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PubMed1999

Syndecan-4 and integrins: combinatorial signaling in cell adhesion.

It is now becoming clear that additional transmembrane components can modify integrin-mediated adhesion. Syndecan-4 is a transmembrane heparan sulfate proteoglycan whose external glycosaminoglycan chains can bind extracellular matrix ligands and whose core protein cytoplasmic domain can signal during adhesion. Two papers in this issue of JCS demonstrate, through transfection studies, that syndecan-4 plays roles in the formation of focal adhesions and stress fibers. Overexpression of syndecan-4 increases focal adhesion formation, whereas a partially truncated core protein that lacks the binding site for protein kinase C(&agr;) and phosphatidylinositol 4, 5-bisphosphate acts as a dominant negative inhibitor of focal adhesion formation. Focal adhesion induction does not require interaction between heparan sulfate glycosaminoglycan and ligand but can occur when non-glycanated core protein is overexpressed; this suggests that oligomerization of syndecan-4 plays a major role in signaling from the extracellular matrix in adhesion.

Amino Acid Sequence↗
PubMed2002

Syndecan-4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and monocytes.

Antithrombin inhibits chemokine-induced migration of neutrophils by activating heparan sulfate proteoglycan-dependent signaling. Whether antithrombin affects migration of other types of leukocytes is not known. We investigated the effects of antithrombin on spontaneous and chemokine-triggered migration of lymphocytes and monocytes from human peripheral blood in modified Boyden chamber micropore filter assays. Lymphocyte and monocyte populations from human peripheral blood were purified using magnetic antibody cell sorting. The signaling mechanisms required for antithrombin-dependent migration were studied using signaling enzyme blockers. Expression of heparan sulfate proteoglycan core protein was studied by RT-PCR and flow cytometry. The antithrombins used were Kybernin P from human plasma and a monoclonal-antibody-purified preparation from this plasma. Pretreatment of lymphocytes and monocytes with antithrombin inhibited chemotaxis toward optimal concentrations of interleukin-8 or Rantes (regulated upon activation normal T-cell expressed and activated) at concentrations of antithrombin as low as 10 nU/ml. In the absence of the chemokines, direct exposure of cells to gradients of antithrombin stimulated migration. Effects of antithrombin were abolished by pretreating cells with heparinase-1, chondroitinase, sodium chlorate and anti-syndecan-4 antibodies. Expression of syndecan-4 mRNA and protein in monocytes and lymphocytes was demonstrated in RT-PCR and anti-syndecan-4 immunoreactivity assays, respectively. In the presence of pentasaccharide, antithrombin lost its effect on cells. Data indicate that antithrombin directly inhibits chemokine-stimulated migration of monocytes and lymphocytes via the effects of its heparin-binding site on cell surface syndecan-4 by activation of protein kinase C and Rho signaling.

Antibodies, Monoclonal↗
PubMed2001

Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation.

Tenascin-C is an adhesion-modulatory extracellular matrix molecule that is highly expressed in tumors. To investigate the effect of tenascin-C on tumor cells, we analyzed its antiadhesive nature and effect on tumor cell proliferation in a fibronectin context. Glioblastoma and breast carcinoma cell adhesion was compromised by a mixed fibronectin/tenascin-C substratum, which concomitantly caused increased tumor-cell proliferation. We identified the antiadhesive mechanism as a specific interference of tenascin-C with cell binding to the HepII/syndecan-4 site in fibronectin through direct binding of tenascin-C to the 13th fibronectin type III repeat (FNIII13). Cell adhesion and proliferation levels were restored by the addition of FNIII13. Overexpression of syndecan-4, but not syndecan-1 or -2, reverted the cell adhesion defect of tenascin-C. We characterized FNIII13 as the binding site for syndecan-4. Thus we describe a novel mechanism by which tenascin-C impairs the adhesive function of fibronectin through binding to FNIII13, thereby inhibiting the coreceptor function of syndecan-4 in fibronectin-induced integrin signaling.

