Regulation of Wingless (Wg) Signaling and Morphogen Gradient Formation

描述（由申请人提供）：本提案的长期目标是阐明在发育过程中调控无翅（Wg）形态梯度和信号传导的分子机制。果蝇Wg编码Wnt家族的进化上保守的糖蛋白。异常的Wg/Wnt信号传导活性是许多人类发育障碍的基础，并导致多种癌症。因此，阐明Wg/Wnt信号通路将为相关人类疾病的机制提供新的见解。尽管在过去的20年里，Wg/Wnt信号通路在其接收细胞中的组分已经得到了很好的表征，但对于Wg的成熟形式如何分泌并行进到其接收细胞以形成浓度梯度，以及Wg信号传导如何激活其下游靶基因的转录，仍然知之甚少。这是一份持续支持的申请。目前的建议将检查Wg分泌的机制及其在调节其靶基因转录中的信号传导活性。首先，我们将确定三个新发现的ER和高尔基体囊泡蛋白在Wg分泌中的功能（Aim 1）。其次，我们将研究泛素E3连接酶Su（dx）和去泛素化酶USP 8在Wls泛素化和Wg分泌（Aim 2）中的作用。第三，我们将研究果蝇UBR 5在调节Wg信号传导（Aim 3）中的功能。总之，我们的遗传和生化分析的新发现的基因在Wg通路将提供新的见解Wg分泌和Wg靶基因的转录激活的机制。由于Wg信号转导通路在果蝇和人类之间是保守的，因此该项目的结果将清楚地为包括癌症在内的各种疾病过程的机制提供新的见解。 公共卫生相关性：无翅（Wg）/ Wnt信号传导对胚胎发育至关重要，并且与包括癌症在内的多种人类疾病有关。该提案将研究Wg分泌及其信号传导活性在发育中受到调节的分子机制。这一应用的结果将有助于了解相关的人类疾病过程。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the molecular mechanism(s) by which the Wingless (Wg) morphogen gradient and signaling are regulated during development. Drosophila Wg encodes an evolutionarily conserved glycoprotein of the Wnt family. Aberant Wg/Wnt signaling activity underlies a number of human developmental disorders and contributes to a variety of cancers. Thus, elucidation of the Wg/Wnt signaling pathway will provide new insights into the mechanisms of related human diseases. Although the components of the Wg/Wnt signaling pathway in its receiving cells have been well characterized over the past 20 years, it remains poorly understood how the mature form of Wg is secreted and travels to its receiving cells to form a concentration gradient, and how the Wg signaling activates the transcription of its downstram target genes. This is an application for continuing support. The current proposal will examine the mechanisms of Wg secretion and its signaling activity in the regulation of the transcription of its target genes. Fist, we will determine the functions of three newly identified ER and Golgi vesicle proteins in Wg secretion (Aim1). Second, we will examine the role(s) of ubiquitin E3 ligase Su (dx) and the deubiquitinating enzyme USP8 in Wls ubiquitination and Wg secretion (Aim2). Third, we will examine the function of Drosophila UBR5 in regulating Wg signaling (Aim3). Taken together, our genetic and biochemical analyses of the newly identified genes in the Wg pathway will provide new insights into the mechanisms of Wg secretion and the transcriptional activation of Wg target genes. Since the Wg signaling transduction pathway is conserved between Drosophila and humans, the outcomes of this project will clearly provide new insights into the mechanisms of various disease processes including cancers. PUBLIC HEALTH RELEVANCE: Wingless (Wg)/ Wnt signaling is essential for embryonic development and is implicated in a variety of human diseases including cancers. This proposal will examine the molecular mechanisms by which Wg secretion and its signaling activity is regulated in development. The outcomes of this application will help in understanding the related human disease processes.