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PubMed1995

Modulated glycosylation of proteoglycans during differentiation of human B lymphocytes.

Proteoglycans are mediators of cellular adhesion and regulate growth factor activities. Proteoglycans of B lymphocytes undergo structural changes during B cell ontogeny which may correspond to the specific requirements of the respective microenvironment of the maturing cell. We analyzed three human B cell lines representing pre-B cells (Nalm-6), activated B cells (Jok-1) and plasma cells (U266) for their cellular proteoglycans. Gel filtration of the 35S-labeled macromolecules of the three cell lines revealed an increase in size in the order Nalm-6 < Jok-1 < U266. In Jok-1 and U266 cells the major pool of proteoglycans consisted of proteochondroitin sulfates of 50 to 90 kDa. These proteolglycans carried a protein core of approx. 30 kDa to which 1 to 3 glycosaminoglycan chains in the range of 28 to 32 kDa were attached. In Nalm-6 cells only free chondroitin sulfate chains of 23 kDa, but no intact proteoglycans, were detected. Chondroitin sulfate chains were predominantly composed of chondroitin-4-sulfate, those of Nalm-6 and U266 cells additionally contained 10-20% of unsulfated disaccharides. In U266 cells 30% of glycosaminoglycans consisted of heparan sulfate either bound to pure proteoheparan sulfate or to chondroitin sulfate/heparan sulfate hybrid-proteoglycans. Earlier, syndecan-1 was described as a hybrid proteoglycan containing heparan sulfate/chondroitin sulfate chains which is transcribed by murine B cells at early and late maturation stages. In order to see whether syndecan is transcribed by the human B cell lines used here, we measured expression of syndecan mRNA by the reverse transcriptase polymerase chain reaction. Similar to murine lymphocytes, syndecan-specific mRNA was detected in Nalm-6 and U266 cells, equivalent to early and late B cells, but not in lymphoblastoid Jok-1 cells. However, Nalm-6 cells do not produce proteoheparan sulfate. In these cells, syndecan synthesis may be blocked at the translational level. Also, the proteoglycans of U266 are different from syndecan-1 in their composition of glycosaminoglycans and in size of protein cores. Together, these results indicate that the major pool of proteoglycans produced by human B cells consists of proteochondroitin sulfate and additionally in later stages of a smaller proportion of proteoheparan sulfate which is not identical to syndecan-1. During distinct phases of B cell differentiation, modulations in the glycosaminoglycan moiety concerning size and sulfation of glycosaminoglycan chains were also found.

B-Lymphocytes↗

PubMed1999

Heparan sulfate chains with antimitogenic properties arise from mesangial cell-surface proteoglycans.

Heparan sulfate (HS) chains accumulate in both the medium and the cell layer of mesangial cell cultures. When given in fresh medium to quiescent cultures at naturally occurring concentrations, they suppress entry into the cell cycle and progression to DNA synthesis. We have attempted to identify the proteoglycan (PG) source of the antimitogenic HS chains from mesangial cell layers (HS(c)) and medium (HS(c)). When cells were labeled for 16 hours with [35S]sulfate, 25% of the label was found in intracellular HS chains and 5% in extracellular HSPGs. Cell-surface HSPGs accounted for the remaining 70% of the label associated with cell-layer HS and were released by either trypsin or 2% Triton X-100. About 20% of this cell-surface fraction was released by treatment with phosphatidylinositol-specific phospholipase C (PI-PLC), and probably represents glypican-like PG; glypican mRNA was present in the cells. The remainder of this fraction could be incorporated into liposomes, indicating the presence of hydrophobic transmembrane regions suggestive of syndecans. Upon purification and deglycosylation, an antiserum to rat liver HSPGs that reacts primarily with syndecan-2 showed a strong signal corresponding to this protein and three weaker bands that may represent additional syndecans. mRNAs for syndecan-1, -2, and -4 were present in the cultures. Syndecan-1 and -2 mRNAs were increased 30 minutes after stimulation of quiescent rat mesangial cells (RMCs) with serum. Heparin, HS(c), and HS(m) all prevented this increase. Syndecan-4 mRNA was not affected by serum, heparin, or HS. In pulse-chase experiments, the amount of 35S appearing in the cellular protein-free HS fraction was accounted for almost entirely by cell-surface PGs, as matrix-associated label was a minor contribution at the end of the pulse-labeling. The appearance of [35S]HS in cell extracts was unaffected by phospholipase C treatment, indicating that turnover of the newly labeled syndecan fraction is the source of the antimitogenic HS chains.