Animals↗
PubMedDate not supplied

The distribution of syndecan during murine secondary palate morphogenesis.

The distribution of syndecan, an integral membrane proteoglycan, has been immunohistochemically mapped during the course of murine secondary palate morphogenesis, gestational days 12-15. Syndecan has been shown to mediate cell adhesion and shape change and to be involved in epithelial-mesenchymal interactions during the morphogenesis of several structures. Changes in epithelial cell architecture accompany and may serve to direct the reorientation of the murine secondary palatal shelves from a vertical position on either side of the tongue to a horizontal and adhering position above it. Using a monoclonal antibody made to the core protein of the ectodomain of syndecan, staining was observed to correlate with epithelial cell shape, packing and degree of differentiation. Staining of condensing mesenchyme was also observed. Syndecan may be involved in modulating epithelial cell shape, architecture and fates during both major phases of secondary palate morphogenesis: shelf reorientation and midline epithelial seam dissolution.

Animals↗
PubMed2005

Integrin-syndecan cooperation governs the assembly of signalling complexes during cell spreading.

Cell adhesion to fibronectin (FN) triggers the formation and maturation of adhesion complexes by modulating the activity of the Rho family of GTPases. Cells plated onto a ligand of integrin alpha5beta1 spread but fail to form focal adhesions or fully organize actin into bundled stress fibres unless co-stimulated with a ligand of syndecan 4. Engagement of syndecan 4 in such pre-spread cells recapitulates the Rac1 and RhoA activation profiles observed during spreading on whole FN. Furthermore, since adhesion to a ligand of alpha5beta1 alone does not activate Rac1, engagement of syndecan 4 appears to be an absolute requirement. In related work, we have examined differences in the mechanism of focal adhesion formation mediated by the FN-binding integrins alpha4beta1 and alpha5beta1. Two signalling differences were found. First, while alpha5beta1 required syndecan 4 as a co-receptor, alpha4beta1 did not. Second, focal adhesion formation via alpha5beta1 required PKCalpha activation, but only basal PKCalpha activity was observed following adhesion via alpha4beta1. These findings demonstrate that different integrins can signal to induce focal adhesion formation by different mechanisms.

Animals↗
PubMed2002

Syndecan-3 and perlecan are differentially expressed by progenitors and mature oligodendrocytes and accumulate in the extracellular matrix.

Oligodendrocyte progenitors originate in the subventricular zone, proliferate, migrate to their final destinations, differentiate, and interact with axons to produce multilamellar myelin sheaths. These processes are regulated by a variety of environmental signals, including growth factors, the extracellular matrix, and adhesion molecules. Heparan sulfate proteoglycans are premier candidates as participants in this regulation by virtue of their structural diversity and their capacity to function as coreceptors for both growth factors and extracellular matrix molecules. Consistently with this, we have previously shown that oligodendrocyte progenitors are unable to proliferate in response to fibroblast growth factor-2 (FGF-2) in the absence of sulfated heparan sulfate proteoglycan. Here we show that members of three families of heparan sulfate proteoglycans, syndecan, perlecan, and glypican, are developmentally and posttranscriptionally regulated during oligodendrocyte-lineage progression: Syndecan-3 is synthesized by oligodendrocyte progenitors (but not terminally differentiated oligodendrocytes) and is up-regulated by FGF-2; perlecan synthesis increases as oligodendrocytes undergo terminal differentiation; glypican-1 is expressed by both progenitors and differentiated oligodendrocytes. Astrocytes express glypican-1 and perlecan but not syndecan-3. All three of these heparan sulfate proteoglycans are shed from the cell surface and bind to specific substrates. The developmentally regulated expression of these heparan sulfate proteoglycans is indicative of their participation in events involving growth factor receptors and the extracellular matrix that may regulate oligodendrocyte progenitor proliferation, migration, and adhesion phenomena.

