Syndecan-1, a cell surface heparan sulfate proteoglycan, is critically involved in the differentiation and prognosis of various tumors. In this review, we highlight the synthesis, cellular interactions, and the signalling pathways regulated by syndecan-1. The basal syndecan-1 level is also crucial for understanding the sequential changes involving malignant transformation, tumor progression, and advanced or disseminated cancer stages. Moreover, we focus on the cellular localization of this proteoglycan as cell membrane anchored and/or shed, soluble syndecan-1 with stromal or nuclear accumulation and how this may carry different, highly tissue specific prognostic information for individual tumor types.

The syndecans are a type of cell surface adhesion receptor that initiates intracellular signaling events through receptor clustering mediated by their highly conserved transmembrane domains (TMDs). However, the exact function of the syndecan TMD is not yet fully understood. Here, we investigated the specific regulatory role of the syndecan-2 TMD. We found that syndecan-2 mutants in which the TMD had been replaced with that of syndecan-4 were defective in syndecan-2-mediated functions, suggesting that the TMD of syndecan-2 plays one or more specific roles. Interestingly, syndecan-2 has a stronger tendency to form sodium dodecyl sulfate (SDS)-resistant homodimers than syndecan-4. Our structural studies showed that a unique phenylalanine residue (Phe(167)) enables an additional molecular interaction between the TMDs of the syndecan-2 homodimer. The presence of Phe(167) was correlated with a higher tendency toward oligomerization, and its replacement with isoleucine significantly reduced the SDS-resistant dimer formation and cellular functions of syndecan-2 (e.g. cell migration). Conversely, replacement of isoleucine with phenylalanine at this position in the syndecan-4 TMD rescued the defects observed in a mutant syndecan-2 harboring the syndecan-4 TMD. Taken together, these data suggest that Phe(167) in the TMD of syndecan-2 endows the protein with specific functions. Our work offers new insights into the signaling mediated by the TMD of syndecan family members.

Syndecans constitute a family of transmembrane proteoglycans that perform multiple functions during development, damage repair, tumor growth, angiogenesis, and neurogenesis. Through mediating binding of a great number of extracellular ligands to their receptors, these proteoglycans trigger a cascade of reactions regulating, thereby, various processes in a cell: cytoskeleton formation, proliferation, differentiation, adhesion, and migration. In fibroblasts, syndecans are responsible for cell adhesion by modulating functions of integrins through interaction with fibronectin at the external side of a cell and with cytoskeleton and signaling molecules inside the cell. The extracellular domain of syndecans is subjected to periodic shedding from the cell membrane. This process may be stimulated in response to inflammation, tissue damage, and other pathological manifestations. Cleaved domain may act as either competitive inhibitor or activator of signaling cascades. This review summarizes and analyzes the available data regarding structure, main biochemical properties, and functions of syndecans in vertebrates.

Syndecans are transmembrane heparan sulfate proteoglycans involved in the regulation of cell growth, differentiation, adhesion, neuronal development, and lipid metabolism. Syndecans are expressed in a tissue-specific manner to facilitate diverse cellular processes. As receptors and co-receptors, syndecans provide promising therapeutic targets that bind to a variety of physiologically important ligands. Negatively charged glycosaminoglycan chains of syndecans, located in the extracellular compartment, are critical for such binding. Functions of syndecans are as diverse as their ligands. For example, hepatic syndecan-1 mediates clearance of triglyceride-rich lipoproteins. Syndecan-2 promotes localization of Alzheimer's amyloid Aβ peptide to the cell surface, which is proposed to contribute to amyloid plaque formation. Syndecan-3 helps co-localize the appetite-regulating melanocortin-4 receptor with its agonist, leading to an increased appetite. Finally, syndecan-4 initiates the capture of modified low-density lipoproteins by macrophages and thereby promotes the atheroma formation. We hypothesize that syndecan modifications such as desulfation of glycosaminoglycan chains may contribute to a wide range of diseases, from atherosclerosis to type 2 diabetes. At the same time, desulfated syndecans may have beneficial effects, as they can inhibit amyloid plaque formation or decrease the appetite. Despite considerable progress in understanding diverse functions of syndecans, the complex physiological roles of this intriguing family of proteoglycans are far from clear. Additional studies of syndecans may potentially help develop novel therapeutic approaches and diagnostic tools to alleviate complex human diseases such as cardiovascular and Alzheimer's diseases.

