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The Role of Syndecan-1 in Cellular Signaling and Its Effects on Heparan

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The Role of Syndecan-1 in Cellular Signaling and Its Effects on Heparan REVIEW ARTICLE published: 19 December 2013 doi: 10.3389/fonc.2013.00310 The role of syndecan-1 in cellular signaling and its effects on heparan sulfate biosynthesis in mesenchymal tumors Tünde Szatmári and Katalin Dobra* Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Edited by: Proteoglycans (PGs) and in particular the syndecans are involved in the differentiation Elvira V. Grigorieva, Institute of process across the epithelial-mesenchymal axis, principally through their ability to bind Molecular Biology and Biophysics SB growth factors and modulate their downstream signaling. Malignant tumors have indi- RAMS, Russia Reviewed by: vidual proteoglycan profiles, which are closely associated with their differentiation and Markus A. N. Hartl, University of biological behavior, mesenchymal tumors showing a different profile from that of epithelial Innsbruck, Austria tumors. Syndecan-1 is the main syndecan of epithelial malignancies, whereas in sarcomas Swapna Asuthkar, University of Illinois its expression level is generally low, in accordance with their mesenchymal phenotype and College of Medicine at Peoria, USA highly malignant behavior. This proteoglycan is often overexpressed in adenocarcinoma *Correspondence: Katalin Dobra, Department of cells, whereas mesothelioma and fibrosarcoma cells express syndecan-2 and syndecan-4 Laboratory Medicine, Karolinska more abundantly. Increased expression of syndecan-1 in mesenchymal tumors changes Institutet, Karolinska University the tumor cell morphology to an epithelioid direction whereas downregulation results in Hospital F-46, SE-141 86 Stockholm, a change in shape from polygonal to spindle-like morphology. Although syndecan-1 plays Sweden e-mail: [email protected] major roles on the cell-surface, there are also intracellular functions, which are not very well studied. On the functional level, syndecan-1 affects mesenchymal tumor cell proliferation, adhesion, migration and motility, and the effect varies with the different domains of the core protein. Syndecan-1 may exert stimulatory or inhibitory effects, depending on the concen- tration of various mitogens, enzymes, and signaling molecules, the ratio between the shed and membrane-associated syndecan-1 and histological grade of the tumour. Growth fac- tor signaling seems to be delicately controlled by regulatory loops involving the syndecan expression levels and their sulfation patterns. Overexpression of syndecan-1 modulates the biosynthesis and sulfation of heparan sulfate and it also affects the expression of other PGs. On transcriptomic level, syndecan-1 modulation results in profound effects on genes involved in regulation of cell growth Keywords: syndecan-1, heparan sulfate, signaling, cancer, mesenchymal tumor SYNDECAN STRUCTURE both HS and CS then extends in the Golgi by further repetitive Syndecans are transmembrane proteoglycans (PGs) composed of addition of glucuronic acid (GlcA) and a hexosamine derivative, a core protein to which growth factor binding glycosaminoglycan which for HS is GlcNAc and for CS GalNAc. The resulting GAG (GAG) side chains are attached. The syndecan family consists of is thus built up of repeating disaccharide units, consisting of an four members. Syndecan-1 is the major syndecan of epithelial cells uronic acid and a hexosamine derivative (10). (1), syndecan-2 is present mainly on cells of mesenchymal origin Subsequently this basic structure is modified by a series of reac- (2), syndecan-3 is primarily found in neuronal tissue and cartilage tions (epimerization, deacetylation, sulfation), which occur in a (3, 4), and syndecan-4 is ubiquitously expressed (5, 6). The pro- tissue-specific manner. Particularly in HS, this generates a vast tein cores of syndecans consist of a highly conserved C-terminal diversity of the fine structure and hence alters the capacity of this cytoplasmic domain, a single-pass transmembrane domain and GAG to bind to other structures. These modification reactions a large N-terminal extracellular domain (7, 8)(Figure 1). The thus represent one way to regulate the protein binding capacity ectodomain carries up to five GAG chains, and syndecan-1 from of PGs. different tissues display different GAG types comprising heparan sulfate (HS) and chondroitin-sulfate (CS) of varying length and SHEDDING OF SYNDECANS FROM THE CELL SURFACE fine structure (9)(Figure 2). Syndecans are usually present on the cell surface (1, 7, 11), but Both HS and CS are attached to serine residues via the they can also be released by the action of sheddases or accumu- same linkage sequence (Xylose-Galactose-Galactose-Glucuronic late in the cell nucleus (12); in the tumor