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PubMed1998

Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses.

CASK, the rat homolog of a gene (LIN-2) required for vulval differentiation in Caenorhabditis elegans, is expressed in mammalian brain, but its function in neurons is unknown. CASK is distributed in a punctate somatodendritic pattern in neurons. By immunogold EM, CASK protein is concentrated in synapses, but is also present at nonsynaptic membranes and in intracellular compartments. This immunolocalization is consistent with biochemical studies showing the presence of CASK in soluble and synaptosomal membrane fractions and its enrichment in postsynaptic density fractions of rat brain. By yeast two-hybrid screening, a specific interaction was identified between the PDZ domain of CASK and the COOH terminal tail of syndecan-2, a cell surface heparan sulfate proteoglycan (HSPG). The interaction was confirmed by coimmunoprecipitation from heterologous cells. In brain, syndecan-2 localizes specifically at synaptic junctions where it shows overlapping distribution with CASK, consistent with an interaction between these proteins in synapses. Cell surface HSPGs can bind to extracellular matrix proteins, and are required for the action of various heparin-binding polypeptide growth/differentiation factors. The synaptic localization of CASK and syndecan suggests a potential role for these proteins in adhesion and signaling at neuronal synapses.

Amino Acid Sequence↗

PubMed1999

The syndecans, tuners of transmembrane signaling.

Syndecans, a family of transmembrane proteoglycans, are putative integrators of extracellular signals. The interaction of syndecans with extracellular ligands via particular motifs in their heparan sulfate chains, their clustering, association with particular cytoskeletal structures, binding to cytoplasmic effectors, and intracellular phosphorylation represent as many means to bring this role to a successful conclusion. In this review, we will briefly address the characteristics of syndecans as heparan sulfate proteoglycans (HSPGs) and focus mainly on the properties, binding interactions, and potential signaling functions of the cytoplasmic domains of these molecules.

Amino Acid Sequence↗

PubMed2003

Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin.

Circulating endotoxin is elevated in sepsis and plays a role in endothelial dysfunction whereas antithrombin is decreased by virtue of its consumption during complex formation with clotting factors and by proteolytic degradation by granulocyte elastase. Dysfunction of endothelium results in enhanced leukocyte rolling and diapedesis into tissues leading to edema formation and injury. Antithrombin exerts beneficial effects on endothelial function in sepsis. A direct anti-inflammatory action of anti-thrombin in inflammatory cells is exerted via heparan sulfate proteoglycans. In this study, we investigated whether antithrombin affects endotoxin-induced adhesion of neutrophils to human endothelial cells in vitro and whether glycosaminoglycans are involved in its signaling. Adhesion of human neutrophils to monolayers of umbilical vein endothelial cells was tested under static conditions. Endothelial cells were pretreated with endotoxin, interleukin-1, heparinase-I, chondroitinase-ABC or anti-syndecan-4-antibody. Endotoxin and interleukin-1 increased neutrophil adherence to human umbilical vein endothelial cells which was inhibited by antithrombin. Concomitant incubation with pentasaccharide abolished this effect of antithrombin. Treatment of endothelial cells with heparinase or chondroitinase led to higher adhesion and prevented effects of antithrombin. With antibodies to syndecan-4, enhanced adhesion of neutrophils was observed. As studied by Western blotting, endotoxin-induced signaling was diminished by antithrombin and the effect was reversible by chondroitinase or heparinase. From our results, we can conclude that endotoxin-induced adhesion of leukocytes to endothelium can be reversed by ligation of syndecan-4 with antithrombin's heparin-binding site and interferences with stress response signaling events in endothelium.

Antithrombin III↗

PubMed2000

Control of extracellular matrix assembly by syndecan-2 proteoglycan.