Because intrinsically disordered proteins are incapable of forming unique tertiary structures in isolation, their interaction with partner structures enables them to play important roles in many different biological functions. Therefore, such proteins are usually multifunctional, and their ability to perform their major function, as well as accessory functions, depends on the characteristics of a given interaction. The present paper demonstrates, using predictions from two programs, that the transmembrane proteoglycans syndecans are natively disordered because of their diverse functions and large number of interaction partners. Syndecans perform multiple functions during development, damage repair, tumor growth, angiogenesis, and neurogenesis. By mediating the binding of a large number of extracellular ligands to their receptors, these proteoglycans trigger a cascade of reactions that subsequently regulate various cell processes: cytoskeleton formation, proliferation, differentiation, adhesion, and migration. The occurrences of 20 amino acids in syndecans 1-4 from 25 animals were compared with those in 17 animal proteomes. Gly + Ala, Thr, Glu, and Pro were observed to predominate in the syndecans, contributing to the lack of an ordered structure. In contrast, there were many fewer amino acids in syndecans that promote an ordered structure, such as Cys, Trp, Asn, and His. In addition, a region rich in Asp has been identified between two heparan sulfate-binding sites in the ectodomains, and a region rich in Lys has been identified in the conserved C1 site of the cytoplasmic domain. These particular regions play an essential role in the various functions of syndecans due to their lack of structure.

The syndecans are the major family of transmembrane proteoglycans in animals and are known for multiple roles in cell interactions and growth factor signalling during development, inflammatory response, wound-repair and tumorigenesis. Although syndecans have been cloned from several invertebrate and vertebrate species, the extent of conservation of the family across the animal kingdom is unknown and there are gaps in our knowledge of chordate syndecans. Here, we develop a new level of knowledge for the whole syndecan family, by combining molecular phylogeny of syndecan protein sequences with analysis of the genomic contexts of syndecan genes in multiple vertebrate organisms.

We identified syndecan-encoding sequences in representative Cnidaria and throughout the Bilateria. The C1 and C2 regions of the cytoplasmic domain are highly conserved throughout the animal kingdom. We identified in the variable region a universally-conserved leucine residue and a tyrosine residue that is conserved throughout the Bilateria. Of all the genomes examined, only tetrapod and fish genomes encode multiple syndecans. No syndecan-1 was identified in fish. The genomic context of each vertebrate syndecan gene is syntenic between human, mouse and chicken, and this conservation clearly extends to syndecan-2 and -3 in T. nigroviridis. In addition, tetrapod syndecans were found to be encoded from paralogous chromosomal regions that also contain the four members of the matrilin family. Whereas the matrilin-3 and syndecan-1 genes are adjacent in tetrapods, this chromosomal region appears to have undergone extensive lineage-specific rearrangements in fish.

Throughout the animal kingdom, syndecan extracellular domains have undergone rapid change and elements of the cytoplasmic domains have been very conserved. The four syndecan genes of vertebrates are syntenic across tetrapods, and synteny of the syndecan-2 and -3 genes is apparent between tetrapods and fish. In vertebrates, each of the four family members are encoded from paralogous genomic regions in which members of the matrilin family are also syntenic between tetrapods and fish. This genomic organization appears to have been set up after the divergence of urochordates (Ciona) and vertebrates. The syndecan-1 gene appears to have been lost relatively early in the fish lineage. These conclusions provide the basis for a new model of syndecan evolution in vertebrates and a new perspective for analyzing the roles of syndecans in cells and whole organisms.

