Proteoglycans in Cell Signaling and in Morphogenesis
Most of the projects in the lab are related with HSPGs. Studies in our lab and others have illustrated essential in vivo roles of HSPGs in modulating signal transduction pathways including Wnt, Hh, BMP and FGF. Do HSPGs have any specificity in regulating these signaling pathways? How do HSPGs control cell signaling in various tissues or developmental processes? Currently, we have focused our studies on understanding the specificity of individual HSPGs and their modifications in cell signaling and morphogenesis.
HSPGs are composed of a core protein decorated with covalently linked glycosaminoglycan (GAG) chains. The biologic activity of HSPGs is contributed by both core proteins and their attached GAG chains. HSPGs are classified into several families based on the structure of their core proteins. Glypicans and Syndecans are two major cell surface HSPGs and are linked to the plasma membrane by a glycosylphosphatidylinositol (GPI) linkage or a transmembrane domain, respectively. Perlecans are secreted HSPGs that are mainly distributed in the ECM (Lin, 2004). Drosophila genome has two glypicans (Dally and Dlp), one syndecan and one perlecan. These HSPGs play very unique roles in cell signaling and morphogenesis. For example, we showed Dlp, but not other HSPGs, is essential for Hh signaling during embryogenesis. However, both Dlp and Dally are required for Hh signaling in the wing disc (Han et al., 2004). Currently, it is unclear how specific HSPG core proteins control unique signaling event and morphogenesis.
The HS GAG chains are essential for the biological activity of HSPGs. The formation of HS GAG chains is catalyzed in the Golgi apparatus by glycosyltransferases encoded by members of the putative tumor suppressor of EXT family. The HS GAG chains are further modified by various modification enzymes which generate enormous structural variation associated with O-and N-sulfations. The patterns of sulfations on HS GAG chains seem to provide specific protein-recognition domains. Our previous studies in sulfateless (sfl), an enzyme essential for HS GAG sulfation have demonstrated critical roles of sulfations for the biological activity of HSPGs (Lin and Perrimon, 1999). Analysis of other specific modification enzymes such as HS6ST would allow us to further define molecular mechanisms by which HSPGs control specific cell signaling events and morphogenesis.
