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PubMed1994

Core protein structure and sequence determine the site and presence of heparan sulfate and chondroitin sulfate on syndecan-1.

Most proteoglycans bear either chondroitin sulfate or heparan sulfate chains linked to serine residues at Ser-Gly attachment sites on the core protein. However, only a fraction of proteins with Ser-Gly sites exhibit glycosaminoglycan chains. A variable proportion of these sites may be glycanated, and an unknown mechanism distinguishes whether these sites are for chondroitin sulfate or heparan sulfate. To evaluate the core protein features that determine whether and where chondroitin sulfate or heparan sulfate will be linked, we have studied mouse syndecan-1, a transmembrane proteoglycan that is invariably glycanated and can contain both chondroitin sulfate and heparan sulfate chains. The extracellular domain of the syndecan-1 core protein contains five Ser-Gly sites, three clustered near its N terminus and two adjacent to the transmembrane domain near its C terminus. We have established the distribution of glycosaminoglycans on these attachment clusters. In contrast to the C-terminal cluster, the N-terminal cluster was always glycanated, suggesting that this domain of the core protein contains sequences responsible for the invariable attachment of glycosaminoglycan chains. Solely chondroitin sulfate was found on the C-terminal cluster. This cluster contains the sequences EGSGE and ETSGE, both estimated to be on the protein surface in a hydrophilic environment. Heparan sulfate was found solely on the N-terminal cluster, which also bears some chondroitin sulfate. This cluster contains the sequences FSGSGTG and DGSGD, the former estimated to be in a hydrophobic pocket and the latter, similar to the sequence on the C-terminal cluster, in an exposed hydrophilic region. This glycosaminoglycan distribution was identical on mouse syndecan-1 produced by either mouse epithelial (NMuMG) or hamster mesenchymal (CHO) cells, suggesting that site-specific attachment of glycosaminoglycans is independent of cell type. These results implicate a cellular mechanism that distinguishes among the potential sites and attaches the correct glycosaminoglycan type unambiguously. Thus, structural elements of the core protein other than the Ser-Gly attachment sites determine if a site will be glycanated and, if so, whether with chondroitin sulfate or heparan sulfate.

Amino Acid Sequence↗

PubMed1998

Syndecan-3 in limb skeletal development.

Syndecan-3 is a member of a family of heparan sulfate proteoglycans that function as extracellular matrix receptors and as co-receptors for growth factors and signalling molecules. A variety of studies indicate that syndecan-3 is involved in several aspects of limb morphogenesis and skeletal development. Syndecan-3 participates in limb outgrowth and proliferation in response to the apical ectodermal ridge; mediates cell-matrix and/or cell-cell interactions involved in regulating the onset of chondrogenesis; may be involved in regulating the onset of osteogenesis and joint formation and, plays a role in regulating the proliferation of epiphyseal chondrocytes during endochondral ossification.

Animals↗

PubMed1998

Role of sperm head syndecan at fertilization in fish.

Fish sperm head plasma membranes have been demonstrated to contain syndecan (transmembrane heparan sulfate proteoglycan) immunofluorohistochemically and using immunoblot analysis and transglutaminase (TGase) by histochemistry. In order to examine the involvement of syndecan in fertilization, mature eggs were inseminated by direct mixing with untreated sperm or with sperm pretreated with an antiheparan sulfate (HS) antibody monoclonal (mAb), bovine serum albumin, human transferrin, or a TGase inhibitor (monodansylcadaverine, cystamine, and iodoacetamide). The fertilization rates of eggs inseminated with untreated and albumin-pretreated sperm were approximately 99.3% and 94.7%, respectively. Those of eggs pretreated with the anti-HS antibody and transferrin were 0% and 5.4%, respectively, whereas use of sperm pretreated with TGase inhibitors resulted in fertilization rates of approximately 13.2-17.8%. These results indicate that sperm head syndecan play an important role in fish sperm-egg contact and/or binding and that TGase inhibitors may reduce the fertilization rate by inhibiting sperm motility.

