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 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. We have dissected the muscle and neuronal disorders in Drosophila muscular dystrophy and analyzed the binding motifs in DG that are required for function (Deng et al., 2003; Shcherbata et al., 2006; Gray et al., 2006). We are now taking a multidisciplinary approach towards understanding the function of the Dystroglycan protein in Drosophila. Computational analysis, biochemistry and easy-to-manipulate genetics in Drosophila are used to further dissect the role of the different potential binding partners of the cytoplasmic tail of Dystroglycan in signaling. The long term goal of this project is to better understand the Dystroglycan pathway in hopes that this information can lead to new gene therapy approaches for curing muscular dystrophy.