Cell surface heparan sulfate proteoglycans (HSPGs), 1 substantially more abundant than most receptors, modulate encounters of extracellular protein ligands with their receptors by forming HSprotein complexes. Two gene families account for most cell surface HSPGs. Both consist of discrete core proteins covalently attached to two or three chains of HS, an N-and O-sulfated linear polysaccharide of repeating disaccharides containing N-acetylglucosamine (GlcNAc) and uronic acid (glucuronic acid (GlcA) or iduronic acid (IdoUA)). The syndecan family was the first discovered, which in mammals contains four gene products with distinctive extracellular domains (ectodomains) and highly conserved short cytoplasmic domains. These apparently extended proteins place the HS chains distal from the plasma membrane (1, 2). The syndecan family contrasts with the glypican family, which in mammals contains six gene products that are covalently linked to plasma membrane lipid by glycosylphosphatidylinositol anchor (1, 3). The glypican core proteins contain six invariant disulfide bonds, are likely to be globular, and place HS chains adjacent to the plasma membrane. Expression of both the syndecans and glypicans is extensively regulated during mouse embryogenesis and results in discrete adult expression patterns for each HSPG such that every adherent cell exhibits a distinct repertoire of cell surface HSPGs.Binding to HS chains is remarkably widespread among extracellular proteins, especially matrix proteins, proteases and their inhibitors, lipases, lipoproteins, growth factors and their binding proteins, cytokines, chemokines, collectins, and antimicrobial peptides. These proteins are involved in morphogenesis, tissue repair, energy balance, and host defense (Fig. 1). Additionally, numerous pathogens (e.g. herpes simplex virus, Neisseria, Plasmodium) bind to the cell surface via HS (4). Importantly, many of these ligand-HS interactions are essentially identical from Drosophila to the mouse, including those involved in generation of the basic metazoan body plan, e.g. dpp (bone morphogenetic proteins 2-4), wg (Wnt-1), and sog (chordin).Formation of the complexes can enhance or reduce receptor activation, often depending on the concentrations of ligand, receptor, and HSPG. The HS chains catalyze encounters between ligand and signaling receptor by bringing them together. Because binding to the HS chain reduces the dimensionality of this interaction from three (when the ligand is soluble) to two (when the ligand is bound to the HS chain), interaction could result from a localized increase in ligand concentration at optimal HS concentrations (5). However, at HS levels lower or higher than optimal, the effective ligand concentration for engaging the receptor will fall, potentially accounting for the bell-shaped activity curve typically seen experimentally when HSPG (or heparin) concentrations are varied. The curve may be concave or convex depending on whether ligand binding to the HSPG is inhibitory or stimulatory (6). Furthermore, the cytop...