stroma (13), and in Acid). Following the synthesis of this sequence, the first hex- body fluids (14–17). Shedding of the ectodomain is biologically osamine derivative – N -acetyl-glucosamine (GlcNac) or N -acetyl- important, converting the cell-bound syndecan to a soluble active galactosamine (GalNac) – is added; this step being the decisive for ligand. Syndecan-1 shedding is regulated by matrix metallopro- the type of GAG subsequently formed. The basic GAG chain for teinases (MMPs), including MMP-7, MMP-9, membrane-bound www.frontiersin.org December 2013 | Volume 3 | Article 310 | 1 Szatmári and Dobra Syndecan-1 in signaling FIGURE 1 |The syndecan family. Schematic illustration of structurally related variable with the exception of the GAG attachment sites and the proteolytic syndecan genes, showing the two subfamilies of syndecans: syndecan-1 and cleavage site near the plasma membrane. In contrast the endo- and -3, and syndecans -2 and -4, respectively. The extracellular domain is highly transmembrane domains are well preserved. surface HSPGs can themselves participate in regulation of met- alloproteinases, anchoring them to the cell surface via the GAG chains (23), and particularly for syndecan-1 it was demonstrated that the HS chains on the core protein suppresses shedding (28), giving an additional explanation on the above mentioned role of heparanase in this process. The released ectodomain carries intact GAG chains, thus it has preserved ability to modulate growth factor responses and biolog- ical processes. Experimental studies have shown that membrane- bound and soluble forms of syndecan-1 have opposing effects on cancer cell functions (19, 30–33). High level of shed syndecan-1 is associated with infection, inflammation, and cancer. Recently it was found that chemotherapy can induce shedding of syndecan-1, particularly via ADAMs and this shed syndecan-1 being function- ally active, leads to establishment of a more aggressive phenotype in case of relapse (34). Soluble syndecan-1 binds pro-angiogenic factors like VEGF or FGF, activates them, creating a chemotactic gradient, and by this promotes endothelial cell’s invasion and angiogenesis. Besides, it activates the integrins aVb3 and aVb5 (35), which are also impor- tant for angiogenesis (36) and regulates the association of IGF1R to aVb3 integrin, essential in endothelial cell migration (37). The FIGURE 2 | Biochemical structure of the repeating disaccharide units of heparan sulfate and chondroitin-sulfate. pro-angiogenic effect of syndecan-1 was shown in myeloma (27), medulloblastoma (24), and in a variety of tumors of epithelial ori- gin like endometrial cancer (38), breast cancer (39), and in stromal metalloproteinases (MT-MMP1), and a disintegrin and metallo- fibroblasts of breast cancer (32), but the effects of syndecan-1 in proteases (ADAM10,ADAM17) (18–22). They act by proteolytical the angiogenesis of mesenchymal tumors is largely unknown. cleavage of the juxtamembrane site of the core protein. The mecha- Understanding of the importance of syndecan-1 shedding nism of shedding is currently not completely understood (23), but might help to resolve the seemingly contradictory expression levels recently a new mechanism where MMP-9 enhances syndecan-1 documented in various malignancies. shedding via suppression of miR-494 was described (24). Acceler- ated shedding is mediated by MMPs (21), Rab-5 (25), growth fac- SUB-CELLULAR LOCALIZATION OF SYNDECAN-1 IN THE CELL NUCLEUS tors (GFs) (26), heparanase, and HS (27, 28). It is also known that Syndecan-1 translocates to the cell nucleus of various tumor cells, FGF-2 activates MMP-7 mediated shedding (29) and heparanase including malignant mesothelioma,fibrosarcoma,neuroblastoma, accelerate MMP-9 mediated shedding of syndecan-1 (27). Cell breast- and lung adenocarcinoma, and multiple myeloma (12, Frontiers in Oncology | Molecular and Cellular Oncology December 2013 | Volume 3 | Article 310| 2 Szatmári and Dobra Syndecan-1 in signaling 40–42). This translocation is tubulin dependent and the same proliferative index (56). In carcinoma of the uterine cervix expres- transport route operates also for FGF-2 but not for the FGF Recep- sion of syndecan-1 is associated with histological differentiation tor. The minimal structural requirement for nuclear translocation grade but not with clinical outcome (57). Thus, syndecan-1 seems is the RMKKK sequence at the cytoplasmic tail of syndecan-1 to have antithetic roles in different cancer types having inhibitory serving as a nuclear localization signal (NLS) (43). The nuclear role on tumor formation and progression in many different epithe- translocation correlates to the differentiation and proliferation of lial malignancies but also promoting the growth of others (48, 58). certain tumor cells. One compound that seems to modulate the The shed
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