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PubMed2004

A role for lipoprotein lipase during synaptic remodeling in the adult mouse brain.

Lipoprotein lipase (LPL) is a member of a lipase family known to hydrolyze triglyceride molecules found in lipoprotein particles. This particular lipase also has a role in the binding of lipoprotein particles to different cell-surface receptors. LPL has been identified in the brain but has no specific function yet. This study aimed at elucidating the role of LPL in the brain in response to injury. Mice were subjected to hippocampal deafferentation using the entorhinal cortex lesion and mRNA and protein expression were assessed over a time-course of degeneration/reinnervation. Hippocampal LPL levels peaked at 2 days post-lesion (DPL) both at the mRNA and protein levels. No change was observed for receptors of the LDL-receptor family or RAP at DPL 2 in the hippocampus but the glia-specific syndecan-4 was found to be significantly upregulated at DPL 2. These results suggest that LPL is involved in the recycling of cholesterol and lipids released from degenerating terminals after a lesion through a syndecan-4-dependent pathway.

Animals↗

PubMed2006

Identification of proteoglycan-binding proteins.

There are many proteins that bind to proteoglycans; they include proteins in extracellular matrices, growth factors or cytokines, plasma proteins, transmembrane proteins, and cytoplasmic proteins as listed in this chapter. Proteins that bind to a proteoglycan have been searched by using a proteoglycan as a ligand. Alternatively, a ligand protein has been used to find a proteoglycan as a binding partner. When the glycosaminoglycan (GAG) portion of a proteoglycan is responsible for the binding, a native proteoglycan is necessary for the analysis of binding. When the protein portion is responsible for the binding, a recombinant core protein without GAG chains may be used for analysis. This chapter describes experimental procedures dealing with two native proteoglycans, versican (PG-M) and syndecan-4 (ryudocan). Versican has been identified as a proteoglycan with binding capability to a growth factor, midkine. Purified syndecan-4 has been used to identify proteins that bind to the proteoglycan.

Animals↗

PubMed2003

Leukocyte motility in response to neuropeptides is heparan sulfate proteoglycan dependent.

Activation of neuropeptide receptors on leukocytes induces chemotaxis. We determined in Boyden chambers with micropore filters, whether in human monocytes and lymphocytes this migratory response is heparan sulfate proteoglycan (HSPG) dependent. Chemotaxis toward calcitonin gene-related peptide, secretoneurin, vasoactive intestinal peptide (VIP), and substance P (SP) was abolished by removal of heparan sulfate side chains from cell surface proteoglycans or by addition of anti-syndecan-4 antibodies. Inhibition of neuropeptide-induced chemotaxis by dimethyl sphingosine (DMS), an inhibitor of sphingosine kinase, indicates transactivation of the sphingosine-1-phosphate chemotaxis pathway which was previously identified as being syndecan-4-related. Data suggest that HSPGs are involved in neuropeptide-induced chemotaxis of leukocytes.

Antibodies↗

PubMed2003

PDZ tandem of human syntenin: crystal structure and functional properties.

Syntenin, a 33 kDa protein, interacts with several cell membrane receptors and with merlin, the product of the causal gene for neurofibromatosis type II. We report a crystal structure of the functional fragment of human syntenin containing two canonical PDZ domains, as well as binding studies for full-length syntenin, the PDZ tandem, and isolated PDZ domains. We show that the functional properties of syntenin are a result of independent interactions with target peptides, and that each domain is able to bind peptides belonging to two different classes: PDZ1 binds peptides from classes I and III, while PDZ2 interacts with classes I and II. The independent binding of merlin by PDZ1 and syndecan-4 by PDZ2 provides direct evidence for the coupling of syndecan-mediated signaling to actin regulation by merlin.

Actins↗

PubMed2006

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma.

The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro. To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-alpha were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) - neuregulin-1, amphiregulin, HB-EGF - promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10(5) molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.

