Regulation of Wingless (Wg) Signaling and Morphogen Gradient Formation

Wingless (Wg) 信号传导和形态发生梯度形成的调节

• 批准号: 8633041
• 负责人: XINHUA LIN
• 金额: $ 30.6万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633041
• 关键词: Address; Apical; Biochemical; Caliber; Cell surface; Cells; Cellular biology; Deubiquitinating Enzyme; Development; Developmental Process; Disease; Drosophila genus; Embryonic Development; Family; Family Dasypodidae; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Glycoproteins; Goals; Golgi Apparatus; Grant; Heparan Sulfate Proteoglycan; Homologous Gene; Human; Hyperplasia; Integral Membrane Protein; Lipids; Malignant Neoplasms; Molecular; Outcome; Pathway interactions; Pattern; Process; Proteins; RNA Interference; Regulation; Resources; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Tissues; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Transgenic Organisms; Travel; USP8 gene; Ubiquitin Specific Protease 8; Ubiquitination; Vesicle; Wing; Wnt proteins; Work; base; developmental disease; human disease; in vivo; insight; member; morphogens; mutant; research study; trafficking; ubiquitin-protein ligase

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.

描述（由申请人提供）：该提案的长期目标是阐明在发育过程中调节 Wingless (Wg) 形态发生素梯度和信号传导的分子机制。果蝇 Wg 编码 Wnt 家族的进化保守糖蛋白。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成部分已经得到了很好的表征，但人们对成熟形式的 Wg 是如何分泌并移动到其接收细胞形成浓度梯度以及如何形成浓度梯度的了解仍然知之甚少。 Wg 信号激活其下游靶基因的转录。这是一份持续支持的申请。目前的提案将研究 Wg 分泌的机制及其在靶基因转录调节中的信号活性。首先，我们将确定三种新鉴定的 ER 和高尔基体囊泡蛋白在 Wg 分泌中的功能 (Aim1)。其次，我们将研究泛素 E3 连接酶 Su (dx) 和去泛素化酶 USP8 在 Wls 泛素化和 Wg 分泌 (Aim2) 中的作用。第三，我们将检查果蝇 UBR5 在调节 Wg 信号传导 (Aim3) 中的功能。总而言之，我们对 Wg 途径中新发现的基因的遗传和生化分析将为 Wg 分泌机制和 Wg 靶基因的转录激活提供新的见解。由于 Wg 信号转导通路在果蝇和人类之间是保守的，因此该项目的结果将为包括癌症在内的各种疾病过程的机制提供新的见解。