Animals↗

PubMed2004

Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer.

PURPOSE: Heparan sulfate proteoglycans have been implicated in cancer cell growth, invasion, metastasis, and angiogenesis. This study was designed to compare their expression in normal ovary and ovarian tumors and then to examine their prognostic significance in ovarian cancer. EXPERIMENTAL DESIGN: The expression of syndecan-1, -2, -3, and -4, glypican-1, and perlecan was assessed by immunohistochemistry in 147 biopsies that included normal ovary and benign, borderline, and malignant ovarian tumors. Clinical data, including tumor stage, performance status, treatment, and survival, were collected. Univariate and multivariate analyses were performed to evaluate prognostic significance. RESULTS: The expression patterns of syndecan-1 and perlecan were altered in ovarian tumors compared with normal ovary. Syndecan-1 was not detected in normal ovary but was present in the epithelial and stromal cells of benign and borderline tumors and in ovarian adenocarcinomas. Perlecan expression was decreased in basement membranes that were disrupted by cancer cells but maintained in the basement membranes of blood vessels. Syndecan-2, -3, and -4, and glypican-1 were expressed in normal ovary and benign and malignant ovarian tumors. Stromal expression of syndecan-1 and glypican-1 were poor prognostic factors for survival in univariate analysis. CONCLUSION: We report for the first time distinct patterns of expression of cell surface and extracellular matrix heparan sulfate proteoglycans in normal ovary compared with ovarian tumors. These data reinforce the role of the tumor stroma in ovarian adenocarcinoma and suggest that stromal induction of syndecan-1 contributes to the pathogenesis of this malignancy.

Adult↗

PubMed2001

PR-39 coordinates changes in vascular smooth muscle cell adhesive strength and locomotion by modulating cell surface heparan sulfate-matrix interactions.

PR-39 is proline-rich peptide produced at sites of tissue injury. While the functional properties of this peptide have not been fully defined, PR-39 may be an important regulator of processes related to cell-matrix adhesion since it reportedly upregulates syndecan-4, which is a critical determinant of focal adhesion formation. The ability of PR-39 to modulate the adhesion and chemokinetic migration behavior of arterial smooth muscle cells (SMCs) in a fashion coordinated with syndecan-4 expression was investigated. Treatment of SMCs with PR-39 did not alter syndecan-1 mRNA, but did induce a two-fold increase in syndecan-4 mRNA (P < 0.0001) and significantly enhanced cell surface expression of both syndecan-4 (P < 0.01) and heparan sulfate (HS) (P < 0.05). These observations were consistent with an observed increase in cell-matrix adhesive strength (P < 0.05) and a reduction in cell speed (P < 0.01) on fibronectin-coated substrates. Incubation of PR-39 treated cells with a soluble fibronectin derived heparin-binding peptide, as a competitive inhibitor of heparan sulfate/matrix interactions, abolished these effects. These data suggest that PR-39 mediated alterations of cell adhesion and motility may be related, in part, to the increased expression of heparan sulfate glycosaminoglycans (GAGs) that accompany the upregulation of cell surface syndecan-4. Furthermore, this investigation supports the notion that factors which control syndecan-4 expression may play an important role in regulating adhesion related cell processes.

Animals↗

PubMed2000

Differentiation of mesothelioma cells is influenced by the expression of proteoglycans.

Malignant mesothelioma characteristically shows epithelial and/or sarcomatous morphology, this phenotypic differentiation being correlated to the prognosis. The present study was undertaken to see whether proteoglycan (PG) expression influences mesothelioma differentiation. To assess this hypothesis, we studied a mesothelioma model, where the cells were induced to differentiate into epithelial or fibroblast-like morphology, mimicking the biphasic growth of this sarcoma. Series of PGs were analyzed in parallel by semiquantitative reversed transcriptase polymerase chain reaction, showing increased expression of syndecan-2, syndecan-4, and hyaluronan synthase in the epithelial phenotype, whereas the fibroblast-like cells expressed more matrix PGs: versican, decorin, and biglycan. Western blotting confirms these differences and provides evidence of extensive shedding and rapid turnover of cell membrane PGs. Experimental down-regulation of the studied syndecans by antisense targeting resulted in a change in shape from polygonal to spindle-like morphology, while syndecan-1 and -4, but not syndecan-2, could be associated with cell aggregation, indicating distinct functions of different syndecans. The PG profile is thus closely associated with the morphology and biological behavior of tumor cells, mesotheliomas showing a different profile than true epithelial tumors.

Biglycan↗

PubMed2001

Immunohistochemical studies on proteoglycan expression in normal skin and chronic ulcers.

BACKGROUND: Proteoglycans (PGs) represent a large family of complex molecules. They are found either as integral membrane components or constituents of the extracellular matrix. Their protein backbones are linked to different glycosaminoglycans, such as dermatan-, chondroitin-, keratan- or heparan sulphate. The molecules have specific functions during developmental processes as well as in diseases, such as cancer and inflammation. OBJECTIVES: The expression patterns of various cell-associated heparan and chondroitin/dermatan-sulphate PGs in human skin and chronic venous ulcers were investigated. METHODS: Tissue sections from 11 patients with chronic venous ulcers were used in this study. Monoclonal antibodies were used for detection of the proteoglycans syndecan-1, -2 and -4, glypican, CD44 and perlecan. RESULTS: The different PGs exhibited individual staining patterns. Syndecan-1 and -4 and glypican expression in chronic ulcers differed from the staining in normal skin. Whereas the expression of syndecan-4 and glypican in intact skin was mostly in the pericellular regions of keratinocytes, the epidermal cells from the wound edge contained mostly intracellular PGs. In the wound edge, syndecan-4 was predominantly expressed by epidermal basal layer cells. Syndecan-1 was less expressed at the epidermal wound margins. PGs bind growth factors, regulate proteolytic activity and act as matrix receptors. CONCLUSIONS: The altered expression patterns of glypican and syndecan-1 and -4 in chronic ulcers reflect their possible roles during inflammation and cell proliferation. Hence, analysis of PG expression should be of interest in future studies on normal as well as defective wound healing.

Aged↗

PubMed1998

[Alteration of genomic structure and/or expression of cancer associated genes in hepatocellular carcinoma].

Cancer is thought to arise from the accumulation of several genetic mutations in a single cell. These include integration of viral genomes, activation of protooncogenes and inactivation of tumor suppressor genes. HCC is one of the most common cancers in Asia and Africa. Various studies have revealed its association with hepatitis B or C viral infection. While activation of known protooncogenes, such as ras genes does not seem to play an important role, frequent allelic loss on specific chromosomal arms, 4q, 13q, 16q and 17p, indicates that dysfunction of diverse tumor suppressor genes located on these chromosome arms is involved in the development of HCC. An informative p53 mutational spectrum of frequent G to T transversions in codon 249 is found in HCCs from either Qidong, People's Republic of China, or southern Africa. This observation links exposure to aflatoxin B1, a known cancer risk factor in these geographic regions. Recently, we found that expression of syndecan-1, which is a transmembrane heparan sulfate proteoglycan involved in cell matrix interactions and growth factor bindings, was inversely associated with metastatic potential in human hepatocellular carcinoma as like nm23-H1 expression was. Transfection with syndecan-1 gene suppresses invasive activity of hepatoma cells. These data support our hypothesis that syndecan-1 is one of important metastasis suppressor factors in hepatoma cells. PR-39 is a proline-rich antimicrobial peptide which was isolated from a pig small intestine and has been reported to induced syndecan-1 on mouse mesenchymal cells. Transfection with PR-39 gene caused induction of syndecan-1 and altered invasive phenotype and actin structure on hepatoma cells. Syndecan-1 and PR-39 may serve as a basis for design of drug or gene therapy effective against metastasis of hepatocellular carcinomas.

Amino Acid Sequence↗

PubMed2001

Cell surface heparan sulfate proteoglycans control the response of renal interstitial fibroblasts to fibroblast growth factor-2.

BACKGROUND: While the progression of renal disease to end stage is strongly correlated with tubulointerstitial changes, the control of the fibrotic process within the interstitium is poorly understood. Basic fibroblast growth factor (FGF-2) has been implicated as a major growth factor involved in fibroblast activation and extracellular matrix synthesis. Furthermore, in many cells, the activity of FGF-2 is controlled by a low-affinity but high-capacity interaction with heparan sulfate (HS) proteoglycans (PGs), such as members of the syndecan family. These molecules are likely to be central to the control of interstitial fibrosis, but as yet, there has been no characterization of their synthesis by interstitial cells. METHODS: The expression of HSPG on the surface of NRK 49F fibroblasts was demonstrated by immunohistochemistry and by metabolic labeling with [(35)S]-sulfate. HSs were characterized by specific enzymatic digestion, size exclusion chromatography, and anion exchange chromatography. The mRNA for syndecan 1 through syndecan 4 in the fibroblasts was detected by semiquantitative reverse transcription-polymerase chain reaction. Fibroblast proliferation was measured by the MTT assay. RESULTS: Immunohistochemistry and [(35)S]-sulfate-labeling demonstrated that renal fibroblasts expressed HSPGs on their surface. Furthermore, enzymatic removal of these HS (but not chondroitin sulfate) glycosaminoglycan (GAG) chains, or inhibition of GAG sulfation, abolished the proliferative response of both NRK cells and primary human cortical fibroblasts to FGF-2 but not to platelet-derived growth factor. The addition of conditioned medium, containing HS-GAG fragments, restored the proliferative response to FGF-2, confirming the specificity of the interaction. Finally, the mRNA for all four syndecans was detected in the fibroblasts, and that for syndecan 1 in particular was up-regulated by FGF-2. CONCLUSIONS: The present study demonstrates that the expression of cell surface HSPG was essential for the proliferation of renal fibroblasts in response to FGF-2, and therefore may play a major role in the development and persistence of a proliferating phenotype during interstitial nephritis.

Animals↗

PubMed2000

Cell surface proteoglycan expression by human periodontal cells.

Cell surface proteoglycans are known to be involved in many functions including interactions with components of the extracellular microenvironment and serve to influence cell shape, adhesion, proliferation, and differentiation. They also can act as co-receptors, to help bind and modify the action of various growth factors and cytokines. Despite their strategic location and relevance to cell function, few studies have considered the nature of the cell surface proteoglycans associated with cells of the periodontium. Due to the structural complexity and multiplicity of cell types in the periodontium, we have selected three different cell lines (gingival connective tissue fibroblast, periodontal ligament fibroblast, and osteoblast) which each represent the unique functions within the periodontium to study the expression of cell surface proteoglycans. We hypothesized that a number of cell surface proteoglycans will be expressed by human periodontal cells and these may be related to the source and function of the cell. Western blotting and RT-PCR methods were used to study the expression of five cell surface proteoglycans (syndecan-1, -2, -4, glypican and betaglycan) in three cell lines of human periodontal cells in vitro. Our results demonstrated the expression of protein cores for syndecan-1 (43 kDa), syndecan-2 (48 kDa), syndecan-4 (35 kDa), glypican (64 kDa), and betaglycan (100-110 kDa). RT-PCR results confirmed that all of these cells produced mRNA for the cell surface proteoglycans under study, of which syndecan-2 showed a significant difference in expression between the periodontal ligament fibroblasts, gingival fibroblasts and osteoblasts. We conclude that the presence of specific cell surface proteoglycans on periodontal cells implies a likely role for these molecules in cell-cell, cell-matrix interactions involved in periodontal disease and/or regeneration of the periodontium, of which they may have distinctive functions related to the source and function of these cells.

Cell Membrane↗

PubMed2001

EphB/syndecan-2 signaling in dendritic spine morphogenesis.

We previously reported that the cell surface proteoglycan syndecan-2 can induce dendritic spine formation in hippocampal neurons. We demonstrate here that the EphB2 receptor tyrosine kinase phosphorylates syndecan-2 and that this phosphorylation event is crucial for syndecan-2 clustering and spine formation. Syndecan-2 is tyrosine phosphorylated and forms a complex with EphB2 in mouse brain. Dominant-negative inhibition of endogenous EphB receptor activities blocks clustering of endogenous syndecan-2 and normal spine formation in cultured hippocampal neurons. This is the first evidence that Eph receptors play a physiological role in dendritic spine morphogenesis. Our observations suggest that spine morphogenesis is triggered by the activation of Eph receptors, which causes tyrosine phosphorylation of target molecules, such as syndecan-2, in presumptive spines.

Animals↗

PubMed1998

Regulation of mRNA localization by transmembrane signalling: local interaction of HB-GAM (heparin-binding growth-associated molecule) with the cell surface localizes beta-actin mRNA.

Localization of mRNAs is currently thought to be partially responsible for molecular sorting to specific compartments within the cell. In mammalian cells the best-studied example is the beta-actin mRNA that is localized to the cell processes, and its localization is necessary in migratory responses of cells. It is reasonable to assume that mRNA localization within cells is coupled to transmembrane signalling due to extracellular factors, but little is known about such putative mechanisms. We show here that HB-GAM, an extracellular matrix-associated factor that enhances migratory responses in cells, is able to localize beta-actin mRNA when locally applied to cells via microbeads. The HB-GAM-induced mRNA localization is specifically inhibited by low concentrations of heparin and by heparitinase treatment of cells, showing that cell-surface heparin-type glycans are required for the effect. The finding that soluble N-syndecan is also inhibitory suggests that the transmembrane proteoglycan N-syndecan, previously identified as an HB-GAM receptor, is involved in the mRNA-localizing effect of HB-GAM. Inhibition of the mRNA localization by the src-kinase inhibitor PP1 is compatible with an N-syndecan-mediated effect since the receptor function of N-syndecan has been recently found to depend on the src-kinase signalling pathway. The mRNA-localizing activity of N-syndecan is also suggested by the finding that affinity-purified anti-N-syndecan antibodies coated on microbeads are able to localize beta-actin mRNA.

Actins↗

PubMed1992

Differential expression of cell surface heparan sulfate proteoglycans in human mammary epithelial cells and lung fibroblasts.

Treating the liposome-intercalatable heparan sulfate proteoglycans from human lung fibroblasts and mammary epithelial cells with heparitinase and chondroitinase ABC revealed different core protein patterns in the two cell types. Lung fibroblasts expressed heparan sulfate proteoglycans with core proteins of approximately 35, 48/90 (fibroglycan), 64 (glypican), and 125 kDa and traces of a hybrid proteoglycan which carried both heparan sulfate and chondroitin sulfate chains. The mammary epithelial cells, in contrast, expressed large amounts of a hybrid proteoglycan and heparan sulfate proteoglycans with core proteins of approximately 35 and 64 kDa, but the fibroglycan and 125-kDa cores were not detectable in these cells. Phosphatidylinositol-specific phospholipase C and monoclonal antibody (mAb) S1 identified the 64-kDa core proteins as glypican, whereas mAb 2E9, which also reacted with proteoglycan from mouse mammary epithelial cells, tentatively identified the hybrid proteoglycans as syndecan. The expression of syndecan in lung fibroblasts was confirmed by amplifying syndecan cDNA sequences from fibroblastic mRNA extracts and demonstrating the cross-reactivity of the encoded recombinant core protein with mAb 2E9. Northern blots failed to detect a message for fibroglycan in the mammary epithelial cells and in several other epithelial cell lines tested, while confirming the expression of both glypican and syndecan in these cells. Confluent fibroblasts expressed higher levels of syndecan mRNA than exponentially growing fibroblasts, but these levels remained lower than observed in epithelial cells. These data formally identify one of the cell surface proteoglycans of human lung fibroblasts as syndecan and indicate that the expression of the cell surface proteoglycans varies in different cell types and under different culture conditions.

Amino Acid Sequence↗

PubMed1998

Heparan sulphate proteoglycan expression in human primary liver tumours.