Animals↗
PubMed2003

Syndecan-1 and -4 synthesized simultaneously by mouse mammary gland epithelial cells bear heparan sulfate chains that are apparently structurally indistinguishable.

Many of the biological functions attributed to cell surface heparan sulfate (HS) proteoglycans, including the Syndecan family, are elicited through the interaction of their HS chains with soluble extracellular molecules. Tightly controlled, cell-specific sulfation and epimerization of HS precursors endows these chains with highly sulfated, iduronate-rich regions, which are major determinants of cytokine and matrix-protein binding and which are interspersed by N-acetylated, poorly sulfated regions. Until this study, there have been no comprehensive structural comparisons made on HS chains decorating simultaneously expressed, but different, syndecan core proteins. In this paper we demonstrate that the HS chains on affinity-purified syndecan-1 and -4 from murine mammary gland cells are essentially identical by a number of parameters. Size determination, disaccharide analyses, enzymatic and chemical scission methods, and affinity co-electrophoresis all failed to reveal any significant differences in fine structure, domain organization, or ligand-binding properties of these HS species. These findings lead us to suggest that the imposition of the fine structure onto HS occurs independently of the core protein to which it is attached and that these core proteins, in addition to the HS chains, may play a pivotal role in the various biological functions ascribed to these macromolecules.

Animals↗
PubMed2002

Syndesmos, a syndecan-4 cytoplasmic domain interactor, binds to the focal adhesion adaptor proteins paxillin and Hic-5.

Syndecan-4 and integrins are the primary transmembrane receptors of focal adhesions in cells adherent to extracellular matrix molecules. Syndesmos is a cytoplasmic protein that interacts specifically with the cytoplasmic domain of syndecan-4, and it co-localizes with syndecan-4 in focal contacts. In the present study we sought possible interactors with syndesmos. We find that syndesmos interacts with the focal adhesion adaptor protein paxillin. The binding of syndesmos to paxillin is direct, and these interactions are triggered by the activation of protein kinase C. Syndesmos also binds the paxillin homolog, Hic-5. The connection of syndecan-4 with paxillin through syndesmos parallels the connection between paxillin and integrins and may thus reflect the cooperative signaling of these two receptors in the assembly of focal adhesions and actin stress fibers.

Actins↗
PubMed1998

The cell surface proteoglycan syndecan-1 mediates fibroblast growth factor-2 binding and activity.

Binding of fibroblast growth factors (FGFs) to receptor tyrosine kinases (FGFRs) and signaling is facilitated by binding of FGF to heparan sulfate proteoglycans (HSPGs). There are multiple families of HSPGs, including extracellular and cell surface forms. An important and potentially controversial question is whether cell surface forms of HSPGs act as positive or negative regulators of FGF signaling. This study examines the ability of the cell surface HSPG syndecan-1 to regulate FGF binding and signaling. HSPG-deficient Raji lymphoma cells, expressing a transfected syndecan-1 cDNA (Raji S1 cells), were used as HSPG "donor" cells. BaF3 cells, expressing an FGFR1 cDNA (FR1C-11 cells), were used as FGFR "reporter" cells. Using Raji S1 cells preincubated with FGF, it was found that they formed heterotypic aggregates with FR1C-11 cells in the presence of FGF-2, but not FGF-1. In addition, the FR1C-11 cells demonstrated FGF-2, but not FGF-1, dependent survival when cultured on fixed Raji S1 cells. Thus, Raji syndecan-1 1) differentially regulates the binding and signaling of FGFs 1 and 2 and 2) acts as a positive regulator of FGF-2 signaling.

Animals↗
PubMed2004

Expression of syndecan-1 and expression of epidermal growth factor receptor are associated with survival in patients with nonsmall cell lung carcinoma.

