Syndecan

Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin-C.

Family members and Structure
The syndecan protein family has four members. Syndecans 1 and 3 and syndecans 2 and 4, making up separate subfamilies, arose by gene duplication and divergent evolution from a single ancestral gene. The syndecan numbers reflect the order in which the cDNAs for each family member were cloned. All syndecans have an N-terminal signal peptide, an ectodomain, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain. The ectodomains show the least amount of amino acid sequence conservation, not more than 10–20%; in contrast, the transmembrane and cytoplasmic domains share approximately 60–70% amino acid sequence identity. The transmembrane domains contain an unusual alanine/glycine sequence motif, while the cytoplasmic domain is essentially composed of two regions of conserved amino acid sequence (C1 and C2), separated by a central variable sequence of amino acids that is distinct for each family member (V).

In mammalian cells, syndecans are expressed by unique genes located on different chromosomes. This is general lack of evidence of alternate splicing in syndecan genes. All members of the syndecan family have 5 exons. The difference in size of the syndecans is credited to the variable length of exon 3, which encodes a spacer domain [1, 14]. In humans, the amino acid length of syndecan 1, 2, 3 and 4 is 310, 201, 346 and 198 respectively. Glycosaminoglycan chains, a member of the heparan sulfate group, are an important component of syndecan and are responsible for a diverse set of syndecan functions. The addition of glycosaminoglycans to syndecan is controlled by a series of post- translation events. The preferential site for the addition of glycosaminoglycans is on a serine residue followed by glycine residue, where the linker is attached for the elongation of the glycosaminoglycans by α-N-acetylglucosaminyltransferase I [1]. The linker is composed of four saccharides, first one being xylose, which is an unusual sugar in a unique place, attached to serine of the protein core and sequentially followed by two galactose and a β-D-glucuronic acid [1, 12].

Expression
Syndecans are expressed on the cell surface in a cell-specific manner. For example, in mouse cells and tissues, syndecan 1 is highly expressed in fibroblastic and epithelial cells. It is especially high in keratinocytes whereas low in endothelial and neural cells. These tissues include skin, liver, kidney and lungs. Syndecan 2 is highly expressed in endothelial, neural, and fibroblastic cells, whereas it has low expression levels in epithelial cells. It is specific to tissues such as the liver, endothelia and fibroblasts. Syndecan 3 is highly expressed in neural cells, but has low or undetectable amount in epithelial cells. In tissues, it is specific to the brain and expressed at low levels in liver, kidney, lung and small intestine. Syndecan 4 is highly expressed by epithelial and fibroblastic cells, but has low expression levels in neural and endothelial cells. In tissues, it is preferentially expressed in the liver and lungs [11].

Functions
Functionality of syndecan is contributed by glycosaminoglycans which help in the interaction with different extracellular ligands. Depending upon the cellular localization of syndecan, glycosaminoglycans have different structures to accommodate the functional needs of the region. Functions of syndecan can be categorized in four ways. First is growth-factor-receptor activation. Glycosaminoglycans attached to the syndecan help binding of the various growth factors for activation of important cellular signaling mechanisms. Growth factors such as bFGF, HGF, EGF, VEGF, neuregulins and others interact with syndecans [1, 2, 8]. For example, the ectodomain of syndecan 1 acts as an activator of FGF-2 for wound healing responses [13]. Second is matrix adhesion. Syndecans bind to structural extracellular matrix molecules such as collagens I, III, V, fibronectin, thrombospondin and tenascin to provide structural support for the adhesion [1, 2]. A third function is cell–cell adhesion. Evidence for syndecan’s role in cell–cell adhesion comes from the human myeloma cell line. These myeloma cells had a deficiency in the ability to adhere to one another in a rotation-mediated aggregation matrix. This deficiency is attributed to the lack of syndecan 1 expression. Syndecan 4 also interacts with integrin proteins for cell–cell adhesion [1, 2, 12]. A final role is in tumor suppression and progression. Syndecans act as tumor inhibitors by preventing cellular proliferation of tumor cell lines. For example, in the epithelial-derived tumor-cell line, S115, the syndecan 1 ectodomain suppresses the growth of S115 cells without affecting the growth of normal epithelial cells [7]. However, syndecan 1 expression also has a role in tumor progression in myeloma and other cancers [5, 6, 9, 15].

Osteoarthritis
Syndecan4 is upregulated in osteoarthritis and inhibition of syndecan 4 reduces cartilage destruction in mouse models of OA.

Metabolic regulation and body composition
The Drosophila homologue dSdc and human SDC4 have been implicated in energy homeostasis.

Multiple Myeloma
Syndecan1 is upregulated in Multiple Myeloma. High levels of shed syndecan1 in a patient's serum typically is correlated with poor prognosis.

Syndecan 1 is the most studied of all the syndecans in cancer research. Many studies have shown that syndecan 1 plays an important role in cancer progression, and also can be used as cancer biomarker. For example, syndecan 1 expression is higher in the bone marrow of the patients suffering from the multiple myeloma [9]. In one published study, the cells expressing the soluble syndecan 1 ectodomain promoted the growth and metastasis of B-lymphoid tumors more extensively than cells bearing surface syndecan 1 or lacking syndecan 1 expression [16]. Similarly, syndecan 1 expression has been linked with low differentiation in squamous cell carcinoma of the head and neck [15]. Syndecan 1 also has been linked with cancer progression by mediating the effects of growth factors in the cells. For example, syndecan 1 expression is increased in ductal breast carcinomas and is associated with factors of angiogenesis and lymphangiogenesis [5]. Studies from patients suffering from endometrial cancer have shown that these patients have increased syndecan 1 expression, and also that expression of this protein positively regulates the endometrial hyperplasia that can progress to endometrial cancer [6].