Journal articles: 'Syndecan interaction'

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Hudák, Anett, Annamária Letoha, László Szilák, and Tamás Letoha. "Contribution of Syndecans to the Cellular Entry of SARS-CoV-2." International Journal of Molecular Sciences 22, no. 10 (May 19, 2021): 5336. http://dx.doi.org/10.3390/ijms22105336.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus’s interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection.

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Hudák, Anett, Katalin Jósvay, Ildikó Domonkos, Annamária Letoha, László Szilák, and Tamás Letoha. "The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology." International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7070. http://dx.doi.org/10.3390/ijms22137070.

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Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer’s disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (Aβ). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in Aβ pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE–heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated Aβ uptake and aggregation. ApoE2 increased the cellular internalization of monomeric Aβ, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once Aβ aggregated: while ApoE2 reduced the uptake of Aβ aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4′s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of Aβ pathology.

3

Palomino, Rafael, Hsiau-Wei Lee, and Glenn L. Millhauser. "The agouti-related peptide binds heparan sulfate through segments critical for its orexigenic effects." Journal of Biological Chemistry 292, no. 18 (March 6, 2017): 7651–61. http://dx.doi.org/10.1074/jbc.m116.772822.

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Syndecans potently modulate agouti-related peptide (AgRP) signaling in the central melanocortin system. Through heparan sulfate moieties, syndecans are thought to anchor AgRP near its receptor, enhancing its orexigenic effects. Original work proposed that the N-terminal domain of AgRP facilitates this interaction. However, this is not compatible with evidence that this domain is posttranslationally cleaved. Addressing this long-standing incongruity, we used calorimetry and magnetic resonance to probe interactions of AgRP peptides with glycosaminoglycans, including heparan sulfate. We show that mature, cleaved, C-terminal AgRP, not the N-terminal domain, binds heparan sulfate. NMR shows that the binding site consists of regions distinct from the melanocortin receptor-binding site. Using a library of designed AgRP variants, we find that the strength of the syndecan interaction perfectly tracks orexigenic action. Our data provide compelling evidence that AgRP is a heparan sulfate-binding protein and localizes critical regions in the AgRP structure required for this interaction.

4

Baston-Buest, Dunja Maria, Olga Altergot-Ahmad, Sarah Jean Pour, Jan-Steffen Krüssel, Udo Rudolf Markert, Tanja Natascha Fehm, and Alexandra Petra Bielfeld. "Syndecan-1 Acts as an Important Regulator of CXCL1 Expression and Cellular Interaction of Human Endometrial Stromal and Trophoblast Cells." Mediators of Inflammation 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/8379256.

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Successful implantation of the embryo into the human receptive endometrium is substantial for the establishment of a healthy pregnancy. This study focusses on the role of Syndecan-1 at the embryo-maternal interface, the multitasking coreceptor influencing ligand concentration, release and receptor presentation, and cellular morphology. CXC motif ligand 1, being involved in chemotaxis and angiogenesis during implantation, is of special interest as a ligand of Syndecan-1. Human endometrial stromal cells with and without Syndecan-1 knock-down were decidualized and treated with specific inhibitors to evaluate signaling pathways regulating CXC ligand 1 expression. Western blot analyses of MAPK and Wnt members were performed, followed by analysis of spheroid interactions between human endometrial cells and extravillous trophoblast cells. By mimicking embryo contact using IL-1β, we showed less ERK and c-Jun activation by depletion of Syndecan-1 and less Frizzled 4 production as part of the canonical Wnt pathway. Additionally, more beta-catenin was phosphorylated and therefore degraded after depletion of Syndecan-1. Secretion of CXC motif ligand 1 depends on MEK-1 with respect to Syndecan-1. Regarding the interaction of endometrial and trophoblast cells, the spheroid center-to-center distances were smaller after depletion of Syndecan-1. Therefore, Syndecan-1 seems to affect signaling processes relevant to signaling and intercellular interaction at the trophoblast-decidual interface.

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Vainio, S., M. Jalkanen, and I. Thesleff. "Syndecan and tenascin expression is induced by epithelial-mesenchymal interactions in embryonic tooth mesenchyme." Journal of Cell Biology 108, no. 5 (May 1, 1989): 1945–53. http://dx.doi.org/10.1083/jcb.108.5.1945.

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Morphogenesis of embryonic organs is regulated by epithelial-mesenchymal interactions associating with changes in the extracellular matrix (ECM). The response of the cells to the changes in the ECM must involve integral cell surface molecules that recognize their matrix ligand and initiate transmission of signal intracellularly. We have studied the expression of the cell surface proteoglycan, syndecan, which is a matrix receptor for epithelial cells (Saunders, S., M. Jalkanen, S. O'Farrell, and M. Bernfield. J. Cell Biol. In press.), and the matrix glycoprotein, tenascin, which has been proposed to be involved in epithelial-mesenchymal interactions (Chiquet-Ehrismann, R., E. J. Mackie, C. A. Pearson, and T. Sakakura. 1986. Cell. 47:131-139) in experimental tissue recombinations of dental epithelium and mesenchyme. Our earlier studies have shown that in mouse embryos both syndecan and tenascin are intensely expressed in the condensing dental mesenchyme surrounding the epithelial bud (Thesleff, I., M. Jalkanen, S. Vainio, and M. Bernfield. 1988. Dev. Biol. 129:565-572; Thesleff, I., E. Mackie, S. Vainio, and R. Chiquet-Ehrismann. 1987. Development. 101:289-296). Analysis of rat-mouse tissue recombinants by a monoclonal antibody against the murine syndecan showed that the presumptive dental epithelium induces the expression of syndecan in the underlying mesenchyme. The expression of tenascin was induced in the dental mesenchyme in the same area as syndecan. The syndecan and tenascin positive areas increased with time of epithelial-mesenchymal contact. Other ECM molecules, laminin, type III collagen, and fibronectin, did not show a staining pattern similar to that of syndecan and tenascin. Oral epithelium from older embryos had lost its ability to induce syndecan expression but the presumptive dental epithelium induced syndecan expression even in oral mesenchyme of older embryos. Our results indicate that the expression of syndecan and tenascin in the tooth mesenchyme is regulated by epithelial-mesenchymal interactions. Because of their early appearance, syndecan and tenascin may be used to study the molecular regulation of this interaction. The similar distribution patterns of syndecan and tenascin in vivo and in vitro and their early appearance as a result of epithelial-mesenchymal interaction suggest that these molecules may be involved in the condensation and differentiation of dental mesenchymal cells.

6

Miettinen, H. M., and M. Jalkanen. "The cytoplasmic domain of syndecan-1 is not required for association with Triton X-100-insoluble material." Journal of Cell Science 107, no. 6 (June 1, 1994): 1571–81. http://dx.doi.org/10.1242/jcs.107.6.1571.

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Cell surface heparan sulfate proteoglycans such as syndecan-1 bind various extracellular matrix proteins and have been suggested to interact with the cytoskeleton. Such interactions are thought to be important for stabilizing cell morphology. Syndecan-1 resists extraction with Triton X-100. This insolubility was reported not to be affected by removal of the glycosaminoglycan chains, suggesting that the insolubility is not due to binding to the extracellular matrix, but rather to an association with the actin cytoskeleton (Rapraeger, A., Jalkanen, M. and Bernfield, M. (1986) J. Cell Biol. 103, 2683–2696). To examine further the interaction of syndecan-1 with the Triton X-100-insoluble residue, we expressed wild-type mouse syndecan-1 and a cytoplasmic deletion mutant (tail-less) in Chinese hamster ovary cells. We observed that both the wild-type and the tail-less syndecan-1 were partly insoluble in Triton X-100. The insolubility was not affected by increasing temperature (37 degrees C or 50 degrees C) or by cytochalasin D. Removal of the glycosaminoglycan chains from the ectodomain, however, resulted in complete Triton X-100 solubility, unlike previous reports. Syndecan-1 could also be released into the Triton X-100-soluble fraction by addition of heparin or heparan sulfate to the extraction medium. We conclude that the cytoplasmic domain of syndecan-1 is not responsible for Triton X-100 insolubility. Instead, our results indicate that Triton X-100 insolubility is caused by an interaction of syndecan-1 molecules with other cellular and/or extracellular molecules mediated by the heparan sulfate chains.