BACKGROUND: Recently, the authors identified molecular signatures and pathways associated with nonsmall cell lung carcinoma histology and lung development. They hypothesized that genetic classifiers of histology would provide insight into lung tumorigenesis and would be associated with clinical outcome when evaluated in a broader set of specimens. METHODS: Associations between patient survival and immunostaining for 11 representative histologic classifiers (epidermal growth factor receptor [EGFR], CDK4, syndecan-1, singed-like, TTF-1, keratin 5, HDAC2, docking protein 1, integrin alpha3, P63, and cyclin D1) were examined using a tissue microarray constructed from nonsmall cell lung carcinoma specimens. RESULTS: Sixty-three tumors were examined, including 43 adenocarcinomas, 11 large cell carcinomas, and 9 squamous cell carcinomas. Sixty-three percent of tumors were clinical Stage I lesions, and 37% were Stage II-III lesions. In a multivariate analysis that controlled for age, gender, and race, syndecan-1 expression was found to be associated with a significant reduction in the risk of death (hazard ratio, 0.31 [95% confidence interval, 0.18-0.87]; P < 0.05). Multivariate analysis also indicated that EGFR expression was associated with a significant reduced risk of death. CONCLUSIONS: The authors demonstrated that expression of either of the nonsmall cell lung carcinoma subtype classifiers syndecan-1 and EGFR was associated with a 30% reduction in the risk of death, with this reduction being independent of histology and other confounders. The results of the current study suggest that loss of expression of these histologic classifiers is associated with biologic aggressiveness in lung tumors and with poor outcome for patients with such tumors. If their significance can be validated prospectively, these biomarkers may be used to guide therapeutic planning for patients with nonsmall cell lung carcinoma.

Adenocarcinoma↗
PubMed2003

Tissue microarray analysis reveals prognostic significance of syndecan-1 expression in prostate cancer.

BACKGROUND: Tissue microarrays (TMA) have recently emerged as powerful tools to rapidly analyze the clinical significance of new molecular markers in human tumors. Here, we have tested several molecular markers on a prostate TMA containing 637 different specimens. METHODS: The specimens were from 551 patients with prostate cancer and long-term follow-up information on progression (median 5.3 years), tumor-specific and overall survival (median 5.9 years). Eighty-six specimens from benign prostatic hyperplasia were included as controls. Expression of Ki67, Bcl-2, p53, CD-10 (neutral endopeptidase), and syndecan-1 (CD-138) was analyzed by immunohistochemistry. RESULTS: Gleason grade and Ki67 Labeling Index (LI) were independent predictors of early recurrence and poor survival. Bcl-2 predicted early recurrence, whereas p53 was associated with poor survival. Syndecan-1 overexpression also predicted early recurrence and was significantly associated with tumor specific survival, high Gleason grade, Ki67 LI, and Bcl-2 overexpression. Neoadjuvant hormonal therapy was associated with overexpression of Bcl-2 and inhibition of Ki67 LI and CD-10, but did not affect the expression of the remaining markers. CONCLUSIONS: The results of this TMA study confirm a dominant prognostic significance of Gleason grading and Ki67 LI in prostate cancer, as compared to a less pronounced role of Bcl-2, and p53. We identified syndecan-1 as a new prognostic factor and provide evidence for an androgen-dependent regulation of CD-10 expression.

Aged↗
PubMed1997

The mapping and visual ordering of the human syndecan-1 and N-myc genes near the telomeric region of chromosome 2p.

The chromosomal locations of the human and mouse syndecan genes have been shown to associate with the corresponding locations of members of the myc gene family, proto-oncogenes that code for transcription factors. Here, we demonstrate the precise localization and order of the human syndecan-1 and N-myc genes using fluorescence in situ hybridization techniques that provide different levels of resolution. By visualizing the actual centromere-telomere orientation of these two genes, the human syndecan-1 gene is localized to 2p23-24, just centromeric to the N-myc gene at 2p24.1.

