Syndecans: transmembrane modulators of adhesion and matrix assembly

Syndecans are transmembrane heparan sulfate proteoglycans (HSPGs) that are present on most cell types. HSPGs have been known for some time to regulate a variety of biological processes, ranging from coagulation cascades, growth factor signaling, lipase binding and activity, cell adhesion to ECM and subsequent cytoskeletal organization, to infection of cells with microorganisms. They are complex molecules, with specific core protein to which a variable number of glycosaminoglycan (GAG) chains are attached. Not only the number of chains varies; although syndecans mainly bear heparan sulfate GAGs, some have additional chondroitin/dermatan sulfate chains. Furthermore, heparan sulfate chains can vary in length, epimerization of glucuronic acid to iduronic acid, overall sulfation of the chains, and position of sulfation of the monosaccharides. Early studies relied on structurally nonspecific approaches such as competition with heparin or treatment with heparinases or chlorate to remove GAG chains or prevent their sulfation, respectively. These approaches defined a number of interacting ligands for heparan sulfates including insoluble ECM components and soluble growth factors and cytokines, and they helped to implicate HSPGs in a variety of biological processes (1–5). Cell surface HSPGs, including syndecans, appear to play modulatory roles, such as presenting growth factors to their primary receptors or increasing the infectivity of viruses by interacting with their primary receptors. In addition, these molecules can modify adhesion mediated by the integrins, the major family of receptors for ECM. This last function establishes a parallel between the syndecans (as well as other cell surface HSPGs) and the secreted matricellular proteins discussed elsewhere in this Perspective series. This is an exciting time to be in the field of syndecan research. Recently, there has been a surge of interest in the role of HSPGs and in identifying both the specific sequences of monosaccharides and sulfation patterns involved in ligand binding. With the cloning of various core proteins, it has become possible to study the features of these proteins that affect the ligand-binding ability and subsequent biological responses (reviewed in ref. 5; Table ​Table1).1). Now that tools are available to analyze individual protein cores, and techniques are becoming available to determine the sequence of their GAG chains, it is becoming evident that the protein and carbohydrate components of these molecules each play specific biological roles. Recent advances in “sequencing” of GAG chains present on individual proteoglycans have begun to allow structure to be correlated with function in these complex molecules. For example, a decasaccharide containing 2-O-sulfated iduronic acid and 6-O-sulfated N-acetylglucosamine is needed to potentiate the interaction of FGF-2 with its receptor. In contrast, a less specific sequence of seven to eight N-sulfated disaccharides containing iduronic acid (with or without 2-O-sulfation) serves to bind the higher affinity heparin-binding domain of fibronectin (HepII; ref. 5). This Perspective will concentrate on the syndecan family of transmembrane HSPGs and their roles in adhesion to ECM and subsequent matrix modification. In addition, it will address how syndecans may be pivotal in coordinating growth factor and adhesion signaling mechanisms. For discussion of some recent advances concerning the roles of cell surface proteoglycans in other fundamental biological processes, see refs. 2, 5, 6, and 7 and references therein. Table 1 Known ligands for HSPGs, where sulfation/epimerization patterns have been determined