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Ethell, Iryna M., Kazuki Hagihara, Yoshiaki Miura, Fumitoshi Irie, and Yu Yamaguchi. "Synbindin, a Novel Syndecan-2–Binding Protein in Neuronal Dendritic Spines." Journal of Cell Biology 151, no. 1 (October 2, 2000): 53–68. http://dx.doi.org/10.1083/jcb.151.1.53.

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Dendritic spines are small protrusions on the surface of dendrites that receive the vast majority of excitatory synapses. We previously showed that the cell-surface heparan sulfate proteoglycan syndecan-2 induces spine formation upon transfection into hippocampal neurons. This effect requires the COOH-terminal EFYA sequence of syndecan-2, suggesting that cytoplasmic molecules interacting with this sequence play a critical role in spine morphogenesis. Here, we report a novel protein that binds to the EFYA motif of syndecan-2. This protein, named synbindin, is expressed by neurons in a pattern similar to that of syndecan-2, and colocalizes with syndecan-2 in the spines of cultured hippocampal neurons. In transfected hippocampal neurons, synbindin undergoes syndecan-2–dependent clustering. Synbindin is structurally related to yeast proteins known to be involved in vesicle transport. Immunoelectron microscopy localized synbindin on postsynaptic membranes and intracellular vesicles within dendrites, suggesting a role in postsynaptic membrane trafficking. Synbindin coimmunoprecipitates with syndecan-2 from synaptic membrane fractions. Our results show that synbindin is a physiological syndecan-2 ligand on dendritic spines. We suggest that syndecan-2 induces spine formation by recruiting intracellular vesicles toward postsynaptic sites through the interaction with synbindin.

8

Sanderson, R. D., T. B. Sneed, L. A. Young, G. L. Sullivan, and A. D. Lander. "Adhesion of B lymphoid (MPC-11) cells to type I collagen is mediated by integral membrane proteoglycan, syndecan." Journal of Immunology 148, no. 12 (June 15, 1992): 3902–11. http://dx.doi.org/10.4049/jimmunol.148.12.3902.

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Abstract Differentiating B lymphocytes undergo changes in cell-cell and cell-matrix adhesion that control their movement through a series of distinct microenvironments. The integral membrane proteoglycan, syndecan, is a candidate for mediating B lymphocyte-matrix interactions because it is expressed on B lymphocytes only at times when they associate with matrix, and because syndecan is known to behave as a matrix receptor on simple epithelia. However, syndecan from B lymphocytes is significantly smaller in molecular mass than syndecan from simple epithelia (85 vs 160 kDa) suggesting that syndecan may have distinct functions on these two cell types. Our study was undertaken to determine if syndecan mediates adhesion of B lineage cells to extracellular matrix. The murine myeloma cell line MPC-11 was used because syndecan is the only major heparan sulfate proteoglycan detected on these cells and because they express a form of syndecan almost identical to that found on normal B lymphocytes. Cell binding assays demonstrate that syndecan binds MPC-11 cells to type I collagen. Binding is inhibited by heparin, by pretreatment of cells with heparitinase or by growth of cells before the assay in chlorate, an inhibitor of sulfation. Solid phase assays show that syndecan purified from MPC-11 cells binds to type I collagen but not type IV collagen, laminin, or fibronectin. The interaction of MPC-11-derived syndecan with type I collagen is of relatively high affinity (Kd app = 143 nM) as measured by affinity coelectrophoresis. However, the 160-kDa form of syndecan isolated from epithelial cells has a greater than fourfold higher affinity for type I collagen (Kd app = 31 nM) than does the MPC-11 syndecan, suggesting that different molecular forms of syndecan have distinct ligand binding properties. These results demonstrate that syndecan can mediate B lymphocyte interactions with matrix and suggest that changes in syndecan expression during B cell differentiation are a mechanism for controlling B cell localization within specific microenvironments.