B-Lymphocytes↗

PubMed2001

C-terminal heparin-binding domain of fibronectin regulates integrin-mediated cell spreading but not the activation of mitogen-activated protein kinase.

Fibronectin (FN) stimulates multiple signalling events including mitogen-activated protein kinase (MAPK) activation. During cell spreading, both the cell-binding domain and the C-terminal heparin-binding domain (HepII) of FN co-operatively regulate cytoskeleton organization. However, in comparison with the large number of studies on the functions of cell-binding domain, there is little information about the role of HepII. We therefore investigated the effect of HepII on integrin-mediated cell spreading and adhesion on FN and MAPK activation. In contrast with cells on FN substrates, rat embryo fibroblasts on FN120, which lacks HepII, were less spread, had weaker adhesion to FN and failed to form focal adhesions and actin stress fibres. Phosphotyrosine was present in the focal contacts of rat embryo fibroblasts on FN within 30 min but was absent from cells on FN120. Overall, tyrosine phosphorylation was much less in cell lysates from cells on FN120, with decreased phosphorylation of focal adhesion kinase ('pp125FAK') on tyrosine-397, implying additional regulation of tyrosine phosphorylation by HepII. Nevertheless, adhesion-mediated MAPK activity was similar in cells on FN and on FN120. Furthermore, cells spread on FN and on FN120 substrates showed similar MAPK activation in response to treatment with epidermal growth factor and with platelet-derived growth factor. Consistently, overexpression of syndecan-4, which binds to HepII, enhanced cell spreading and adhesion on FN but did not affect integrin-mediated MAPK activation. We therefore conclude that both HepII and syndecan-4 regulate integrin-mediated cell spreading but not MAPK activation.

Actins↗

PubMed2004

Heparan sulphate proteoglycans interact with neurocan and promote neurite outgrowth from cerebellar granule cells.

We found that neurocan, a major brain chondroitin sulphate proteoglycan, interacts with HSPGs (heparan sulphate proteoglycans) such as syndecan-3 and glypican-1. Binding of these HSPGs to neurocan was prevented by treatment of the HSPGs with heparitinases I and II, but not by treatment of neurocan with chondroitinase ABC. Scatchard plot analysis indicated that neurocan has two binding sites for these HSPGs with different affinities. It is known that neurocan in the rodent brain is proteolytically processed with aging into N- and C-terminal fragments. When a mixture of whole neurocan and N- and C-terminal fragments prepared from neonatal mouse brains or recombinant N- and C-terminal fragments was applied to a heparin column, the whole molecule and both the N- and C-terminal fragments bound to heparin. A centrifugation cell adhesion assay indicated that both the N- and C-terminal neurocan fragments could interact with these HSPGs expressed on the cell surface. To examine the biological significance of the HSPG-neurocan interaction, cerebellar granule cells expressing these HSPGs were cultured on the recombinant neurocan substrate. A significant increase in the rate of neurite outgrowth was observed on the wells coated with the C-terminal neurocan fragment, but not with the N-terminal one. Neurite outgrowth-promoting activity was inhibited by pretreatment of neurocan substrate with heparin or the addition of heparitinase I to culture medium. These results suggest that HSPGs such as syndecan-3 and glypican-1 serve as the cell-surface receptor of neurocan, and that the interaction of these HSPGs with neurocan through its C-terminal domain is involved in the promotion of neurite outgrowth.

Animals↗

PubMed1994

Sulphated and undersulphated heparan sulphate proteoglycans in a Chinese hamster ovary cell mutant defective in N-sulphotransferase.

