Syndecans, a cell surface heparin sulfate proteoglycan family, are generally expressed on the surface of all adherent cells and many nonadherent cells. Based on its function as an anchor that stabilizes epithelial sheet morphology by connecting the extra cellular matrix (ECM) to intracellular cytoskeleton, this family of proteoglycans was termed as “syndecan,” derived from Greek word “syndein” meaning to bind together. They consist of four members: syndecan-1, syndecan-2 (fibroglycan), syndecan-3(N-syndecan), and syndecan-4 (amphiglycan/ryudocan) each encoded by a distinct gene (Teng et al. 2011). In 1989, Merton Bernfield’s group cloned the first member, syndecan-1, followed by identification of other members in the following years. It soon became apparent that they could support cell adhesion, and now it is known that all four mammalian members can interact with the actin cytoskeleton (Couchman et al. 2015). Syndecan-1 is expressed by epithelial cells, syndecan-2 is present mainly on cells of mesenchymal origin, syndecan-3 is seen within neuronal tissue and cartilage, and syndecan-4 is expressed by most tissues (Gharbaran 2015).
Gene Structure and Its Transcription
Structure and Distribution
Syndecan-1 is most abundantly expressed in stratified squamous epithelia, such as epidermis, oral mucosa, and vagina. It is also expressed on basolateral surfaces of the epithelial cells, endothelial cells of sprouting capillaries, and embryonic condensing mesenchymal cells. In normal tongue tissue, the basal, suprabasal, and lower prickle cell layers of the epithelium showed positivity for syndecan-1, which were distinct on the cell surfaces, while the cell membrane facing the basement membrane was essentially negative for syndecan-1 staining. The upper prickle cell and superficial layer of the epithelium also lacked syndecan-1 reactivity suggestive of the fact that syndecan may have different functions in stratified squamous epithelium (David et al. 1993; Sanderson et al. 1989). Syndecan-1 was also expressed in distinct differentiation stages of normal lymphoid cells and was expressed when and where lymphoid cells interact with type I collagen (Sanderson et al. 1989), thus confirming its presence on the cell surface of B cells in the pre-B-cells stage and immature B cells, absence from matured B cells, and reappearance on plasma cells (Sebestyen et al. 1999). Sydecan-1 may mediate the adhesion of lymphoid cells to bone marrow matrix and to the interstitial matrix of peripheral lymphoid organs (Sanderson et al. 1989; Sebestyen et al. 1999).
Syndecan-1 in Physiology
Syndecan-1 has been said to play various physiological roles such as the following:
Regulation of Cell Matrix Interaction
Syndecan-1 plays a role of matrix receptor in transducing information between extracellular matrix and outside of the cell. This role has been based on the findings that syndecan (1) binds with several interstitial matrix components through its ectodomain, (2) is expressed at the basolateral surface of cultured epithelial cells as well as in simple epithelia in vivo, and (3) is colocalized with cytoskeletal actin filaments in polarized epithelial cells. Studies show evidences in regulation of cell morphology by changing the expression of syndecan-1 at cell surface. Studies have also shown syndecan-like molecules to function as coreceptors for other kinds of matrix receptors, like integrins, making the matrix ligand more available or changing its conformation as demonstrated in studies concerning the formation of focal adhesions of fibroblasts cultured on fibronectin. Epithelial syndecan-1 has also shown to interact with several matrix proteins such as fibrillar collagens, fibronectin, thrombospondin, and tenascin but not with basement membrane components, thus implying on its role in cell adhesion either by self-assembly or with the help of other molecules (Elenius and Jalkanen 1994).
Regulation of Cell Proliferation
On cells deficient of syndecan-1 heparin sulfate, fibroblast growth factor (FGF) has been demonstrated to neither bind to its receptor (FGFR-1) nor exert its growth stimulatory or inhibitory actions, thus suggesting the formation of ternary complex between FGF-2, its tyrosine kinase receptor, and a heparan sulfate cell surface proteoglycan before the signal from growth factor is tranduced to inside of the cell through multimerization and transphosphorylation of FGFRs. It has also been shown that FGF-1, FGF-4, FGFRs, vascular endothelial cell growth factor (VEGF), lipoprotein receptor, heparin-binding epidermal growth factor (HB-EGF), hepatocyte growth factor (HGF), and integrins also are prerequisite of heparan sulfate binding for signaling and induction of their action (Elenius and Jalkanen 1994).