Extracellular matrix (ECM) deposition and organization is maintained by transmembrane signaling and integrins play major roles. We now show that a second transmembrane component, syndecan-2 heparan sulfate proteoglycan, is pivotal in matrix assembly. Chinese Hamster Ovary (CHO) cells were stably transfected with full length (S2) or truncated syndecan-2 lacking the C-terminal 14 amino acids of the cytoplasmic domain (S2deltaS). No differences in the amount of matrix assembly were noted with S2 cells, but those expressing S2deltaS could not assemble laminin or fibronectin into a fibrillar matrix. The loss of matrix formation was not caused by a failure to synthesize or externalize ECM components as determined by metabolic labeling or due to differences in surface expression of alpha5 or beta1 integrin. The matrix assembly defect was at the cell surface, since S2deltaS cells also lost the ability to rearrange laminin or fibronectin substrates into fibrils and to bind exogenous fibronectin. Transfection of activated alphaIIbalphaLdeltabeta3 integrin into alpha(5)-deficient CHO B2 cells resulted in reestablishment of the previously lost fibronectin matrix. However, cotransfection of this cell line with S2deltaS could override the presence of activated integrins. These results suggest a regulatory role for syndecan-2 in matrix assembly, along with previously suggested roles for activated integrins.

Amino Acid Sequence↗

PubMed1991

Localization of integrin and syndecan in vivo in a corneal epithelial abrasion and keratectomy.

We compared the localization of integrin, a glycoprotein adhesion receptor, and syndecan, a transmembrane proteoglycan receptor, in vivo during the process of corneal epithelial wound healing to determine if the contact between migrating epithelium and substrata influence the expression of these two adhesion proteins. The expression of three integrin subunits of the alpha/beta heterodimer complex, beta 1, alpha 5, and alpha 6, were examined over a 48 hr in response to an abrasion. We also examined their expression in a keratectomy and compared their two conditions. The beta 1 subunit, which is expressed basolaterally in a normal cornea, was localized during epithelial migration over the basal lamina and keratectomy. Negligible levels of the fibronectin binding receptor subunit, alpha 5, were detected in a normal cornea. The levels of staining between a normal cornea, an abrasion and a keratectomy did not differ. Detection of alpha 6, the laminin binding receptor subunit, was expressed most intensely along the basal side of basal cells in a normal cornea. During the course of wound healing, alpha 6 was only detected in the basal cells and by two days the localization resembled that seen in the normal cornea. Epithelial staining for the alpha 6 subunit was also detected during the migration of cells over the keratectomy, more intensely than the other two subunits. Syndecan, which acts as a more permanent adhesion receptor in stratified epithelium, was only detected 48 hr post-abrasion, throughout all layers of epithelium, as was expected. These results indicate a predominance of alpha 6 expression by corneal epithelial cells at all times of in vivo wound healing and the presence of syndecan only upon restratification of the epithelium.

Animals↗

PubMed1998

Immunohistochemical expression of syndecan-1 in human endometrial cancer cells.

There are indications of increased frequency of endometrial cancer, one of the most common malignancies in women. Tissue samples of normal and malignant endometria were obtained post operatively from 30 women. We noted expression of syndecan-1 in 40% of investigated cancers. The most differentiated cancers showed 75% of positively stained specimens, moderately differentiated 40% and poorly differentiated neoplasm did not stain at all. In normal endometrial tissue syndecan-1 expression was regular and distinct in each specimen, but immunoreactivity of the hyperplastic endometrial specimens was absent. The detection of syndecan-1 in endometrial cancer of different clinical and histological stages could be of prognostic value in clinical diagnosis.

Aged↗

PubMed1994

[Anders Jahre Prize for young researchers 1993. Syndecan--a regulator of growth factor activities between cells and cell matrix interface].

Syndecans are a four member family of cell surface proteoglycans, which via their heparan sulfate chains can bind both extracellular matrix molecules and heparin-binding growth factors. In signal transduction they cooperate with tyrosine kinase receptors and thus can participate in the regulation of cell growth and behaviour. Besides the fact that their developmental expression follows morphogenetic rather than histological boundaries, also changes in their expression take place during development of diseases. Among these, the loss of syndecan expression during malignant transformation suggests that syndecans could play a role in restricting tumor growth and metastasis.

Awards and Prizes↗

PubMed2004

Syndecan-dependent binding of Drosophila hemocytes to laminin alpha3/5 chain LG4-5 modules: potential role in sessile hemocyte islets formation.