The Chinese hamster ovary cell mutant, pgsE-606, synthesizes undersulphated heparan sulphate glycosaminoglycans because of a deficiency in N-sulphotransferase activity [Bame and Esko (1989) J. Biol. Chem. 264, 8059-8065]. We compared the heparan sulphate proteoglycans synthesized by mutant and wild-type cells to determine what effect the undersulphation defect had on proteoglycan structure. The majority of heparan sulphate proteoglycans synthesized by pgsE-606 were undersulphated, but the mutant also synthesized a population of proteoglycans that were sulphated to the same extent as wild-type molecules. Anion-exchange analysis of the glycosaminoglycans in each proteoglycan population showed that they were all modified in the same way. The length of the glycosaminoglycans in each proteoglycan population were similar, suggesting that N-sulphation does not affect chain polymerization. To examine whether the sulphation state of the attached heparan sulphate glycosaminoglycans was dependent on the protein core, we purified syndecan-1 from mutant and wild-type cells using antibodies against the core protein. As with the unfractionated heparan sulphate proteoglycans, pgsE-606 synthesized both undersulphated and sulphated syndecan-1. Each pool contained either undersulphated or sulphated glycosaminoglycan chains respectively. Thus the modification of all heparan sulphate chains on a core protein occurs on a proteoglycan-wide basis (i.e. to the same extent).

Animals↗

PubMed2000

Molecular biology of ryudocan, an endothelial heparan sulfate proteoglycan.

Ryudocan is a type I integral membrane heparan sulfate proteoglycan, which was originally cloned from rat microvascular endothelial cells. We have cloned the cDNA of rat ryudocan. The deduced amino acids of ryudocan has homologous transmembrane and intracellular domains with syndecan but very distinct extracellular regions. We also cloned the human ryudocan cDNA, of which the gene localizes on the chromosome 20q12. To better understand the regulation of ryudocan expression, we have determined the structural organization of the human ryudocan gene. The human ryudocan gene extends approximately 24 kb and is divided into five exons that appear conserved in syndecan family members. The 5'-flanking sequences of the human ryudocan gene contain a variety of potential binding sites for transcription factors and are capable of functioning as a promoter. We purified human ryudocan and evaluated its interactions with several extracellular ligands. It was found that basic fibroblast growth factor (bFGF), midkine, and tissue factor pathway inhibitor exhibited significant ryudocan bindings. Heparitinase, but not chondroitin ABC lyase treatment, destroyed those ryudocan bindings; thus, the heparan sulfate chains of ryudocan appear to be responsible for those bindings. Immunohistochemical analysis revealed that ryudocan is expressed in peripheral nerve tissues, fibrous connective tissues, and placental trophoblasts. These findings suggest that ryudocan may possess multiple biologic functions, such as bFGF modulation, neurite growth promotion, and anticoagulation, via heparan sulfate-binding effectors in the cellular microenvironment.

Amino Acid Sequence↗

PubMed2000

Localization and quantitation of hyaluronan and sulfated glycosaminoglycans in the tissues and intraluminal fluid of the pig oviduct.

Glycosaminoglycans (GAGs), hyaluronan (HA) and heparan sulfate (HS) were localized in the pre- and post-ovulatory oviducts of inseminated and control (non-inseminated) sows using biotinylated HA-binding protein (HABP) and anti-syndecan antibodies respectively. In addition, the concentrations of HA and total sulfated GAGs (S-GAGs) were measured in fluid collected in vivo from either a selected tubal segment (isthmus or ampulla) or from the contralateral whole oviduct (WO) of non-inseminated sows during proestrus-metoestrus. HA was localized in the lamina propria of the entire oviduct, but epithelial HA-labelling was only present in the sperm reservoir (uterotubal junction adjacent isthmus) in control and inseminated sows. In contrast, immunolabelling for HS proteoglycans (HSPGs, syndecans) was present on the entire epithelial lining, both pre and post ovulation and in both sow groups. Both HA and S-GAGs could be detected in the intraluminal fluid. Concentrations varied among sows and segments; those of the S-GAGs being higher (P<0.05) than that of HA. Mean levels of S-GAGs and HA tended to increase in the fluid collected from isthmus and ampulla during standing oestrus. Fluid levels from the WO, however, fluctuated less during the collection period. Major statistical differences were not present, owing to the large variation seen between animals. The results confirm, however, that GAGs are present in the pig oviduct. The conspicuous localization in the sperm reservoir and the tendency to higher levels in the fluid during pre-ovulatory oestrus support the hypothesis that GAGs play a role in modulating sperm viability and capacitation during sperm transport in the pig oviduct.