Animals↗

PubMed1996

Syndecans, signaling, and cell adhesion.

Syndecans are transmembrane proteoglycans which can participate in diverse cell surface interactions, involving extracellular matrix macromolecules, growth factors, protease inhibitors, and even viral entry. Currently, all extracellular interactions are believed to be mediated by distinct structures within the heparan sulfate chains, leaving the roles of chondroitin sulfate chains and extracellular portion of the core proteins to be elucidated. Evidence that syndecans are a class of receptor involved in cell adhesion is mounting, and their small cytoplasmic domains may link with the microfilament cytoskeleton, thereby mediating signaling events. The molecular details are unknown, but the conservation of regions of syndecan cytoplasmic domains, and a strong tendency for homotypic association, support the idea that the ligand-induced clustering may be a discrete source of specific transmembrane signaling from matrix to cytoskeleton, as proposed for other classes of adhesion receptors.

Amino Acid Sequence↗

PubMed2000

Syndecan-4 deficiency impairs the fetal vessels in the placental labyrinth.

Syndecan-4 is a transmembrane protein bearing heparan sulfate chains, involved in anticoagulation and focal adhesion formation. Here, we revealed that syndecan-4 was expressed in the fetal vessels in the placental labyrinth by in situ hybridization and immunohistochemical staining. At 17.5 gestational days, the area of degenerated fetal vessels in the placental labyrinth was more diffuse and larger in Synd4(-/-) embryos than wild-type controls. Calcium and fibrin(ogen) depositions in the degenerated vessels were also more extensive and more severe in the placentas of Synd4(-/-) embryos. These findings suggest that syndecan-4 deficiency impairs the fetal vessels in the placenta, probably due to a deficit in the anticoagulation mechanism. This article is the first report demonstrating that among a large number of core proteins of heparan sulfate proteoglycans, a defect of a single core protein caused impaired anticoagulation in a specific site.

Animals↗

PubMed1992

Colocalization of thrombospondin and syndecan during murine development.

Thrombospondin is an adhesive glycoprotein that is thought to play a role in tissue genesis and repair. We have used a monoclonal anti-thrombospondin antibody, designated 5G11, to localize thrombospondin in paraformaldehyde fixed, paraffin-embedded sections of developing mouse embryos. Thrombospondin expression is observed in uterine smooth muscle, endometrial glands, the decidua, and trophoblastic giant cells during the initial phase of post-implantation development in the embryo. Cardiac myocytes and neuroepithelial cells show positive staining for thrombospondin at day 8.5 of gestation, and this expression continues throughout the development of the myocardium and central nervous system. Strong staining for thrombospondin is seen in developing bone and in the liver. Thrombospondin is also observed in developing smooth muscle and skeletal muscle, as well as in a variety of epithelia, including the epidermis, small intestinal epithelium, lens epithelium, renal tubular epithelium, and the epithelium of the developing tooth. Comparison of thrombospondin staining with that of two known cell surface receptors for thrombospondin, syndecan and the vitronectin receptor, reveals remarkable colocalization of thrombospondin and syndecan in all tissues, but almost no coexpression with the vitronectin receptor. Coexpression of thrombospondin and syndecan may play an important role in cell-cell or cell-matrix interactions during development.

Animals↗

PubMed2006

Activation of ERK signaling upon alternative protease nexin-1 internalization mediated by syndecan-1.

Protease nexin-1 (PN-1), an inhibitor of serine proteases, contributes to tissue homeostasis and influences the behavior of some tumor cells. The internalization of PN-1 protease complexes is considered to be mediated by the low-density lipoprotein receptor related protein 1 (LRP1). In this study, both wild-type and LRP1-/- mouse embryonic fibroblasts (MEF) were shown to internalize PN-1. Receptor associated protein (RAP) interfered with PN-1 uptake only in wild-type MEF cells, indicating that another receptor mediates PN-1 uptake in the absence of LRP1. In LRP1-/- MEF cells, inhibitor sensitivity and kinetic values (t(1/2) at 45 min) of PN-1 uptake showed a similarity to syndecan-1-mediated endocytosis. In these cells, PN-1 uptake was increased by overexpression of full-length syndecan-1 and decreased by RNA interference targeting this proteoglycan. Most important, in contrast to PKA activation known to be triggered by LRP1-mediated internalization, our study shows that syndecan-1-mediated internalization of PN-1 stimulated the Ras-ERK signaling pathway.

