Cell-associated proteoglycans provide highly complex and sophisticated systems to control interactions of extracellular cell matrix components and soluble ligands with the cell surface. Syndecans, a conserved family of heparan- and chondroitin-sulfate carrying transmembrane proteins, are emerging as central players in these interactions. Recent studies have demonstrated the essential role of syndecans in modulating cellular signaling in embryonic development, tumorigenesis, and angiogenesis. In this review, we focus on new advances in our understanding of syndecan-mediated cell signaling.

Syndecans New Kids on the Signaling Block

Syndecans function as membrane receptors for a bewildering array of ligands through their glycosaminoglycan chains but their precise roles have been hard to pin down. Syndecans have previously been considered as ligand gatherers, working as co-receptors in collaboration with signalling receptors, but their potential to signal independently is now clear. New structural features of syndecan cytoplasmic domains have been described, together with new insights into signalling across the cell membrane that might involve the concentration of ligands in membrane microdomains.

Syndecans: proteoglycan regulators of cell-surface microdomains?

The semaphorins and their receptors, the neuropilins and the plexins, were originally characterized as constituents of the complex regulatory system responsible for the guidance of axons during the development of the central nervous system. However, a growing body of evidence indicates that various semaphorins can either promote or inhibit tumour progression through the promotion or inhibition of processes such as tumour angiogenesis, tumour metastasis and tumour cell survival. This Review focuses on the emerging role of the semaphorins in cancer.

The semaphorins: versatile regulators of tumour progression and tumour angiogenesis

NRPs (neuropilins) are co-receptors for class 3 semaphorins, polypeptides with key roles in axonal guidance, and for members of the VEGF (vascular endothelial growth factor) family of angiogenic cytokines. They lack a defined signalling role, but are thought to mediate functional responses as a result of complex formation with other receptors, such as plexins in the case of semaphorins and VEGF receptors (e.g. VEGFR2). Mutant mouse studies show that NRP1 is essential for neuronal and cardiovascular development, whereas NRP2 has a more restricted role in neuronal patterning and lymphangiogenesis, but recent findings indicate that NRPs may have additional biological roles in other physiological and disease-related settings. In particular, NRPs are highly expressed in diverse tumour cell lines and human neoplasms and have been implicated in tumour growth and vascularization in vivo. However, despite the wealth of information regarding the probable biological roles of these molecules, many aspects of the regulation of cellular function via NRPs remain uncertain, and little is known concerning the molecular mechanisms through which NRPs mediate the functions of their various ligands in different cell types.

Neuropilins: structure, function and role in disease

Virtually all metazoan cells contain at least one and usually several types of transmembrane proteoglycans. These are varied in protein structure and type of polysaccharide, but the total number of vertebrate genes encoding transmembrane proteoglycan core proteins is less than 10. Some core proteins, including those of the syndecans, always possess covalently coupled glycosaminoglycans; others do not. Syndecan has a long evolutionary history, as it is present in invertebrates, but many other transmembrane proteoglycans are vertebrate inventions. The variety of proteins and their glycosaminoglycan chains is matched by diverse functions. However, all assume roles as coreceptors, often working alongside high-affinity growth factor receptors or adhesion receptors such as integrins. Other common themes are an ability to signal through their cytoplasmic domains, often to the actin cytoskeleton, and linkage to PDZ protein networks. Many transmembrane proteoglycans associate on the cell surface with metzincin proteases and can be shed by them. Work with model systems in vivo and in vitro reveals roles in growth, adhesion, migration, and metabolism. Furthermore, a wide range of phenotypes for the core proteins has been obtained in mouse knockout experiments. Here some of the latest developments in the field are examined in hopes of stimulating further interest in this fascinating group of molecules.

Transmembrane Signaling Proteoglycans

Syndecan-4, a member of the syndecan gene family of proteoglycans, is an important regulator of bFGF signaling. In particular, bFGF-dependent regulation of cell growth and migration has been linked to syndecan-4 cytoplasmic domain-mediated interactions. Screening of a yeast two-hybrid library with a cytoplasmic domain of rat syndecan-4 identified a novel binding partner, here termed synectin. Synectin is highly homologous to semaphorin F binding protein semcap1, glucose 1 transporter binding protein glut1cbp, and RGS-GAIP/neuropilin-1 binding protein GIPC. Overexpression of synectin in ECV304 cells in culture led to a dose-dependent inhibition of migration while not affecting cell adhesion or growth rate. We conclude that synectin is involved in syndecan-4–dependent interactions and may play a role in the assembly of syndecan-4 signaling complex. J. Cell. Physiol. 184:373–379, 2000. © 2000 Wiley-Liss, Inc.

Min Li

Papers

Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration