Syndecan receptors: pericellular regulators in development and inflammatory disease

Abstract

The syndecans are the major family of transmembrane proteoglycans, usually bearing multiple heparan sulfate chains. They are present on virtually all nucleated cells of vertebrates and are also present in invertebrates, indicative of a long evolutionary history. Genetic models in both vertebrates and invertebrates have shown that syndecans link to the actin cytoskeleton and can fine-tune cell adhesion, migration, junction formation, polarity and differentiation. Although often associated as co-receptors with other classes of receptors (e.g. integrins, growth factor and morphogen receptors), syndecans can nonetheless signal to the cytoplasm in discrete ways. Syndecan expression levels are upregulated in development, tissue repair and an array of human diseases, which has led to the increased appreciation that they may be important in pathogenesis not only as diagnostic or prognostic agents, but also as potential targets. Here, their functions in development and inflammatory diseases are summarized, including their potential roles as conduits for viral pathogen entry into cells.

Syndecan-1 (CD138), Carcinomas and EMT

“…Here, the basal layers of the epidermis were disorganized, and subsequent analysis showed the abnormal expression of One potential explanation for the lack of a developmental phenotype in epithelia may be redundancy. There are four mammalian syndecans, and syndecan-4, for example, is widespread, and can be demonstrated as a surface component of many epithelia [6]. Our own data on epidermal differentiation shed a little light on this area.…”

“…Cleavage results in the release of a large portion of the core protein with glycosaminoglycan chains attached [67,68]. These can function as competitive inhibitors of the cell surface population, or may bind ligands and present them to cell surface receptors [6]. Since in many cases, the presence of stromal syndecan-1 is a sign of tumor aggressiveness, it appears likely that shed syndecan-1 is a mediator of invasion, proliferation and permissive alterations in the tumor microenvironment.…”

“…An important adjunct to shedding is the enzyme heparanase. There are two isoforms in the human, but only heparanase-1 has enzymatic activity [6]. This enzyme is notably upregulated in a number of cancer types and is the focus of trials to determine if its inhibition can ameliorate tumor aggressiveness [74,75].…”

“…In short order, three further mammalian members of the family were successfully cloned, though none has the same distribution as syndecan-1 [4]. Through immunohistochemistry, it became clear that syndecan-1 had an epithelial expression pattern in particular, though it is present in other tissue types, notably plasma cells of the B lineage and some stromal cells [5,6]. Wherever it has been analyzed, syndecan-1 bears heparan sulfate chains, but in some epithelia, there are additional chondroitin or dermatan sulfate chains.…”

“…However, binding partners for the syndecan-1 V region have remained elusive. Data from the equivalent region of syndecan-4 suggest that syndecan-specific signaling emanates from interactions through the V region [6], so this remains an important gap in our understanding. In total, little is understood of the signaling repertoire of this proteoglycan.…”