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Carulli, Sonia, Konrad Beck, Guila Dayan, Sophie Boulesteix, Hugues Lortat-Jacob, and Patricia Rousselle. "Cell Surface Proteoglycans Syndecan-1 and -4 Bind Overlapping but Distinct Sites in Laminin α3 LG45 Protein Domain." Journal of Biological Chemistry 287, no. 15 (February 20, 2012): 12204–16. http://dx.doi.org/10.1074/jbc.m111.300061.

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Keratinocyte migration during epidermal repair depends on interactions between cellular heparan sulfate proteoglycan receptors, syndecan-1 and -4, and the C-terminal globular domains (LG45) of the extracellular matrix protein laminin 332. This study investigates the molecular basis of the binding specificity of the syndecan-1 and -4 receptors expressed by human keratinocytes. We used site-directed mutagenesis to alter a recombinant LG45 protein by substituting the most critical basic residues with glutamine. All proteins were expressed in mammalian cells, purified, and characterized biochemically. We used in vitro binding assays, including surface plasmon resonance, to examine interactions between mutated LG45 and heparan sulfates, syndecan-1 and -4. We identify a major heparin binding domain on the outer edge of a β-strand of LG45 surrounded by a track of converging low affinity residues. This domain harbors distinctive syndecan-1 and -4 binding-specific sequences. This is the first study to demonstrate a binding specificity of two proteoglycans produced by a single cell type. In addition, we found that although syndecan-1 interacts exclusively through its glycosaminoglycan chains, syndecan-4 binding relies on both its core protein and its heparan sulfate chains. These results suggest that LG45 may trigger different signals toward keratinocytes depending on its interaction with syndecan-1 or -4.

10

Munesue, Seiichi, Yasuo Yoshitomi, Yuri Kusano, Yoshie Koyama, Akiko Nishiyama, Hayao Nakanishi, Kaoru Miyazaki, et al. "A Novel Function of Syndecan-2, Suppression of Matrix Metalloproteinase-2 Activation, Which Causes Suppression of Metastasis." Journal of Biological Chemistry 282, no. 38 (July 10, 2007): 28164–74. http://dx.doi.org/10.1074/jbc.m609812200.

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The syndecans comprise a family of cell surface heparan sulfate proteoglycans exhibiting complex biological functions involving the interaction of heparan sulfate side chains with a variety of soluble and insoluble heparin-binding extracellular ligands. Here we demonstrate an inverse correlation between the expression level of syndecan-2 and the metastatic potential of three clones derived from Lewis lung carcinoma 3LL. This correlation was proved to be a causal relationship, because transfection of syndecan-2 into the higher metastatic clone resulted in the suppression of both spontaneous and experimental metastases to the lung. Although the expression levels of matrix metalloproteinase-2 (MMP-2) and its cell surface activators, such as membrane-type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinase-2, were similar regardless of the metastatic potentials of the clones, elevated activation of MMP-2 was observed in the higher metastatic clone. Removal of heparan sulfate from the cell surface of low metastatic cells by treatment with heparitinase-I promoted MMP-2 activation, and transfection of syndecan-2 into highly metastatic cells suppressed MMP-2 activation. Furthermore, transfection of mutated syndecan-2 lacking glycosaminoglycan attachment sites into highly metastatic cells did not have any suppressive effect on MMP-2 activation, suggesting that this suppression was mediated by the heparan sulfate side chains of syndecan-2. Actually, MMP-2 was found to exhibit a strong binding ability to heparin, the dissociation constant value being 62 nm. These results indicate a novel function of syndecan-2, which acts as a suppressor for MMP-2 activation, causing suppression of metastasis in at least the metastatic system used in the present study.