Heparan sulphate proteoglycans (HSPGs) play important biological roles in cell-matrix adhesion processes and are essential regulators of growth factor actions (e.g., as co-receptor for hepatocyte growth factor). Since in liver carcinogenesis, interactions between cells, the matrix, and growth factors play a major role, the aim of this study was to investigate whether the distribution pattern of HSPGs is altered in human primary liver tumours. Twenty-two primary liver tumours and five normal liver biopsies were studied, using specific monoclonal antibodies against syndecans-1, -2, -3, and -4; glypican; perlecan; and heparan sulphate chains. Cholangiocarcinomas as well as hepatocellular carcinomas showed an altered immunoreactivity pattern of the different HSPGs in comparison with normal liver parenchyma, probably reflecting the growth regulatory roles of HSPGs. Intracellular positivity for integral membrane HSPGs syndecan-1 and especially syndecan-4 was a constant finding in most tumours, suggesting increased synthesis or internalization of these HSPGs. Syndecan-3 and perlecan expression in tumours was found in an expected distribution pattern. The strong reactivity for syndecan-3 and perlecan in tumoral stromal vessels might suggest a role for these HSPGs in tumoral angiogenesis. In addition, perlecan probably exerts its known growth factor reservoir function also in the stroma of primary liver tumours.

Bile Duct Neoplasms↗

PubMed2003

Fibronectin and adhesion molecules on canine scarred vocal folds.

OBJECTIVE: To examine the expressions of fibronectin and other adhesion molecules on the scarred vocal folds in a short- and long-term animal model. STUDY DESIGN: Animal model. METHODS: Six beagles' vocal folds were stripped unilaterally and left untreated. After wounding the vocal folds were harvested from three dogs at 2 months and three dogs at 6 months. The untouched vocal fold was used as a control, and the stripped vocal fold as scarred. Subsequently, the expressions of fibronectin, cadherin, syndecan-1 and syndecan-4 on both vocal folds were examined by immunohistochemical and image analysis. RESULTS: Compared with the control vocal folds, fibronectin significantly increased in the superficial layer of the lamina propria on the scarred vocal folds at both 2 and 6 months. Co-deposition of collagen was observed only at 6 months. Syndecan-4 was significantly overexpressed at the basal layer cells of the epithelium at both 2 and 6 months. No significant expression of either cadherin or syndecan-1 was detected. CONCLUSIONS: Scar characteristics at 2 and 6 months are not identical, suggesting that a 2-month period may not be a sufficient to study vocal fold scarring. Adhesion molecules are important in reorganization of extracellular matrix during wound healing because of their binding and adhesion characteristics. The results indicate that fibronectin might be important in providing a scaffold for the deposition of other proteins such as collagen, and the binding characteristics might affect the stiffness of the scarred vocal fold. Prolonged expression of syndecan-4 may reflect the role of focal adhesion during the assembly of scar structure. Ultimately, better understanding of the histological features of the scarred vocal fold might lead to new approaches to treatment.

Animals↗

PubMed1995

Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis.

Midkine (MK) and heparin binding-growth associated molecule (HB-GAM or pleiotrophin), constitute a new family of heparin-binding proteins implicated in the regulation of growth and differentiation (T. Muramatsu (1993) Int. J. Dev. Biol. 37, 183-188). We used affinity-purified antibodies against MK and HB-GAM to analyze their distribution during mouse embryonic development. From 9 to 14.5 day post-coitum (dpc), both proteins were detected in central and peripheral nervous systems, facial processes, limb buds, sense organs, respiratory, digestive, urogenital, and skeletal systems. MK and HB-GAM were often localized on the surface of differentiating cells and in basement membranes of organs undergoing epithelial-mesenchymal interactions. The level of MK protein decreased considerably in the 16.5 dpc embryo, whereas HB-GAM staining persisted in many tissues. Our in situ hybridization results revealed a widespread expression of MK transcripts that was not always consistent with the distribution of MK protein in developing tissues. In many epithelio-mesenchymal organs MK and HB-GAM were codistributed with syndecan-1, a cell surface proteoglycan. In limb buds and facial processes, MK, HB-GAM, and syndecan-1 were localized to the apical epithelium and the adjacent proliferating mesenchyme. Both MK and HB-GAM bound syndecan-1 in solid-phase assays in a heparan sulfate-dependent manner. The biological effects of MK and HB-GAM on limb and facial mesenchyme were studied in vitro by application of beads preloaded with the proteins. Neither MK nor HB-GAM stimulated mesenchymal cell proliferation or induced syndecan-1 expression. Taken together these results indicate that MK and HB-GAM may play regulatory roles in differentiation and morphogenesis of the vertebrate embryo, particularly in epithelio-mesenchymal organs, and suggest molecular interactions with syndecan-1.