Animals↗

PubMed2006

Cellular adhesion responses to the heparin-binding (HepII) domain of fibronectin require heparan sulfate with specific properties.

Cell surface heparan sulfate (HS) proteoglycans are required in development and postnatal repair. Important classes of ligands for HS include growth factors and extracellular matrix macromolecules. For example, the focal adhesion component syndecan-4 interacts with the III(12-14) region of fibronectin (HepII domain) through its HS chains. The fine structure of HS is critical to growth factor responses, and whether this extends to matrix ligands is unknown but is suggested from in vitro experiments. Cell attachment to HepII showed that heparin oligosaccharides of >or=14 sugar residues were required for optimal inhibition. The presence of N-sulfated glucosamine in the HS was essential, whereas 2-O-sulfation of uronic acid or 6-O-sulfation of glucosamine had marginal effects. In the more complex response of focal adhesion formation through syndecan-4, N-sulfates were again required and also glucosamine 6-O-sulfate. The significance of polymer N-sulfation and sulfated domains in HS was confirmed by studies with mutant Chinese hamster ovary cells where heparan sulfation was compromised. Finally, focal adhesion formation was absent in fibroblasts synthesizing short HS chains resulting from a gene trap mutation in one of the two major glucosaminoglycan polymerases (EXT1). Several separate, specific properties of cell surface HS are therefore required in cell adhesion responses to the fibronectin HepII domain.

Animals↗

PubMed1997

Cell-surface heparan sulfate proteoglycans: dynamic molecules mediating ligand catabolism.

Though sometimes regarded as merely passive, space-filling components, proteoglycans are in fact metabolically active molecules with carbohydrate and protein domains that are highly conserved throughout evolution, indicating specific, crucial functions. Here we review recent evidence that heparan sulfate proteoglycans, particularly syndecans and perlecan, are able to mediate directly the internalization of lipoproteins and other ligands, without requiring the participation of LDL receptor family members. Thus, heparan sulfate proteoglycans can function as receptors. In the case of syndecan heparan sulfate proteoglycans, efficient internalization is triggered by clustering of the transmembrane and cytoplasmic domains and then proceeds through a noncoated pit pathway, possibly caveolae. The physiologic and pathophysiologic importance of these direct heparan sulfate proteoglycan-mediated catabolic pathways in the liver and in the arterial wall in vivo remains to be settled.

Animals↗

PubMed1993

Hair follicle proteoglycans.

Proteoglycans are polymorphic macromolecules present in all mammalian tissues, including the skin and its appendages. They consist of a core protein to which one or more glycosaminoglycan chains are covalently attached. Broadly, they can be divided into classes based on location and core protein structure. These classes include cell surface proteoglycans, basement membrane proteoglycans, small leucine-rich proteoglycans, large proteoglycans aggregating with hyaluronan, and intracellular granule proteoglycans. They have a wide range of functions, but little is known of the proteoglycans that are present in the epithelial and stromal compartments of hair follicles. However, the transmembrane proteoglycan syndecan may be important in follicle morphogenesis, both with respect to the epithelium and dermal papilla cells. Syndecan may possess both heparan and chondroitin sulfate chains, interacts with growth factors as well as fibronectin and interstitial collagens, and can associate in a transmembrane relationship with the cellular cytoskeleton. It is strongly expressed in mesenchymal cells coincident with stromal-epithelial interactions during tissue morphogenesis. Proteoglycans are present in all basement membranes, including those surrounding the epithelial compartment of hair follicles. Additionally, and quite unlike the dermis, the dermal papilla is enriched in basement-membrane components, especially a chondroitin 6-sulfate-containing proteoglycan, BM-CSPG. The function of this proteoglycan is not known, but developmental studies indicate that it may have a role in stabilizing basement membranes. In the hair cycle, BM-CSPG decreases through catagen and is virtually absent from the telogen papilla. One or more heparan sulfate proteoglycans, including perlecan, are also present in papilla and follicular basement membranes. Some of the leucine-rich proteoglycans, such as decorin, are associated with interstitial collagens, and may influence fibrillogenesis. Because small amounts of types I and III collagens may be present in anagen papillae, decorin may also be a constituent.

