The Role of Dystroglycan in Signal Transduction

肌营养不良聚糖在信号转导中的作用

• 批准号: 6684036
• 负责人: Hannele RUOHOLA-BAKER
• 金额: $ 28.93万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684036
• 关键词: Drosophilidae; SDS polyacrylamide gel electrophoresis; arthropod genetics; biochemistry; biological signal transduction; dystrophin; fluorescence spectrometry; glycoproteins; liquid chromatography mass spectrometry; membrane proteins; microarray technology; polymerase chain reaction; protein binding; protein protein interaction

DESCRIPTION (provided by applicant): Dystroglycan (DG) is a key element of the dystrophin associated glycoprotein complex (DGC), which is closely linked to pathogenesis of several forms of muscular dystrophy. However, the basic cellular function of this DG complex is largely unknown. The overall objective of this project is to study the protein-protein interactions in which DG is involved in and their implications for cellular signaling. The extracellular matrix and cytoskeletal network are intricately interconnected, providing the cell with both structural integrity and a means for signal transduction. As a transmembrane protein, DG provides a physical link between the extra cellular matrix and cytoskeleton by attaching to laminin-2 at its N-terminus and to the cytoskeletal protein dystrophin at its C-terminus. Recent evidence has implicated DG in cellular signaling processes by binding to SH2/SH3 domain containing proteins, but the downstream signaling pathways are not clearly understood. To advance the understanding of DG's role in cellular signaling, this research aims to address the questions below in vitro and in vivo in Drosophila. 1) What is the biochemical basis of selective DG binding to Dystrophin, Grb2 and Src? 2) What is the functional significance of this selective binding? 3) What molecules, other than Dystrophin, Grb2 and Src interact with DG? We have recently isolated mutations in the DG gene and showed that DG is required for establishing the polarity in both the oocyte and the epithelial cell layers. By combining known biochemical data from mammalian systems with the advantages of Drosophila genetics and modern quantitative biochemistry we will dissect the functional role of differential protein binding by DG and identify new signaling molecules interacting with DG. In the future, we will investigate the developmental functions of DG associated signaling molecules. This research will advance the understanding of DG function in signal transduction and how it is regulated to mediate different intracellular pathways.

描述（由申请人提供）：多糖（DG）是肌营养不良蛋白相关的糖蛋白络合物（DGC）的关键要素，该元素与几种形式的肌肉营养不良的发病机理密切相关。但是，该DG复合物的基本细胞功能在很大程度上未知。该项目的总体目的是研究DG参与的蛋白质蛋白质相互作用及其对细胞信号的影响。细胞外基质和细胞骨架网络复杂地相互联系，为细胞提供了结构完整性和信号转导的手段。作为跨膜蛋白，DG通过在其N末端连接到层粘连蛋白-2，并在其C-末端附着在其N末端和细胞骨架蛋白肌营养不良蛋白上，从而提供了额外的细胞基质和细胞骨架之间的物理联系。最近的证据已通过与含有蛋白质的SH2/SH3结构域结合，在细胞信号传导过程中暗示了DG，但是尚未清楚地了解下游信号通路。为了促进对DG在细胞信号传导中的作用的理解，该研究旨在解决果蝇的体外和体内问题。 1）选择性DG与肌营养不良蛋白，GRB2和SRC结合的生化基础是什么？ 2）这种选择性结合的功能意义是什么？ 3）除肌营养不良蛋白，GRB2和SRC与DG相互作用外，哪些分子？我们最近在DG基因中分离了突变，并表明DG是在卵母细胞和上皮细胞层中建立极性所必需的。通过将来自哺乳动物系统的已知生物化学数据与果蝇遗传学和现代定量生物化学的优势相结合，我们将通过DG剖析差异蛋白结合的功能作用，并确定与DG相互作用的新信号分子。将来，我们将研究DG相关信号分子的发育功能。这项研究将促进对信号转导中DG功能的理解，以及如何调节它以介导不同的细胞内途径。