Chromosome Mapping↗
PubMed1999

The Mi15 monoclonal antibody (anti-syndecan-1) is a reliable marker for quantifying plasma cells in paraffin-embedded bone marrow biopsy specimens.

Plasmocyte selective monoclonal antibodies (MAb) recognizing syndecan-1 have recently been described. They belong to a new cluster, CD138. Using the MAb MI15, we investigated the expression of syndecan-1 in routinely paraffin-embedded tissues. Nontumoral lymph nodes (25 cases) and bone marrow biopsy specimens (63 cases) showed strong membrane staining of plasma cells only, allowing accurate analysis of the nuclear structure. The MI15 positivity correlated with kappa and lambda light chain expression in the cytoplasm. The percentages of plasma cells calculated in bone marrow biopsy specimens after MI15 staining were, respectively, 2.1% (range, 1% to 4%) in normal bone marrows, 8.5% (range, 5 to 17) in reactive plasmocytosis, and 4.66% in monoclonal gammapathy of undetermined significance (MGUS) patients (range, 1 to 13), in the same range but slightly higher than those obtained on smears or on hematoxylin and eosin (H&E)-stained sections. In multiple myeloma (40 cases), all plasma cell types were marked, and Mi15 MAb gave additional information in 8 of 40 (20%) patients. In lymph nodes, Mi15 MAb reacted with Reed-Sternberg cells of classical Hodgkin's disease in 23 of 31 cases (74%) with variable intensity. In contrast, nodular lymphocyte predominance Hodgkin's disease (10 cases), most B cell lymphomas (88 of 107 cases) and all T cell lymphomas (30 cases) were negative. In B cell lymphomas, plasmocytomas (8 cases), plasmocytic lymphomas (2 cases), and 5 of 13 cases of immunoblastic lymphoma with plasmocytoid differentiation were stained. In lymphoplasmocytoid lymphomas (4 lymph nodes and 20 bone marrow biopsy specimens), only mature plasma cells were positive. Moreover, a wide distribution of syndecan-1 was observed in normal and tumoral epithelial tissues. Finally, Mi15 MAb appears to be a reliable marker for identifying and quantifying normal and tumoral plasma cells in paraffin-embedded bone marrow and lymph node samples.

Antibodies, Monoclonal↗
PubMed1998

Laminin-1 and laminin-2 G-domain synthetic peptides bind syndecan-1 and are involved in acinar formation of a human submandibular gland cell line.

The culture of human submandibular gland (HSG) cells on laminin-1 induces acinar differentiation. We identified a site on laminin involved in acinar differentiation using synthetic peptides derived from the C-terminal G-domain of the laminin alpha1 and alpha2 chains. The alpha1 chain peptide AG73 (RKRLQVQLSIRT) decreases the size of acini formed on laminin-1. Cells cultured with either AG73 or the homologous alpha2 chain peptide MG73 (KNRLTIELEVRT) form structures that appear acinar-like, but the cell nuclei are not polarized to the basal surface and no lumen formation occurs, indicating that additional sites on laminin are required for complete differentiation. The G-domain of laminin-1 contains both integrin and heparin binding sites, and anti-beta1-integrin antibodies disrupt acinar formation. Cell adhesion to the peptides and to E3, an elastase digest fragment of laminin-1 containing AG73, is specific, since other laminin peptides or EDTA do not compete the binding. Heparin and heparan sulfate decrease cell adhesion to AG73 and MG73 but anti-beta1-integrin antibodies have no effect. Treating the cell surface with heparitinase inhibits adhesion to both AG73 and MG73. We isolated cell surface ligands using both peptide affinity chromatography and laminin-1 affinity chromatography. Treating the material bound to the affinity columns with heparitinase and chondroitinase enriches for a core protein identified as syndecan-1 by Western blot analysis, thus identifying a syndecan-1 binding site in the globular domain of laminin-1 and laminin-2. In summary, multiple interactions between laminin and HSG cells contribute to acinar differentiation, involving both beta1-integrins and syndecan-1.