Animals↗

PubMed2006

Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms.

Mutations in human presenilin (PS) genes cause aggressive forms of familial Alzheimer's disease. Presenilins are polytopic proteins that harbour the catalytic site of the gamma-secretase complex and cleave many type I transmembrane proteins including beta-amyloid precursor protein (APP), Notch and syndecan 3. Contradictory results have been published concerning whether PS mutations cause 'abnormal' gain or (partial) loss of function of gamma-secretase. To avoid the possibility that wild-type PS confounds the interpretation of the results, we used presenilin-deficient cells to analyse the effects of different clinical mutations on APP, Notch, syndecan 3 and N-cadherin substrate processing, and on gamma-secretase complex formation. A loss in APP and Notch substrate processing at epsilon and S3 cleavage sites was observed with all presenilin mutants, whereas APP processing at the gamma site was affected in variable ways. PS1-Delta9 and PS1-L166P mutations caused a reduction in beta-amyloid peptide Abeta40 production whereas PS1-G384A mutant significantly increased Abeta42. Interestingly PS2, a close homologue of PS1, appeared to be a less efficient producer of Abeta than PS1. Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways.

Amyloid Precursor Protein Secretases↗

PubMed1991

The molecular biology of heparan sulfate fibroblast growth factor receptors.

Two distinct classes of cell surface FGF-binding proteins have been identified. These receptors differ in both mode of interaction and in affinity for the FGFs. cDNAs that encode the low-affinity receptor were isolated from a hamster kidney cell line cDNA library by expression cloning. Transfected cells that contained these heparan sulfate proteoglycan FGF receptor cDNAs were enriched for by panning on basic FGF-coated plates. The analogous human cDNA was isolated from a hepatoma cell line cDNA library. The homology of our hamster cDNAs to the previously described murine integral membrane proteoglycan syndecan, together with an exact amino acid sequence match of our human-cDNA-encoded product to human syndecan, clearly indicates the identity of these independently isolated proteoglycans. Further confirmation that the expressed molecule serves as a proteoglycan core protein was achieved by immunoprecipitation of 35SO4-labeled material from solubilized transfected cells. Nitrous acid treatment and chondroitinase digestion revealed that 77% of the label was associated with heparan sulfate chains and 22% with chondroitin sulfate chains. These heparan sulfate chains contributed to the fivefold increase in the total heparan sulfate found to be present on the surface of the transfected cells compared with cells transfected with a vector lacking the cDNA insert.

Amino Acid Sequence↗

PubMed2005

Atrial natriuretic peptide induces shedding of endothelial glycocalyx in coronary vascular bed of guinea pig hearts.