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Couchman, John R., Susan Vogt, Ssang-Taek Lim, Yangmi Lim, Eok-Soo Oh, Glenn D. Prestwich, Anne Theibert, Weontae Lee, and Anne Woods. "Regulation of Inositol Phospholipid Binding and Signaling through Syndecan-4." Journal of Biological Chemistry 277, no. 51 (October 10, 2002): 49296–303. http://dx.doi.org/10.1074/jbc.m209679200.

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Syndecan-4 is a transmembrane heparan sulfate proteoglycan that can regulate cell-matrix interactions and is enriched in focal adhesions. Its cytoplasmic domain contains a central region unlike that of any other vertebrate or invertebrate syndecan core protein with a cationic motif that binds inositol phospholipids. In turn, lipid binding stabilizes the syndecan in oligomeric form, with subsequent binding and activation of protein kinase C. The specificity of phospholipid binding and its potential regulation are investigated here. Highest affinity of the syndecan-4 cytoplasmic domain was seen with phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5P)2) and phosphatidylinositol 4-phosphate, and both promoted syndecan-4 oligomerization. Affinity was much reduced for 3-phosphorylated inositides while no binding of diacylglycerol was detected. Syndecan-2 cytoplasmic domain had negligible affinity for any lipid examined. Inositol hexakisphosphate, but not inositol tetrakisphosphate, also had high affinity for the syndecan-4 cytoplasmic domain and could compete effectively with PtdIns(4,5)P2. Since inositol hexaphosphate binding to syndecan-4 does not promote oligomer formation, it is a potential down-regulator of syndecan-4 signaling. Similarly, phosphorylation of serine 183 in syndecan-4 cytoplasmic domain reduced PtdIns(4,5)P2binding affinity by over 100-fold, although interaction could still be detected by nuclear magnetic resonance spectroscopy. Only protein kinase Cα was up-regulated in activity by the combination of syndecan-4 and PtdIns(4,5)P2, with all other isoforms tested showing minimal response. This is consistent with the codistribution of syndecan-4 with the α isoform of protein kinase C in focal adhesions.

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KEUM, Eunyoung, Yeonhee KIM, Jungyean KIM, Soojin KWON, Yangmi LIM, Innoc HAN, and Eok-Soo OH. "Syndecan-4 regulates localization, activity and stability of protein kinase C-alpha." Biochemical Journal 378, no. 3 (March 15, 2004): 1007–14. http://dx.doi.org/10.1042/bj20031734.

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During cell–matrix adhesion, syndecan-4 transmembrane heparan sulphate proteoglycan plays a critical role in the formation of focal adhesions and stress fibres. We have shown previously that the syndecan-4 cytoplasmic domain directly binds to and activates PKC-α (protein kinase C-α) in vitro [Oh, Woods and Couchman (1997) J. Biol. Chem. 272, 8133–8136]. However, whether syndecan-4 has the same activity in vivo needs to be addressed. Using mammalian two-hybrid assays, we showed that syndecan-4 interacted with PKC-α in vivo and that this interaction was mediated through syndecan-4 cytoplasmic domain. Furthermore, the activation of PKC increased the extent of interaction between syndecan-4 and PKC-α. Overexpression of syndecan-4, but not a mutant lacking its cytoplasmic domain, specifically increased the level of endogenous PKC-α and enhanced the translocation of PKC-α into both detergent-insoluble and membrane fractions. In addition, rat embryo fibroblasts overexpressing syndecan-4 exhibited a slowed down-regulation of PKC-α in response either to a prolonged treatment with PMA or to maintaining cells in suspension culture. PKC-α immunocomplex kinase assays also showed that syndecan-4 overexpression increased the activity of membrane PKC-α. Taken together, these results suggest that syndecan-4 interacts with PKC-α in vivo and regulates its localization, activity and stability.

13

BASS, Mark D., and Martin J. HUMPHRIES. "Cytoplasmic interactions of syndecan-4 orchestrate adhesion receptor and growth factor receptor signalling." Biochemical Journal 368, no. 1 (November 15, 2002): 1–15. http://dx.doi.org/10.1042/bj20021228.

