Role(s) of Heparan Sulfate Proteoglycan(s) in the wnt-1 Signaling Pathway

摘要

Drosophila Wingless (Wg) is the homologue of the vertebrate Wnt-1 that is implicated in breast cancer. I have investigated the role of heparan sulfate proteoglycans (HSPGs) in Wg signaling. HSPGs are cell surface macromolecules that consist of a protein core to which heparan sulfate (HS) glycosaminoglycan (GAG) chains are attached. My genetic studies in Drosophila have uncovered critical functions of HSPGs in Wg signaling. First, I have shown that in the absence Sulfateless (Sfl), an essential enzyme involved in the biosynthsis of HS GAGs, Wg signaling is defective, suggesting that HSPGs play key role(s) in Wg signaling. I further demonstrated that Division abnormally delayed (Dally), a Drosophila HSPG of Glypican-type, is involved in Wg signaling. Genetic interaction experiments are consistent with a model in which Dally acts as a co-receptor for Wg. Finally, I have found that Dally-like protein (Dlp), a 2nd member of Drosophila Glypican play a key role in the regulation of the extracellular distribution of Wg protein. These findings provide new insights into our understanding of the extracellular regulation of Wnt signaling and will help for therapeutic interventions by the development of specific drugs for the prevention and treatment of breast cancer.