Angiogenesis is the formation of new blood vessels from the existing vasculature and is necessary for tumor growth. Syndecan-2 (S2) is highly expressed in the microvasculature of mouse gliomas. When S2 expression was down-regulated in mouse brain microvascular endothelial cells (MvEC), this inhibited cell motility and reduced the formation of capillary tube-like structures in vitro. Pro-angiogenic growth factors and enzymes up-regulated during glioma tumorigenesis stimulated shedding of the S2 ectodomain from endothelial cells in vitro. The effect of shed S2 on angiogenic processes was investigated by incorporating recombinant S2 ectodomain (S2ED) into in vitro angiogenesis assays. S2ED promoted membrane protrusion, migration, capillary tube formation, and cell-cell interactions. We therefore propose that S2 is necessary for angiogenesis of MvEC, proangiogenic factors expressed during glioma progression regulate S2 shedding, and shed S2 ectodomain may increase endothelial cell angiogenic processes.

Chicken Syndecan-2 (cSyndecan-2) is the homologue of Xenopus Syndecan-2, a member of the heparan sulfate proteoglycan family with an important role in left-right patterning in frog embryos. A relationship to LR asymmetry in other species has not been reported. We show that cSyndecan-2 is expressed throughout the primitive streak between st. 1 and 3 in the chick embryo, and is restricted to the rostral and caudal tips of the primitive streak at st. 4. It displays distinct left-right asymmetry, being expressed in the right side of Hensen's node at st. 5. The asymmetric expression of cSyndecan-2 is maintained around the node between st. 5 and 7. At early somite stages, somites and neural folds express cSyndecan-2. The somite expression disappears by st. 11, but strong expression in the neural tube continues. Our data reveal a new asymmetric transcript in the chick embryo and indicate that in contrast to protein-level asymmetries, which underlie syndecan-2 function in Xenopus, chick syndecan-2 exhibits asymmetry at the mRNA level.

Transforming growth factor-beta (TGF-beta) has multiple functions including increasing extracellular matrix deposition in fibrosis. It functions through a complex family of cell surface receptors that mediate downstream signaling. We report here that a transmembrane heparan sulfate proteoglycan, syndecan-2 (S2), can regulate TGF-beta signaling. S2 protein increased in the renal interstitium in diabetes and regulated TGF-beta-mediated increased matrix deposition in vitro. Transfection of renal papillary fibroblasts with S2 or a S2 construct that has a truncated cytoplasmic domain (S2DeltaS) promoted TGF-beta binding and S2 core protein ectodomain directly bound TGF-beta. Transfection with S2 increased the amounts of type I and type II TGF-beta receptors (TbetaRI and TbetaRII), whereas S2DeltaS was much less effective. In contrast, S2DeltaS dramatically increased the level of type III TGF-beta receptor (TbetaRIII), betaglycan, whereas S2 resulted in a decrease. Syndecan-2 specifically co-immunoprecipitated with betaglycan but not with TbetaRI or TbetaRII. This is a novel mechanism of control of TGF-beta action that may be important in fibrosis.

Cell surface heparan sulfate proteoglycans (HSPGs) play a critical role in the cellular invasion of intracellular bacteria and are presumed to have a role in the infection of host cells by Orientia tsutsugamushi. Previously, we showed that O. tsutsugamushi infection decreased markedly after treating host cells with heparinase, which suggests that HSPGs play an important role in oriential infection. We tested oriential infection in REF-Syn4 cells over-expressing syndecan-4, and in REF-Syn4AS cells in which the expression of syndecan-4 was down regulated by transfecting with anti-sense syndecan-4 cDNA. Oriential infection was found to be dependent on the expression level of syndecan-4 on the cell surface. Furthermore, the infectivity of O. tsutsugamushi was specifically reduced by treating O. tsutsugamushi with the purified recombinant core protein of syndecan-4 (Syn4E). These results suggest that the core protein of syndecan-4 and the heparin/heparan sulfate chain of syndecan play an important role in oriential infection by O. tsutsugamushi.