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. ? ?