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Syndecan-4 is a ubiquitous transmembrane proteoglycan that localizes to the focal adhesions of adherent cells and binds to a range of extracellular ligands, including growth factors and extracellular-matrix proteins. Engagement of syndecan-4 is essential for adhesion formation in cells adhering via certain integrins, and for cell proliferation and migration in response to growth factors. The cytoplasmic domain of syndecan-4 interacts with a number of signalling and structural proteins, and both extracellular and cytoplasmic domains are necessary for regulated activation of associated transmembrane receptors. PDZ domain-containing scaffold proteins (syntenin and CASK) bind to the C-terminus of the syndecan-4 cytoplasmic domain and co-ordinate clustering of receptors and connection to the actin cytoskeleton. Syndecan-4 also binds and activates protein kinase Cα in the presence of phosphatidylinositol 4,5-bisphosphate, and regulates signalling by Rho-family GTPases and focal adhesion kinase. This review discusses the cytoplasmic interactions of syndecan-4 and how they affect cell behaviour as a consequence of the interaction with extracellular ligands. These conclusions also offer an insight into the role of syndecan-4 in vivo, and are consistent with phenotypes generated as a consequence of abnormal syndecan-4 expression in pathologies and gene disruption studies.

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Wang, Haiyao, Haining Jin, DeannaLee M. Beauvais, and Alan C. Rapraeger. "Cytoplasmic Domain Interactions of Syndecan-1 and Syndecan-4 with α6β4 Integrin Mediate Human Epidermal Growth Factor Receptor (HER1 and HER2)-dependent Motility and Survival." Journal of Biological Chemistry 289, no. 44 (September 8, 2014): 30318–32. http://dx.doi.org/10.1074/jbc.m114.586438.

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Epithelial cells are highly dependent during wound healing and tumorigenesis on the α6β4 integrin and its association with receptor tyrosine kinases. Previous work showed that phosphorylation of the β4 subunit upon matrix engagement depends on the matrix receptor syndecan (Sdc)-1 engaging the cytoplasmic domain of the β4 integrin and coupling of the integrin to human epidermal growth factor receptor-2 (HER2). In this study, HER2-dependent migration activated by matrix engagement is compared with migration stimulated by EGF. We find that whereas HER2-dependent migration depends on Sdc1, EGF-dependent migration depends on a complex consisting of human epidermal growth factor receptor-1 (HER1, commonly known as EGFR), α6β4, and Sdc4. The two syndecans recognize distinct sites at the extreme C terminus of the β4 integrin cytoplasmic domain. The binding motif in Sdc1 is QEEXYX, composed in part by its syndecan-specific variable (V) region and in part by the second conserved (C2) region that it shares with other syndecans. A cell-penetrating peptide containing this sequence competes for HER2-dependent epithelial migration and carcinoma survival, although it is without effect on the EGFR-stimulated mechanism. β4 mutants bearing mutations specific for Sdc1 and Sdc4 recognition act as dominant negative mutants to block cell spreading or cell migration that depends on HER2 or EGFR, respectively. The interaction of the α6β4 integrin with the syndecans appears critical for it to be utilized as a signaling platform; migration depends on α3β1 integrin binding to laminin 332 (LN332; also known as laminin 5), whereas antibodies that block α6β4 binding are without effect. These findings indicate that specific syndecan family members are likely to have key roles in α6β4 integrin activation by receptor tyrosine kinases.

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Volta, Manuela, Stefano Calza, Anne M. Roberts, and Roland G. Roberts. "Characterisation of the interaction between syndecan-2, neurofibromin and CASK: Dependence of interaction on syndecan dimerization." Biochemical and Biophysical Research Communications 391, no. 2 (January 2010): 1216–21. http://dx.doi.org/10.1016/j.bbrc.2009.12.043.

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Derksen, Patrick W. B., Robert M. J. Keehnen, Ludo M. Evers, Marinus H. J. van Oers, Marcel Spaargaren, and Steven T. Pals. "Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma." Blood 99, no. 4 (February 15, 2002): 1405–10. http://dx.doi.org/10.1182/blood.v99.4.1405.