Amyloid beta-Protein Precursor↗

PubMed2000

Syndecan-4 binding to the high affinity heparin-binding domain of fibronectin drives focal adhesion formation in fibroblasts.

Cell adhesion to extracellular matrix involves signaling mechanisms which control attachment, spreading and the formation of focal adhesions and stress fibers. Fibronectin can provide sufficient signals for all three processes, even when protein synthesis is prevented by cycloheximide. Primary fibroblasts attach and spread following integrin ligation, but do not form focal adhesions unless treated with a heparin-binding fragment of fibronectin (HepII), a peptide from this domain, or phorbol esters to activate protein kinase C. Syndecan-4 heparan sulfate proteoglycan is a transmembrane component present together with integrins in focal adhesions. Syndecan-4 binds and activates protein kinase Calpha, whose activity is needed for focal adhesion formation. We now report that the glycosaminoglycan chains of syndecan-4 bind recombinant HepII and it is incorporated into forming focal adhesions.

Amino Acid Sequence↗

PubMed1994

Proteoglycan core protein syndecan in bladder biopsies.

The etiology of interstitial cystitis (IC) may be related to a dysfunctional epithelium caused by an abnormal permeability barrier. The presence of deleterious urinary substances (quaternary amines) that alter an otherwise normal epithelium may also be contributory. IC disease could reflect an inability of the bladder to repair its protective surface-coat material (glycosaminoglycans and proteoglycans), which is constantly exposed to a toxic urine environment. Bladder biopsy tissue from IC patients and derived explant cells were investigated to determine if mRNA for a proteoglycan core protein could be extracted and evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). Syndecan was chosen for this investigation because the available sequence information permitted PCR primers to be synthesized. The results indicated that biopsy tissue and explant cells could be utilized for the isolation of syndecan core protein mRNA. This proteoglycan was also demonstrated in mouse bladders by immunostaining and immunoblotting (but not in human tissues) using a syndecan-specific monoclonal antibody (281-2). Quantitative differences in IC tissues versus normal bladder tissue with respect to gene expression for this proteoglycan core protein can now be determined.

Animals↗

PubMed2004

Heparan sulfate proteoglycan syndecan promotes axonal and myotube guidance by slit/robo signaling.

Slit, the ligand for the Roundabout (Robo) receptors, is secreted from midline cells of the Drosophila central nervous system (CNS). It acts as a short-range repellent that controls midline crossing of axons and allows growth cones to select specific pathways along each side of the midline. In addition, Slit directs the migration of muscle precursors and ventral branches of the tracheal system, showing that it provides long-range activity beyond the limit of the developing CNS. Biochemical studies suggest that guidance activity requires cell-surface heparan sulfate to promote binding of mammalian Slit/Robo homologs. Here, we report that the Drosophila homolog of Syndecan (reviewed in ), a heparan sulfate proteoglycan (HSPG), is required for proper Slit signaling. We generated syndecan (sdc) mutations and show that they affect all aspects of Slit activity and cause robo-like phenotypes. sdc interacts genetically with robo and slit, and double mutations cause a synergistic strengthening of the single-mutant phenotypes. The results suggest that Syndecan is a necessary component of Slit/Robo signaling and is required in the Slit target cells.

Animals↗

PubMed1998

Identification and location on syndecan-1 core protein of the epitopes of B-B2 and B-B4 monoclonal antibodies.

