HSPGs

Heparan sulfate proteoglycans (HSPGs) are a diverse family of proteoglycans defined by covalently attached heparan sulfate glycosaminoglycan chains. They are ubiquitous components of the cell surface and extracellular matrix, where they regulate signaling, adhesion, and morphogenetic processes.

The core proteins include cell-surface syndecans (syndecan-1 to -4) and glypicans (GPC1-6) attached to the plasma membrane or GPI-anchored, as well as secreted basement membrane proteoglycans such as perlecan (HSPG2) and agrin. The HS chains are long, sulfated polysaccharides that interact with a wide range of proteins.

HS chains are synthesized in the Golgi through a stepwise process: formation of a tetrasaccharide linkage to a serine on the core protein, chain initiation and elongation by glycosyltransferases (EXT family), and extensive, cell-type-specific sulfation (NDST, 2-O- and 6-O-sulfotransferases) and epimerization. The resulting sulfation pattern determines ligand binding and receptor interactions.

Functions of HSPGs include modulating signaling by presenting growth factors and morphogens to their receptors, including FGF, VEGF, and Hedgehog pathways; shaping extracellular matrix and basement membranes; and influencing cell adhesion, migration, proliferation, and angiogenesis. They also serve as attachment factors for certain pathogens and can modulate anticoagulant activity via binding to antithrombin.

Clinical and research relevance: defects in HS biosynthesis or core proteins contribute to developmental disorders and cancer progression; mutations in EXT1/EXT2 cause hereditary multiple exostoses. HS mimetics and proteoglycan modulators are explored in therapeutics and biomaterials research, with ongoing work to map sulfation patterns to specific biological interactions.