Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Syndecan-1

  • Niharika Swain
  • Rashmi Maruti Hosalkar
  • Samapika Routray
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_102002

Synonyms

Historical Background

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

Studies have suggested that syndecans have evolved from gene duplication of a single ancestral gene and have been supported by the occurrence of similar exon-intron organization. The syndecan gene was first cloned from mouse mammary epithelial cells and is localized on chromosome 2p23-24-2p24.1. It consists of five exons and four introns of which the first intron is larger as compared to others. Exon 1 encodes the 5′- untranslated region and signal peptide, exon 2 encodes the N-terminal cluster of glycosaminoglycan-attachment sites, exon 3 encodes the ectodomain spacer region, exon 4 encodes the membrane proximal cluster of glycosaminoglycan-attachment sites and 10 bp of the transmembrane domain sequence, and exon 5 encodes the remainder of the transmembrane domain, cytoplasmic domain, and 3′-untranslated region (Fig. 1). The position of the intron separating exons 4 and 5 is conserved. Exon 3 is the most variable exon, containing the coding information for the spacer domains of syndecans-1 and -3. It ranges in size from only 54 bp in syndecan-4 to approximately 700 bp in syndecan-3. All the exons are situated in between the two nontranslated ends. The promoter region of the gene has three transcription-initiation sites, with AP2-TF and Sp1-TF being the common promoter regions for transcriptions and Antp-TF, NFκB-TF, MyoD-TF, and C/EBP acting as binding sites for initiations (Kopper et al. 1997).
Syndecan-1, Fig. 1

Structure of syndecan-1 gene expression and its encoding

Structure and Distribution

Syndecan-1 is an integral membrane proteoglycan composed of 310 amino acids (AA) having a 34 AA long C-terminal intracellular domain, 25 AA transmembrane domain, and a 252 AA extracellular domain called ectodomain having N-terminal. Both intracellular and transmembrane domains are highly conserved between the species and family, while the ectodomain contains three and two serine-glycine sites (AA-37.45, 47) (AA-210,220) for attachment of glycosaminoglycans (GAGs) such as heparin sulfate and chondroitin sulfate, respectively. Heparin sulfate (HS) is the most predominant and frequent GAG involved in various interactions which also varies depending on the cell type and tissue and is also the reason for variable functions of syndecan-1. A protease sensitive site, located on ectodomain close to transmembrane domain, is used for shedding of extracellular part of syndecan-1. The transmembrane domain, which is highly conserved among the syndecan family members, contains an unusual glycine/alanine dimerization motif (GxxxG) that mediates both homodimerization and heterodimerization. The noncatalytic COOH terminal, cytoplasmic domain, is relatively short (30 amino acids), composed of two highly conserved regions (C1 and C2) identical in each of the four syndecan family members (the exception being a conservative substitution of arginine for lysine in syndecan-2) and a central variable region (V) that is distinct for each family member (Fig. 2). The conserved C1 site is immediately adjacent to plasma membrane mediating syndecan dimerization and interaction with numerous intracellular proteins such as ezrin, tubulin, and cortactin that regulates the organization of the cytoskeleton. The conserved C2 domain contains a postsynaptic density-95/disc large protein/zonula occludens-1 (PDZ2)-binding site at the C-terminal end and two tyrosine residues which bind to PDZ-binding proteins, such as synbindin, synectin, CASK, CASK/LIN-2, and syntenin, which play an important role in vesicular transportation, adhesion, synaptic signaling, neuronal migration, and metastasis formation. The cytoplasmic domain of syndecan-1 also interacts with α6β4 integrin and regulates activation of ErbB2 (Kopper et al. 1997; Szatmari et al. 2015).
Syndecan-1, Fig. 2

Structure of syndecan-1 protein molecule showing ectodomain (shades of blue color), transmembrane domain (yellow color), and cytoplasmic domain (shades of red color)

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.

Inflammatory Diseases

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).