Using a phage display peptide library, we characterized the epitope of two monoclonal antibodies reacting with syndecan-1: B-B2 and B-B4. The identified epitopes QDIT, for B-B2, and LPEV, for B-B4, were found to align with residues 36-39 and 90-93 of the mature protein, respectively. In contrast to B-B4, the B-B2 epitope is close to a potential glycosaminoglycan attachment site. Since syndecan-1 is heavily glycosylated and post-translational modifications are cell type specific, these results might explain the differences observed in the reactivity pattern of B-B2 and B-B4 and suggest that these monoclonal antibodies are useful probes to study cell surface exposed syndecan-1.

Amino Acid Sequence↗

PubMed2003

Regulation of cytoskeletal organization by syndecan transmembrane proteoglycans.

Syndecans, a family of transmembrane proteoglycans, interact with numerous extracellular ligands through specific sequences in their heparan sulfate chains and have been considered to be co-receptors for matrix molecules and growth factors. In addition to their roles as co-receptors, many studies have recently suggested that signaling through core protein of syndecans can regulate cytoskeletal organization through their clustering, association with cytoskeletal structures, binding to cytoplasmic binding proteins, and intracellular phosphorylation. Here we will review current understanding of signaling through syndecans in cytoskeletal organization.

Actins↗

PubMed2001

Syndecan-4 and focal adhesion function.

Two groups have now reported the viability of mice that lack syndecan-4. These mice have wound healing/angiogenesis problems, and fibroblasts from these animals differ in adhesion and migration from normal. This is consistent with recent in vitro data indicating a need for signaling via syndecan-4 for focal adhesion formation, and reports that overexpression of proteins that bind syndecan-4 can modify cell adhesion and migration.

Animals↗

PubMed2003

Decreased syndecan-2 expression correlates with trichostatin-A induced-morphological changes and reduced tumorigenic activity in colon carcinoma cells.

The inhibition of histone deacetylase activity is known to induce morphological changes of transformed cells. In this study, we investigated the effect of the specific HDAC inhibitor, trichostatin A (TSA), on colon carcinoma cell lines. Treatment of human colorectal carcinoma cells, KM1214 and KM12SM, with TSA induced distinct morphological changes. Both cell lines, which normally piled up in layers without clear boundary, became more flattened, and formed monolayers with evident boundaries between cells, with concomitant increased actin filament organization. Cell-cell interaction was not affected much, based on expression level, membrane localization, and interaction of E-cadherin with beta-catenin. In contrast, syndecan-2 expression was dramatically reduced and it was correlated with the morphological changes of colon carcinoma cells. Consistently, downregulation of syndecan-2 expression by antisense cDNA clearly mimicked the morphological changes in KM12SM and reduced anchorage-independent growth of colon cancer cells. All these results indicate that reduced syndecan-2 expression correlates with TSA-induced morphological changes and reduced tumorigenic activity in colon carcinoma cells.

Cadherins↗

PubMed1996

Phosphorylation of a membrane-intercalated proteoglycan, syndecan-2, expressed in a stroma-inducing clone from a mouse Lewis lung carcinoma.

We previously reported that a mouse Lewis lung carcinoma-derived stroma-inducing clone, P29, highly expresses a syndecan-like proteoglycan exhibiting specific binding to fibronectin, a major constituent of the interstitial matrix formed by the induced stromal cells, via its heparan sulphate chains [Itano, Oguri, Nakanishi and Okayama (1993) J. Biochem. (Tokyo) 114, 862-873]. On metabolic labelling of the proteoglycan with [32P]Pi, followed by identification of the radiolabelled material using glycanases, almost all the isotope was found to have been incorporated into a core portion of molecular mass 48 kDa, which was generated by digestion with heparan sulphate lyase I plus chondroitin ABC lyase. Immunoblotting of the core protein with a monoclonal antibody, F58-6G12, demonstrated that the proteoglycan was mouse syndecan-2. CsCl-density-gradient centrifugation after mild treatment of liposome-intercalated 32P-labelled syndecan-2 with trypsin resulted in clear separation of the radioactivity into a bottom fraction containing all the glycosaminoglycans (accounting for 40% of the total radioactivity) and a top fraction containing liposome-associated peptides (60%). The former isotope was shown to be linked covalently to both heparan sulphate and chondroitin sulphate chains, probably at their bridge regions. The latter was mostly attributed to phosphoserine, the one and only phosphorylated amino acid released on acid hydrolysis of this proteoglycan, strongly suggesting that the phosphorylation occurs at a specific serine residue(s) in the cytoplasmic domain of the core protein.