Atrial natriuretic peptide (ANP) is reported to enhance vascular permeability in vivo. Our aim was to evaluate the impact of ANP on coronary extravasation of fluids and macromolecules and on the integrity of the endothelial glycocalyx. Isolated guinea pig hearts (n = 6/group) were perfused with Krebs-Henseleit buffer in a Langendorff mode. A 6% hydroxyethyl starch (HES) solution was infused into the coronary system for 20 min without (Control group) and simultaneously with (ANP group) ANP at 10(-9) M. In two further series, the glycocalyx was enzymatically degraded by means of heparinase (Hep) application (10 IU over 15 min), followed again by the infusion of HES in the absence (Hep group) and presence (ANP+Hep group) of ANP. Net fluid filtration, extravasation of HES, electron microscopic visualization of the glycocalyx, and quantification of shedding of syndecan-1, a component of the glycocalyx, were determined. An increase in fluid leak was observed in ANP, ANP+Hep, and Hep hearts [+29%, +31%, +14%, respectively; a decrease was observed in Control hearts (-13%)]. Similarly, an accelerated extravasation of colloid was observed in these three groups. Coronary release of syndecan-1 increased 9- to 18-fold during infusion of ANP. Electron microscopy revealed a dramatic degradation of the glycocalyx after ANP. These results indicate that the endothelial glycocalyx serves as a barrier to transmural exchange of fluid and colloid in the coronary vascular system. ANP causes rapid shedding of individual components of the glycocalyx and histologically detectable degradation. Thus the permeability-increasing effect of ANP may be at least partially related to changes in the integrity of the endothelial glycocalyx.

Animals↗

PubMed2004

EPHB receptor signaling in dendritic spine development.

Dendritic spines are small bulbous protrusions on the surface of dendrites that serve as principle postsynaptic targets for excitatory synapses (1-3). Structural modifications of dendritic spines have been implicated as a cellular basis for learning and memory. Morphological abnormalities of spines are observed in some neurological diseases such as mental retardation and schizophrenia (4). Thus, studies on the morphological regulation of dendritic spines could have strong relevance to our understanding of the molecular mechanisms of the higher brain function and the pathophysiology of neurological disorders. Here we review recent progress on the role of the cell surface heparan sulfate proteoglycan syndecan-2 and ephrin-Eph signaling in dendritic spine development. Information from these new developments suggests a model in which cell surface ephrin-Eph signaling induces clustering of syndecan-2 and recruitment of cytoplasmic molecules, which leads to localized actin polymerization via Rho family GTPases, N-WASP, and the Arp2/3 complex.

Animals↗

PubMed1999

Differential involvement of the transcription factor Blimp-1 in T cell-independent and -dependent B cell differentiation to plasma cells.

Along humoral immune responses, different stimuli drive the differentiation of B lymphocytes to Ig-secreting plasma cells in discrete microenvironments. The Blimp-1 transcription factor is up-regulated early during the transition of mature B cells to IgM-secreting plasma cells. In the present study, we have examined the requirement of Blimp-1 in plasma cell formation after both T cell-independent (LPS) and -dependent (CD40 + IL-4, Th cell lines) stimulation of spleen B cells. B lymphocyte-induced maturation protein (Blimp-1) was expressed early after in vitro LPS stimulation, mainly in a population of IgM+Syndecan+CD43+ preplasma cells. In contrast, the BSAP transcription factor expressed in mature B cells was down-regulated during the differentiation to plasma cells. Treatment of these cultures with Blimp-1-specific antisense phosphorothioate oligonucleotides suppressed both Blimp-1 protein levels and the emergence of IgM+Syndecan+ cells and plasma cells. However, T-B cell cocultures of spleen B cells from C3H/HeJ (H-2k) mice and syngeneic autoreactive SR.10 Th2 cells submitted to the anti-Blimp-1 therapy did not show any significant reduction in IgM- and IgG1-secreting plasma cell formation. Spleen B cells treated with anti-CD40 mAb + IL-4 differentiated to IgG1-secreting cells without significant transcription of the Blimp-1 gene; anti-Blimp-1 treatment subsequently did not have any effect in the later cultures. Altogether, these results suggest that Blimp-1 transcription factor specifically promotes T cell-independent B cell differentiation to plasma cells, probably at preplasma cell stages. In contrast, T cell-dependent plasma cell formation likely evolves through Blimp-1-independent pathways.

Animals↗