Heparan Sulfate Proteoglycans

Heparan sulfate proteoglycans (HSPGs) are glycoproteins, with the common characteristic of containing one or more covalently attached heparan sulfate (HS) chains, a type of glycosaminoglycan (GAG) (Esko et al. 2009). Cells elaborate a relatively small set of HSPGs (∼17) that fall into three groups according to their location: membrane HSPGs, such as syndecans and glycosylphosphatidylinositol-anchored proteoglycans (glypicans), the secreted extracellular matrix HSPGs (agrin, perlecan, type XVIII collagen), and the secretory vesicle proteoglycan, serglycin (Table 1). Much of the early work in the field concentrated on composition (size, chain number, and structure of the HS chains), biosynthesis, and binding properties of the chains. In 1985, the first somatic cell mutants altered in HSPG expression were identified (Esko et al. 1985), which allowed functional studies in the context of a cell culture model (Zhang et al. 2006). A decade later, the first HSPG mutants in a model organism (Drosophila melanogaster) were identified (Rogalski et al. 1993; Nakato et al. 1995; Hacker et al. 1997; Bellaiche et al. 1998; Lin et al. 1999), which was followed by identification of mutants in nematodes, tree frogs, zebrafish, and mice (Tables 2 and ​and3).3). HS is evolutionarily ancient and its composition has remained relatively constant from Hydra to humans (Yamada et al. 2007; Lawrence et al. 2008). Table 1. Heparan sulfate proteoglycans Table 2. Mutants altered in HSPG core proteins Table 3. Mouse mutants altered in HS biosynthesis Figure 1 shows in pictorial form many of the systems in which HSPGs participate. HSPGs are present in basement membranes (perlecan, agrin, and collagen XVIII), where they collaborate with other matrix components to define basement membrane structure and to provide a matrix for cell migration. HSPGs are found in secretory vesicles, most notably serglycin, which plays a role in packaging granular contents, maintaining proteases in an active state, and regulating various biological activities after secretion such as coagulation, host defense, and wound repair. HSPGs can bind cytokines, chemokines, growth factors, and morphogens, protecting them against proteolysis. These interactions provide a depot of regulatory factors that can be liberated by selective degradation of the HS chains. They also facilitate the formation of morphogen gradients essential for cell specification during development and chemokine gradients involved in leukocyte recruitment and homing. HSPGs can act as receptors for proteases and protease inhibitors regulating their spatial distribution and activity. Membrane proteoglycans cooperate with integrins and other cell adhesion receptors to facilitate cell-ECM attachment, cell–cell interactions, and cell motility. Membrane HSPGs act as coreceptors for various tyrosine kinase-type growth factor receptors, lowering their activation threshold or changing the duration of signaling reactions. Membrane HSPGs act as endocytic receptors for clearance of bound ligands, which is especially relevant in lipoprotein metabolism in the liver and perhaps in the formation of morphogen gradients during development. Figure 1. HSPGs have multiple activities in cells and tissues. (Adapted from Bishop et al. 2007; reprinted with permission from Nature Publishing Group © 2007.) This article is divided into 10 subsections. The first three are written for investigators outside the field who may need some background information on the diversity of HSPGs and the interactions that occur with protein ligands. The subsequent sections describe seven systems that illustrate general principles or ideas that have undergone a significant shift over the last decade. Because of space limitations not all subjects can be considered or treated in appropriate depth and therefore the reader is referred to excellent recent review articles (Tkachenko et al. 2005; Bulow and Hobert 2006; Bishop et al. 2007; Lamanna et al. 2007; Bix and Iozzo 2008; Filmus et al. 2008; Ori et al. 2008; Rodgers et al. 2008; Sanderson and Yang 2008; Iozzo et al. 2009; Couchman 2010).