Cancer

Syndecan-1 expression is dysregulated in many cancers, including carcinomas of the prostate (Kiviniemi et al. 2004), breast (Lendorf et al. 2011), pancreas (Juuti et al. 2005), ovary (Kusumoto et al. 2010), and oral cavity (Muramatsu et al. 2008). Syndecan-1 modulates several key processes of tumorigenesis, such as cancer cell proliferation and apoptosis, angiogenesis, and metastasis. Full-length syndecan-1 enhances cell-ECM cohesion and restricts cell migration, whereas the loss of the syndecan-1 ectodomain from the cell surface increases the migratory capacity of tumor cells. Similarly, overexpression of the full-length syndecan-1 enhances fibrosarcoma cell adhesion, while constructs lacking the ectodomain inhibit adhesion. Syndecan-1 functions as a coreceptor for Wnt signaling in an HS-dependent manner and affect tumorigenesis by regulating mediators of tumor cell survival and proliferation (e.g., oncogenes, growth factors). However, its regulation of Wnt in other target tissues is yet not known. In myeloma cells, the interaction of heparanase with syndecan-1 activates hepatocyte growth factor-Met-interleukin 11-RANKL signaling pathways causing promotion of myeloma bone disease. Syndecan-1 expression in reactive stromal fibroblasts stores and presents heparin-binding growth factors such as FGFs, HGFs, and EGFs to cancer cells, thus providing a conductive milieu for the growth and progression of tumor cells. Indeed, shedding of syndecan-1 ectodomains from stromal fibroblasts stimulated tumor cell growth through the activation of FGF2 and SDF1 signaling. Studies have also proved that tumor cells utilize syndecan-1 shedding to derive growth factors from the neighboring stroma to maintain their growth conducive environment. Studies have also proven that syndecan-1 regulated tumor cell-induced growth and apoptosis possibly due to diminished prosurvival signals as a result of reduced levels of cell surface HSPG coreceptors for growth factor signaling. Cell surface syndecan-1 promotes cell adhesion to ECM and retards cancer cell migration. However, studies have proven that loss in expression of syndecan-1 in cancer cells leads to diminished cell adhesion, thus enhancing the cell motility and invasion causing metastasis. Syndecan-1 potentiates activation and signaling of αvβ3 and αvβ5 integrin via αv ligand vitronectin, thus functioning to stabilize focal adhesions and actin cytoskeleton causing restriction in cell locomotion. However, studies have shown that loss or gene silencing of cell surface syndecan-1 in cancer cells reduced the levels of active Rho A, enhanced Rac1 activity, and triggered filopodia and lamellopodia formation, thus favoring in acquisition of metastatic phenotype. Epithelial–stromal interactions are crucial in the acceleration of carcinoma growth and progression with stromal fibroblasts and the ECM contributing to allow a more supportive microenvironment for cancer progression. Syndecan-1 expressing fibroblasts are expressed in various cancer cells; however, how it modulates the fibronectin assembly directly or indirectly with the help of integrin is yet to be understood. Syndecan-1 has also said to play a role in angiogenesis by binding to proangiogenic factors like FGF-2 and VEGF, and subsequently present them to their respective receptors on endothelial cells thus initiating endothelial invasion and budding. Soluble syndecan-1 ectodomains with bound proangiogenic factors also foster angiogenesis at premetastatic niches. Syndecan-1 present in the reactive stroma may requisite proangiogenic factors, increasing its local concentration and thus promoting angiogenesis (Teng et al. 2011; Szatmári et al. 2015) (Fig. 3).
Syndecan-1, Fig. 3

Role of syndecan-1 in various cellular responses in tumorigenesis (in boxes) along with its putative role in tumor microenvironment (cross talk between tumor cells and stromal fibroblasts through shredded syndecan-1)

Infectious Diseases

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.

Summary

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.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Niharika Swain
    • 1
  • Rashmi Maruti Hosalkar
    • 2
    • 3
  • Samapika Routray
    • 4
  1. 1.MGM Dental College and HospitalNavi MumbaiIndia
  2. 2.Indian Association of Oral and Maxillofacial PathologistsMumbaiIndia
  3. 3.Maharashtra State Dental CouncilMumbai, MaharashtraIndia
  4. 4.Department of Dental SurgeryAll India Institute of Medical SciencesBhubaneswarIndia