notch to promote uncontrolled cell division and lead to tissues in the flies becoming more disorganized. The JNK pathway is also activated by Notch working with Src42A or Src64B, but in a different manner to how it is activated by Mef2 and Notch, and with different consequences for cells. This study provides new insights into how genes work together in order to influence cell division and other events in development. Also, it suggests that Notch activity may regulate the growth of cancers linked with defects in the Src proteins. DOI: http://dx.doi.org/10.7554/eLife.05996.002