Heparin-column chromatography and elastase-digestion of medium from hemocyte Kc167 gave Drosophila laminin alpha3/5betagamma trimer, alpha3/5LG2-3 and alpha3/5LG4-5 modules with eluting NaCl concentrations of 450, 280 and 450 mM, respectively. Kc167 cells bound dish surface with alpha3/5betagamma trimer or alpha3/5LG4-5, but not with alpha3/5LG2-3 modules. Cell binding was counteracted by treating with heparin or heparan sulfate. RNA interference of syndecan in Kc167 cells impaired the binding, but that of dally or dally-like did not. Green fluorescent protein-expressing hemocytes also bound surface with alpha3/5betagamma trimer or alpha3/5LG4-5 module. Thus, syndecan-dependent binding of hemocytes to laminin may have a potential role in sessile hemocytes islets formation in T2-A8 segments of Drosophila.

Amino Acid Sequence↗

PubMed2005

Syndecans: new kids on the signaling block.

Cell-associated proteoglycans provide highly complex and sophisticated systems to control interactions of extracellular cell matrix components and soluble ligands with the cell surface. Syndecans, a conserved family of heparan- and chondroitin-sulfate carrying transmembrane proteins, are emerging as central players in these interactions. Recent studies have demonstrated the essential role of syndecans in modulating cellular signaling in embryonic development, tumorigenesis, and angiogenesis. In this review, we focus on new advances in our understanding of syndecan-mediated cell signaling.

Animals↗

PubMed2001

Alterations in expression of mucin, tenascin-c and syndecan-1 in the conjunctiva following retinal surgery and plaque radiotherapy.

PURPOSE: Disturbances of the ocular tear film layer and dry eye symptoms are common complications following retinal surgery and ocular tumour therapy. Examined were the histopathological changes of the conjunctiva following posterior segment surgery and plaque radiotherapy. METHODS: Biopsy specimens of the superior bulbar conjunctiva were obtained during cataract surgery between 2 weeks and 7 years following vitrectomy (n=92) or plaque radiotherapy for uveal melanoma (n=20) and from control subjects without previous ocular surgery (n=29). These were examined using conventional histology (HE, PAS, Van Gieson) and immunochemistry [APAAP, using antibodies directed against MUC1, MUC5AC, syndecan-1 and tenascin-C (TN-C)]. The histopathological changes were graded and statistical analysis was performed using Wilcoxon and Kruskal-Wallis rank sum tests. RESULTS: Conjunctival specimens of patients following vitrectomy or plaque radiotherapy for uveal melanoma demonstrated increased epithelial stratification, a significant decrease in the number of PAS- and MUC5AC-positive goblet cells, and distributional changes in expression of MUC1, syndecan- and TN-C within conjunctival epithelium or stroma. These alterations - in particular the goblet cell reduction and stromal fibrosis - were most prominent in those patients who had undergone radiotherapy. CONCLUSIONS: Posterior segment surgery can lead to morphological alterations of the conjunctiva and distributional changes in ocular mucins, which may cause dry eye symptoms.

Adult↗

PubMed1997

Large scale and clinical grade purification of syndecan-1+ malignant plasma cells.

For cancer immunotherapy, it is usually necessary to obtain a large number of tumor cells from patients. We have previously reported that syndecan-I is present only on malignant plasma cells in samples from patients with multiple myelomatosis. We report here that this antigen is cleaved by chymopapain. This makes it possible to develop a rapid and clinical grade procedure to purify large numbers of myeloma cells using anti-syndecan-1 mAb, magnetic beads and chymopapain.

Chymopapain↗

PubMed2003

Expression of syndecan-1 is a sensitive marker for cutaneous plasmacytoma.

BACKGROUND: Cutaneous plasmacytoma is a well-recognized, yet infrequent, occurrence in multiple myeloma (MM). There are limitations in the morphologic assessment, and as such, the diagnosis presents some difficulty, particularly with the plasmablastic type. METHODS: Pathology reports of 2357 patients with a diagnosis of MM were reviewed. Twenty patients yielded a total of 25 plasmacytomas, 10 of which were analyzed for syndecan-1 immunoreactivity. Bartl grade of bone marrow and cutaneous plasmacytoma was compared and immunoglobulin secretory status of the patients was assessed. RESULTS: The incidence of cutaneous plasmacytoma was found to be 1 in 118 patients with MM. Immunoglobulin secretion was found to be predominantly IgG. There was a trend for the plasmacytoma Bartl grade to be equal to or greater than that of the corresponding bone marrow Bartl grade, suggesting a more aggressive phenotype in the metastatic lesion. CONCLUSION: Syndecan-1 was found to be a sensitive marker for plasmacytomas, independent of cytologic differentiation.

