EGF RECEPTOR MEDIATED SIGNALING IN DROSOPHILA

受体酪氨酸激酶（RTK）是控制细胞生长的关键分子 和分化，以及主要RTK中的突变与 某些形式的癌症。该项目的目标是分析 信号转导通路涉及鱼雷，果蝇EGF 受体同系物（top/DER）。与脊椎动物相似， top/DER参与了几个特定的细胞信号事件， 果蝇发育。在果蝇卵子发生过程中， 体细胞滤泡细胞中的top/DER建立了前-后 以及卵和胚胎的背腹模式。我们建议 分析鱼雷（=top/DER）被激活的分子机制 在卵子发生过程中， 细胞 我们将构建一个激活形式的top/DER， 在某些脊椎动物肿瘤中发现的受体的致癌形式，和 在卵泡细胞中表达这种形式。我们将确定哪些表型 是由这样一个激活的结构产生的，我们将使用 构建以寻找抑制基因， 毛囊细胞中TOP/DER的靶点。 我们以前的工作表明，top/DER是由一个生长因子激活的- 类似于gurken（grk）分子，由生殖细胞分泌。期间 正常的发展，这种生长因子的生产必须严格 控制以防止不受调节的受体激活。了解 控制机制在生殖系中运作，我们正在分析三个 在生殖细胞系中起作用的基因，cornichon，秋葵和spindle-B。我们有 克隆了cornichon（cni）基因。它是激活 top/DER受体并编码一种新的蛋白质。我们建议分析 cni的功能，使用果蝇以及其他物种， 包括酵母。我们还将确定分子的功能， 基因okra和spindle-B。 我们还将关注我们已经展示的三种细胞反应， 依赖于顶部/DER活动：建立后和背侧 卵泡细胞的命运，以及一个新的，腹侧化的负调节， 在毛囊细胞中产生的信号， 到胚胎。我们将测试可能作为top/DER靶点的基因， 滤泡细胞镶嵌我们已经确定了一个基因（windbeutel）， 在第二个反应途径，并参与生产的 新的信号，建立腹胚胎细胞的命运。我们将克隆 该基因与top/DER的相互作用。 这项拟议中的研究将使我们能够描述如何激活一个主要的 RTK在果蝇的卵室中被控制。我们的分析将 补充了这种受体作用的生物化学描述， 已经在脊椎动物组织培养系统中获得，并且将允许 对这种调节和细胞反应的理解 发展过程中的信号处理。

Receptor tyrosine kinases (RTK) are key molecules controlling cell growth and differentiation, and mutation in major RTKs have been implicated in certain forms of cancer. The goal of this project is the analysis of the signal transduction pathway involving torpedo, the Drosophila EGF receptor homolog (top/DER). Similar to its vertebrate counterpart, top/DER is involved in several specific cell signaling events during Drosophila development. During Drosophila oogenesis, activation of top/DER in the somatic follicle cells establishes the anterior-posterior and dorso-ventral pattern of both the egg and the embryo. We propose to analyze the molecular mechanisms by which torpedo (=top/DER) is activated during oogenesis and the response mechanisms operating in the follicle cells. We will construct an activated form of top/DER that will mimic the oncogenic forms of the receptor found in certain vertebrate tumors, and express this form in follicle cells. We will determine what phenotypes are produced by such an activated construct, and we will use the construct to search for suppressor genes that might identify downstream targets of top/DER in follicle cells. Our previous work has shown that top/DER is activated by a growth factor- like molecule, gurken (grk), that is secreted by the germline. During normal development the production of such growth factors must be tightly controlled to prevent unregulated receptor activation. To understand the control mechanisms operating in the germline we are analyzing three genes, cornichon, okra and spindle-B, that act in the germ line. We have cloned the gene cornichon (cni). It is required for activation of the top/DER receptor and encodes a novel protein. We propose to analyze the function of cni in detail, using Drosophila as well as other species, including yeast. We will also determine the molecular function of the genes okra and spindle-B. We will also focus on-the three cellular responses that we have shown to depend on top/DER activity: the establishment of posterior and dorsal follicle cell fates, and the negative regulation of a new, ventralizing signal which is produced in the follicle cells and is transmitted back to the embryo. We will test genes that may act as targets of top/DER in follicle cell mosaics. We have identified a gene (windbeutel) that acts in the second response pathway and participates in the production of a new signal that establishes ventral embryonic cell fates. We will clone this gene and characterize its interaction with top/DER. The proposed research will allow us to describe how activation of a major RTK is controlled in the egg chamber of Drosophila. Our analysis will complement the biochemical description of the role of such receptors that has been obtained in vertebrate tissue culture systems, and will allow an understanding of the regulation and cellular responses to such signaling processes during development.