Animals↗

PubMed2004

[Proteoglycans in the liver].

Proteoglycans are macromolecules formed by a protein core to which sugar chains are covalently attached. They are present on the cell surface and in the ECM of living things. In normal liver syndecan-1 is the dominant transmembrane proteoglycan, trace amounts of ECM proteoglycans are in the stromal components. The amounts of proteoglycans we studied increase in liver cirrhosis. In liver cancer abnormal localization of syndecan-1 and stroma rich in agrin was characteristic. The core proteins as well as the sugar chains of proteoglycans interact with and modulate the effect of regulatory factors. This implies that structural alterations of proteoglycans contribute to the development of malignant phenotype. Heparan sulfate chains of liver cancer are undersulfated with decreased or altered biological activity. Their binding capacity for transcription factor decreases, and they do not inhibit topoisomerase I enzyme. Truncated form of syndecan-1 lacking the extracellular domain of the molecule induces differentiation of hepatoma cell line and inhibits the shedding of syndecan-1. This phenomenon calls attention to the importance of syndecan-1 shedding in the regulation of cell behavior.

Animals↗

PubMed1992

Molecular cloning and expression of two distinct cDNA-encoding heparan sulfate proteoglycan core proteins from a rat endothelial cell line.

The cloned rat fat pad endothelial cell (RFP-EC) line synthesizes anticoagulantly active heparan sulfate proteoglycans (HSPGact) and anticoagulantly inactive heparan sulfate proteoglycans (HSPGinact), both of which exhibit 25-, 30-, and 50-kDa core proteins of extremely similar structure. The primary sequences of internal peptides obtained from HSPGinact core proteins and the NH2-terminal sequence analyses of the 25-kDa component from the HSPGinact core proteins demonstrate that the 30-kDa component is a previously unidentified species, designated as ryudocan, with the 25-kDa component representing a proteolytic degradation product, while the 50-kDa component is the rat homolog of syndecan (Saunders, S. Jalkanen, M., O'Farrell, S., and Bernfield, M. (1989) J. Cell Biol. 108, 1547-1556). Specific oligonucleotide probes were obtained for ryudocan and syndecan by polymerase chain reaction, and the corresponding cDNAs were isolated from a RFP-EC library. The cDNAs encode type I integral membrane proteins of 202 and 313 amino acids, respectively, which have homologous transmembrane and intracellular domains but very distinct extracellular regions. In particular, ryudocan exhibits only three potential glycosaminoglycan attachment sites within the extracellular region while syndecan has five glycosaminoglycan attachment sites within the same domain. Both species are expressed in RFP-EC lines, primary rat aortic smooth muscle cells and primary rat skin fibroblast cells. The levels of ryudocan and syndecan mRNA were measured by quantitative polymerase chain reaction in primary microvascular endothelial cells and closely associated non-endothelial cells isolated by cell sorting. Ryudocan and syndecan mRNAs were abundantly expressed in both populations representing about 0.1-0.5% of mRNA.

Amino Acid Sequence↗

PubMed2006

Mapping heparanase expression in the spinal cord of adult rats.

This work addresses the cellular localization of heparanase and its colocalization with syndecan-3, a transmembrane heparan sulfate proteoglycan in spinal cords of adult rats. Reverse transcriptase/polymerase chain reaction (RT-PCR) and in situ hybridization for the heparanase transcript revealed expression in neurons and white matter glia. This was confirmed by immunohistochemistry showing cytoplasmic localization of the heparanase protein. Double immunofluorescence for heparanase and syndecan-3 revealed colocalization of the proteins in cell bodies of neurons and oligodendrocytes, suggestive of constitutive expression in these cell types. In contrast, only subpopulations of astrocytes and NG2-expressing glia in the white matter expressed heparanase, and these did not show expression of syndecan-3. Cultures of astrocytes further evidenced upregulation of heparanase expression with TGF-beta(1) treatment, but no accompanying upregulation of syndecan-3 was detectable. These first findings of heparanase expression in the adult cord therefore provide the cellular basis for understanding functional interactions of heparanase and syndecan-3 in the normal neural network or otherwise in glial reactions to spinal cord injury.

Animals↗