Adult↗

PubMed2001

Structural characterization of heparan sulfate and chondroitin sulfate of syndecan-1 purified from normal murine mammary gland epithelial cells. Common phosphorylation of xylose and differential sulfation of galactose in the protein linkage region tetrasaccharide sequence.

Syndecan-1, present on the surfaces of normal murine mammary gland epithelial cells, is a transmembrane hybrid proteoglycan, which bears glycosaminoglycan (GAG) side chains of heparan sulfate (HS) and chondroitin sulfate (CS). Purified syndecan-1 ectodomains were analyzed for disaccharide composition and the GAG-protein linkage region after digestion with bacterial lyases. The HS chains contained predominantly a nonsulfated unit with smaller proportions of two monosulfated, two disulfated, and a trisulfated unit, whereas CS chains were demonstrated for the first time to bear GlcUA-GalNAc(4-O-sulfate) as a major component as well as GlcUA-GalNAc, GlcUA-GalNAc(6-O-sulfate), and an E disaccharide unit GlcUA-GalNAc(4,6-O-disulfate) as minor yet appreciable components. Two kinds of linkage region tetrasaccharides, GlcUA-Gal-Gal-Xyl and GlcUA-Gal-Gal-Xyl(2-O-phosphate), were found for the HS chains in a molar ratio of 55:45. In marked contrast, an additional sulfated tetrasaccharide, GlcUA-Gal(4-O-sulfate)-Gal-Xyl, was demonstrated only for the CS chains, and the unmodified phosphorylated and sulfated components were present at a molar ratio of 55:26:19. The present study thus provided conclusive evidence for the hypothesis that 4-O-sulfation of Gal is peculiar to CS chains in contrast to the phosphorylation of Xyl, which is common to both HS and CS chains. These modifications may be required for biosynthetic maturation of the linkage region tetrasaccharide sequence, which is a prerequisite for creating the repeating disaccharide region of GAG chains and/or biosynthetic selective chain assembly of CS and HS chains.

Animals↗

PubMed2003

ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1.

C-terminal truncation of ADAMTS-4 from the p68 form to the p53 form is required for activation of its capacity to cleave the Glu(373)-Ala(374) interglobular domain bond of aggrecan. In transfected human chondrosarcoma cells, this process is not autoproteolytic because the same products form with an inactive mutant of ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin-like motif 4) and truncation is completely blocked by tissue inhibitor of metalloproteinase-1. Instead, activation can be mediated by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase (MT4-MMP, MMP-17) because co-transfection with the active form of MT4-MMP markedly enhanced activation, whereas an inactive mutant of MT4-MMP was ineffective. Treatment of co-transfected cells with phosphatidylinositol-specific phospholipase C liberated the complex of MT4-MMP and p68 ADAMTS4 from the cell membrane, but the p53 ADAMTS4 remained associated. Specific glycosaminoglycan lyase digestions, followed by product analyses using fluorescence-assisted carbohydrate electrophoresis and immunoprecipitation experiments, showed that the p53 form is associated with syndecan-1 through both chondroitin sulfate and heparan sulfate. We conclude that ADAMTS-4 activation in this cell system involves the coordinated activity of both glycosylphosphatidyl inositol-anchored MT4-MMP and the proteoglycan form of syndecan-1 on the cell surface.

ADAM Proteins↗

PubMed2001

Characterization of syntenin, a syndecan-binding PDZ protein, as a component of cell adhesion sites and microfilaments.

Syntenin is a PDZ protein that binds the cytoplasmic C-terminal FYA motif of the syndecans. Syntenin is widely expressed. In cell fractionation experiments, syntenin partitions between the cytosol and microsomes. Immunofluorescence microscopy localizes endogenous and epitope-tagged syntenin to cell adhesion sites, microfilaments, and the nucleus. Syntenin is composed of at least three domains. Both PDZ domains of syntenin are necessary to target reporter tags to the plasma membrane. The addition of a segment of 10 amino acids from the N-terminal domain of syntenin to these PDZ domains increases the localization of the tags to stress fibers and induces the formation of long, branching plasma membrane extensions. The addition of the complete N-terminal region, in contrast, reduces the localization of the tags to plasma membrane/adhesion sites and stress fibers, and reduces the morphotypical effects. Recombinant domains of syntenin with the highest plasma membrane localization display the lowest nuclear localization. Syndecan-1, E-cadherin, beta-catenin, and alpha-catenin colocalize with syntenin at cell-cell contacts in epithelial cells, and coimmunoprecipitate with syntenin from extracts of these cells. These results suggest a role for syntenin in the composition of adherens junctions and the regulation of plasma membrane dynamics, and imply a potential role for syntenin in nuclear processes.