Syndecan-1 in Disease
Syndecan-1 plays a key role in inflammatory diseases, cancer, and infection.
Inflammation is a fundamental host response to endogenous or exogenous insults that have the potential to cause injury and is regulated through multiple mechanisms that have evolved to contain and resolve the inflammation. Syndecan-1 binds to many such factors involved in mediating and regulating the inflammatory response. The primary function of syndecan-1 in inflammation is to negatively regulate leukocyte adhesion and migration, possibly by inhibiting the interactions between leukocyte integrins and endothelial ICAM-1 and VCAM-1. Syndecan-1 has also been shown to be involved in negative regulation of neutrophil adhesion to endothelial cells in an HS-dependent manner. All these functions are suggestive of the fact that syndecan-1 on endothelial cells or of epithelial cells functions as inhibitors of leukocyte adhesion. Syndecan-1 also regulates the generation and activity of chemokine gradients in inflammatory diseases by tethering the chemokines to the endothelial cell surface at site of injury/infection, thus activating the weakly bound leukocytes and inducing their firm adhesion onto the endothelium while generating a chemokine gradient that guides the directional migration of leukocytes. Syndecan-1 regulates Th1/Th2 balance in this inflammatory disease, while its shedding facilitates resolution of neutrophil inflammation by removing sequestered CXC chemokines in an HS-dependent manner. However, the exact mechanism through which this happens is not known but the newly synthesized CXC chemokines tethered to syndecan-1 on the endothelial cell surface, and syndecan-1 shedding may release the sequestered chemokines, resulting in dispersion of the CXC chemokine gradient for neutrophil infiltration. Syndecan-1 is expressed in excess of CXCL1 and CXCL2, with syndecan-1 shedding causing release of large amounts of unbound syndecan-1 ectodomains that can displace CXC chemokines tethered to endothelial syndecan-1 and other HSPGs. Thus it confines, attenuates, or resolves inflammation by modulating HS-binding proinflammatory factors. Syndecan-1 has been shown to remodulate matrix assembly in several models of inflammatory diseases and at the same time promote fibrosis by amplifying the angiotensin II and TGFβ1 signaling in an HS-dependent manner. Thus, cell surface syndecan-1 apparently attenuates fibrosis by promoting repair, whereas syndecan-1 ectodomain promotes fibrosis by inhibiting epithelial repair and upregulating fibrotic factors and processes. Syndecan-1 has also been shown to regulate protein leakage in the intestinal epithelium, smooth muscle cell (SMC) proliferation in vascular injury, keratinocyte proliferation in dermal injury, and lipoprotein metabolism (Teng et al. 2011).
Syndecan-1 is subverted in several steps of infection, including the initial attachment and subsequent entry of pathogens into host cells and inhibition of host defense mechanisms. Several studies have also shown that cell surface and shed syndecan-1 can promote pathogenesis through distinct molecular mechanisms. Human papilloma virus (HPV) attaches to host cells via the L1-syndecan-1 interaction leading to activation of L2, thus allowing L2-mediated HPV entry and supporting the role of syndecan-1 as a viral attachment receptor. The theory is further supported by study showing herpes simplex virus internalization if HS chains of syndecan-1 are modified to contain sufficient 3-O-sulfated HS domains to potentiate gD signaling and thus its entry. Human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome (AIDS), binds to HSPGs on macrophages, dendritic cells, spermatozoa, endothelial cells, and epithelial cells via syndecan cytoplasmic domain signaling through HIV entry receptors, primarily gp120 but also through CD4, CD209, and mannose receptors.
Syndecan-1 plays a varied role in physiology as well as pathology implying that it is just not a bystander but an important player. Though it plays a unique role in cell-cell adhesion and proliferation, new properties have to be identified and understood pertaining to its role in inflammation, cancer, and infectious disease and whether therapeutic targeting would be relevant if any.
- Elenius K, Jalkanen M. Function of the syndecans – a family of cell surface proteoglycans. J Cell Sci. 1994;107(Pt 11):2975–82.Google Scholar