Regulation of Wingless (Wg) Signaling and Morphogen Gradient Formation

描述(申请人提供)：本提案的长期目标是阐明无翅(Wg)形态原梯度和信号在发育过程中受到调控的分子机制(S)。果蝇Wg编码一种进化上保守的Wnt家族糖蛋白。Aberant Wg/Wnt信号活性是许多人类发育障碍的基础，并与多种癌症有关。因此，Wg/Wnt信号通路的阐明将为人类相关疾病的发病机制提供新的认识。尽管在过去的20年里，Wg/Wnt信号通路在其受体细胞中的组成已经得到了很好的描述，但对于Wg的成熟形式是如何分泌并到达其受体细胞以形成浓度梯度，以及Wg信号如何激活其下游靶基因的转录仍然知之甚少。这是一份申请继续支持的申请。目前的建议将研究Wg分泌的机制及其信号活性在其靶基因转录调控中的作用。首先，我们将确定三个新发现的ER和高尔基囊泡蛋白(Aim1)在Wg分泌中的功能。其次，我们将考察泛素E3连接酶SU(DX)和去泛素化酶USP8在WLS泛素化和Wg分泌中的作用(S)。第三，我们将研究果蝇UBR5在调节Wg信号(Aim3)中的功能。综上所述，我们对Wg途径中新发现的基因的遗传和生化分析将为Wg分泌和Wg靶基因的转录激活机制提供新的见解。由于Wg信号转导通路在果蝇和人类之间是保守的，该项目的结果显然将为包括癌症在内的各种疾病过程的机制提供新的见解。

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.