Actin Cytoskeleton↗

PubMed2005

Syndecan-1 is involved in osteoprotegerin-induced chemotaxis in human peripheral blood monocytes.

Chronic inflammation is characterized by tissue infiltration with monocytes/macrophages, which possess broad proinflammatory, destructive, and remodeling capacities. Elevated levels of osteoprotegerin, an important regulator of differentiation and activation of osteoclasts that also affects different cells of the immune system, were found in the serum of patients with chronic inflammatory diseases. The study of whether osteoprotegerin affects monocyte locomotion in vitro and the possible mechanisms and pathways involved was investigated using Boyden microchemotaxis chambers and Western blot analyses. Osteoprotegerin significantly stimulated monocyte chemotaxis, whereas preincubation of monocytes with osteoprotegerin inhibited monocyte migration toward optimal concentrations of regulated upon activation normal T cell expressed and secreted, monocyte chemotactic protein -1, and procalcitonin. The effects of osteoprotegerin were abolished by pretreating cells with heparinase I and chondroitinase or antibodies against the ectodomain of syndecan-1. Osteoprotegerin signaling was shown to involve protein kinase C, phosphatidylinositol 3-kinase/Akt, and tyrosine kinase. Data suggest that osteoprotegerin affects monocyte mi-gration and protein kinase C and phosphatidylinositol 3-kinase/Akt activation via syndecan-1. Osteoprotegerin-induced deactivation of monocyte chemotaxis toward different chemokines is due to interaction of osteoprotegerin with heparan sulfate and chondroitin sulfate.

Cell Movement↗

PubMed2004

Solitary plasmacytoma of the skull: immunohistochemical study of angiogenic factors and syndecan-1--two case reports.

Two cases of solitary plasmacytomas of the skull are presented, and some biological aspects of the tumor examined. A 75-year-old woman presented with a tumor in the right parietal region. The serum level of immunoglobulin G (IgG) was high and a urine test for Bence Jones protein was negative. A reddish vascular mass was totally removed at surgery. The serum level of IgG was within normal limits after the operation. Postoperative radiotherapy was not performed. A 58-year-old woman presented with a tumor in the occipital region. Serum levels of Igs were within normal limits. A urine test for Bence Jones protein was positive for Ig kappa chain. Bone marrow aspiration revealed no evidence of systemic myelomatosis. The tumor mass was totally removed at surgery and she received local radiation therapy (total 50 Gy). Three months after the surgery, Bence Jones protein (kappa chain) was detected in both the urine and serum and bone scintigraphy showed a weak hot spot in the iliac bone, suggesting development to multiple myeloma. Immunohistochemical studies showed that most tumor cells were positive for vascular endothelial growth factor and syndecan-1, and some tumor cells were strongly positive for basic fibroblast growth factor in both cases. The Ki-67 staining indices were 11.3% and 15.6%. Tumor tissues were negative for p53. These results suggest that solitary plasmacytoma of the skull expresses the angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor, in accordance with the high vascularity of the tumors, and syndecan-1 may be an immunohistochemical marker of solitary plasmacytoma of the skull.

Aged↗

PubMed2002

[Syndecan-1 (CD138): an immunohistochemical marker of plasma cell tumors].

The immunohistochemical detection of syndecan-1 (belonging to the cluster CD138) is a sensitive and reliable method for identifying normal and neoplastic plasma cells. It may be used in paraffin-embedded bone marrow specimens, as well as in extramedullary tumours of unknown origin. The three anaplastic tumours reported by us in the lymph node, the gingiva, and pleura were negative for other markers, but the syndecan-1 positivity elucidated their plasmocytic histogenesis.

Aged↗