Amino Acid Sequence↗
PubMed2005

Utility of syndecan-1 (CD138) expression in the diagnosis of undifferentiated malignant neoplasms: a tissue microarray study of 1,754 cases.

Syndecan-1, a heparan sulfate-rich membrane glycoprotein, is expressed in plasma cells and is considered a reliable marker of plasmacytic differentiation. However, it has not been widely tested in non-hematolymphoid tissues, and thus its utility in the setting of an undifferentiated malignant neoplasm has not been evaluated. The authors conducted an extensive study of CD138 staining in over 1,700 normal, benign, and malignant non-hematolymphoid tissues, using five tissue microarrays. Immunohistochemical staining was performed with two commercially available CD138 monoclonal antibodies directed against syndecan-1 (Serotec, Oxford, UK, and DAKO, Carpenteria, CA). In addition to the specific membrane staining, many normal tissues and epithelial tumors showed strong cytoplasmic immunoreactivity. A small subset of mesenchymal neoplasms also showed membrane and cytoplasmic immunoreactivity. In squamous cell carcinoma of the head and neck, renal cell carcinoma, and prostate adenocarcinoma, the intensity of CD138 staining inversely correlated with the histologic grade of the carcinoma. However, statistically significant staining differences and their correlation with histologic grades differed depending on whether the Serotec or the DAKO antibody was used. These results indicate that CD138 immunoreactivity is widespread in normal and neoplastic epithelial tissues, as well as a variety of undifferentiated epithelial and mesenchymal processes. The authors conclude that the expression of syndecan-1, although relatively specific to plasma cells within the hematolymphoid system, should be interpreted with extreme caution in the setting of an undifferentiated neoplasm. Furthermore, the two commercially available monoclonal CD138 antibodies tested in this study showed significant differences in their immunoreactivity in different tumor types.

Adult↗
PubMed2003

Different mechanisms of syndecan-1 activation through a fibroblast-growth-factor-inducible response element (FiRE) in mucosal and cutaneous wounds.

Syndecan-1 expression is enhanced in cutaneous and mucosal wounds. We have previously demonstrated that wounding-induced syndecan-1 expression in the skin occurs transcriptionally, through a fibroblast-growth-factor-inducible element (FiRE). Here, we show that FiRE is also activated in mucosal wounds. However, both the expression patterns and the activation mechanisms of FiRE are different from those in the skin. In the mucosa in vivo, the activation starts and ends earlier than in cutaneous wounds. FiRE is first detected at around 12 hours in keratinocytes, and the activation declines by the third day after wounding occurs. The activation is seen on the migrating sheet of epithelial mucosa, as in the case of cutaneous wounding. In contrast to the situation in vivo, organ-cultured mucosal wounds exhibit no FiRE activity, while organ-cultured cutaneous wounds show robust activity. Activation in mucosal wounds is enhanced, however, by the application of epidermal growth factor. This suggests that exogenous growth factor activity is required for activation of syndecan-1 in mucosal wounds but not in cutaneous wounds.

Animals↗
PubMed2003

[The expression of cell adhesion molecule Syndecan-1 and E-candherin in laryngeal cancer].

OBJECTIVE: To observe Syndecan-1 and E-candherin expression and their relationship with clinico-pathologic factors in primary laryngeal squamous cell carcinoma(LSCC). METHOD: Syndecan-1 and E-candherin proteins were determined with immunohistochemical technique. RESULT: In invasive LSCC the expression of these two adhesion molecules were very similar. Both diminished with decreasing cell differentiation, lacked often in poorly differentiated tumors. And their expression were significantly correlated with each other. CONCLUSION: Our results suggest that Syndecan-1 and E-candherin expression correlates significantly with the histological differentiation grade of the tumors and the tumors size. They may play important roles in the pathogensis and the development of LSCC.

Adult↗