Amino Acid Sequence↗

PubMed1999

Syndecan-4 signals cooperatively with integrins in a Rho-dependent manner in the assembly of focal adhesions and actin stress fibers.

The assembly of focal adhesions and actin stress fibers by cells plated on fibronectin depends on adhesion-mediated signals involving both integrins and cell-surface heparan sulfate proteoglycans. These two cell-surface receptors interact with different domains of fibronectin. To attempt to identify the heparan sulfate proteoglycans involved, we used fibronectin-null (FN-/-) mouse fibroblasts to eliminate the contribution of endogenous fibronectin during the analysis. FN-/- fibroblasts plated on the cell-binding domain of fibronectin or on antibodies directed against mouse beta1 integrin chains attach but fail to spread and do not form focal adhesions or actin stress fibers. When such cells are treated with antibodies directed against the ectodomain of mouse syndecan-4, they spread fully and assemble focal adhesions and actin stress fibers indistinguishable from those seen in cells plated on intact fibronectin. These results identify syndecan-4 as a heparan sulfate proteoglycan involved in the assembly process. The antibody-stimulated assembly of focal adhesions and actin stress fibers in cells plated on the cell-binding domain of fibronectin can be blocked with C3 exotransferase, an inhibitor of the small GTP-binding protein Rho. Treatment of cells with lysophosphatidic acid, which activates Rho, results in full spreading and assembly of focal adhesions and actin stress fibers in fibroblasts plated on the cell-binding domain of fibronectin. We conclude that syndecan-4 and integrins can act cooperatively in generating signals for cell spreading and for the assembly of focal adhesions and actin stress fibers. We conclude further that these joint signals are regulated in a Rho-dependent manner.

Actin Cytoskeleton↗

PubMed2002

Syndecan-4 associates with alpha-actinin.

Cell adhesion to the extracellular matrix influences many cellular functions. The integrin family of matrix receptors plays major roles in the formation of adhesions, but other proteins modulate integrin signaling. Syndecan-4, a transmembrane proteoglycan, cooperatively signals with integrins during the formation of focal adhesions. To date, a direct link between syndecan-4 and the cytoskeleton has remained elusive. We now demonstrate by Triton X-100 extraction immunoprecipitation and in vitro binding assays that the focal adhesion component alpha-actinin interacts with syndecan-4 in a beta-integrin-independent manner.

Actinin↗

PubMed1998

Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells.

In Caenorhabditis elegans, mutations in the lin-2 gene inactivate the LET-23 receptor tyrosine kinase/Ras/MAP kinase pathway required for vulval cell differentiation. One function of LIN-2 is to localize LET-23 to the basal membrane domain of vulval precursor cells. LIN-2 belongs to the membrane-associated guanylate kinase family of proteins. We have cloned and characterized the human homolog of LIN-2, termed hCASK, and Northern and Western blot analyses reveal that it is ubiquitously expressed. Indirect immunofluorescence localizes CASK to distinct lateral and/or basal plasma membrane domains in different epithelial cell types. We detect in a yeast two-hybrid screen that the PDZ domain of hCASK binds to the heparan sulfate proteoglycan syndecan-2. This interaction is confirmed using in vitro binding assays and immunofluorescent colocalization. Furthermore, we demonstrate that hCASK binds the actin-binding protein 4.1. Syndecans are known to bind extracellular matrix, and to form coreceptor complexes with receptor tyrosine kinases. We speculate that CASK mediates a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with protein 4.1. Like other membrane-associated guanylate kinases, its multidomain structure enables it to act as a scaffold at the membrane, potentially recruiting multiple proteins and coordinating signal transduction.

Animals↗