Heparan Sulfate Proteoglycans

While there are reports of growth factors binding to a wide range of ECM components, the large number of growth factors that have been shown to bind to heparin, coupled with the structural complexity of HS, indicates that these polysaccharides play particularly important roles in controlling growth factors in vivo. Heparan sulfate proteoglycans (HSPGs) represent a class of complex macromolecules that are comprised of a protein core and at least one covalently linked HS chain. HS chains are linear polysaccharides characterized by repeating disaccharide units of alternating N-substituted glucosamine and hexuronic (glucuronic or iduronic) acid residues (46). HS chains are subject to extensive modification during biosynthesis, including sulfation at the N-position as well as at the C-6 and C-3 O-positions of the glucosamine and at the C-2 O-position of the uronic acid (47,48). Thus, there are theoretically as many as 48 potential disaccharide units that together make this class of compounds one of the most information dense in biology. In addition, HS has domain structures made up of extended sequences of high or low levels of sulfation, making its overall structure and sequence considerably complex (49). The high degree of structural complexity likely underlies the ability of heparin and HS to interact with a wide array of proteins as a means to modulate their biodistribution and activity (4,47,48,50-52).

HSPGs are physically positioned on the cell surface, within the ECM, or in soluble form. Approximately 20 HSPG core proteins have been identified. They include the syndecans 1 to 4 and the glypicans 1 to 6, which are widely expressed in nearly all mammalian cell types and tissues where they are linked to plasma membrane surfaces either through a transmembrane core protein (syndecans) or by a glycosylphosphatidylinositol tail (glypicans) (53,54). In addition, the ectodomain of the syndecans, which contains the attached HS chains, can be shed from the cell surface through the action of extracellular proteases to produce "soluble" HSPG fragments (HSPGfs) (55-58). In contrast to the cell surface HSPGs, several HSPGs, such as perlecan, are localized to basement membranes and other extracellular matrices where their HS chains modulate matrix structure and molecular transport (3). In addition to the traditional role of HSPG within the extracellular space, evidence has suggested roles for these molecules within cells (59-64). Indeed, the principal role of the highly sulfated HS produced by mast cells (heparin) is to store mast cell proteases in an inactive form within secretory granules (65). Consequently, the physical location and specific HS structure allow HSPG to alternatively inhibit or promote cellular responses through direct and indirect mechanisms (29,66,67).

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