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Heparan sulfate proteoglycans (HSPGs) play a crucial role in growth regulation by assembling signaling complexes and presenting growth factors to their cognate receptors. Within the immune system, expression of the HSPG syndecan-1 (CD138) is characteristic of terminally differentiated B cells, ie, plasma cells, and their malignant counterpart, multiple myeloma (MM). This study explored the hypothesis that syndecan-1 might promote growth factor signaling and tumor growth in MM. For this purpose, the interaction was studied between syndecan-1 and hepatocyte growth factor (HGF), a putative paracrine and autocrine regulator of MM growth. The study demonstrates that syndecan-1 is capable of binding HGF and that this growth factor is indeed a potent stimulator of MM survival and proliferation. Importantly, the interaction of HGF with heparan sulfate moieties on syndecan-1 strongly promotes HGF-mediated signaling, resulting in enhanced activation of Met, the receptor tyrosine kinase for HGF. Moreover, HGF binding to syndecan-1 promotes activation of the phosphatidylinositol 3-kinase/protein kinase B and RAS/mitogen-activated protein kinase pathways, signaling routes that have been implicated in the regulation of cell survival and proliferation, respectively. These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.

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Baciu, P. C., S. Saoncella, S. H. Lee, F. Denhez, D. Leuthardt, and P. F. Goetinck. "Syndesmos, a protein that interacts with the cytoplasmic domain of syndecan-4, mediates cell spreading and actin cytoskeletal organization." Journal of Cell Science 113, no. 2 (January 15, 2000): 315–24. http://dx.doi.org/10.1242/jcs.113.2.315.

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Syndecan-4 is a cell surface heparan sulfate proteoglycan which, in cooperation with integrins, transduces signals for the assembly of focal adhesions and actin stress fibers in cells plated on fibronectin. The regulation of these cellular events is proposed to occur, in part, through the interaction of the cytoplasmic domains of these transmembrane receptors with intracellular proteins. To identify potential intracellular proteins that interact with the cytoplasmic domain of syndecan-4, we carried out a yeast two-hybrid screen in which the cytoplasmic domain of syndecan-4 was used as bait. As a result of this screen, we have identified a novel cellular protein that interacts with the cytoplasmic domain of syndecan-4 but not with those of the other three syndecan family members. The interaction involves both the membrane proximal and variable central regions of the cytoplasmic domain. We have named this cDNA and encoded protein syndesmos. Syndesmos is ubiquitously expressed and can be myristylated. Consistent with its myristylation and syndecan-4 association, syndesmos colocalizes with syndecan-4 in the ventral plasma membranes of cells plated on fibronectin. When overexpressed in NIH 3T3 cells, syndesmos enhances cell spreading, actin stress fiber and focal contact formation in a serum-independent manner.

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Choi, Youngsil, Seungin Kim, Junghyun Lee, Sung-gun Ko, Weontae Lee, Inn-Oc Han, Anne Woods, and Eok-Soo Oh. "The oligomeric status of syndecan-4 regulates syndecan-4 interaction with α-actinin." European Journal of Cell Biology 87, no. 10 (October 2008): 807–15. http://dx.doi.org/10.1016/j.ejcb.2008.04.005.

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Cohen, Alexandra R., Daniel F. Wood, Shirin M. Marfatia, Zenta Walther, Athar H. Chishti, and James Melvin Anderson. "Human CASK/LIN-2 Binds Syndecan-2 and Protein 4.1 and Localizes to the Basolateral Membrane of Epithelial Cells." Journal of Cell Biology 142, no. 1 (July 13, 1998): 129–38. http://dx.doi.org/10.1083/jcb.142.1.129.

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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.

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Miftode, Radu-Stefan, Ionela-Lăcrămioara Şerban, Amalia-Stefana Timpau, Ionela-Larisa Miftode, Adriana Ion, Ana-Maria Buburuz, Alexandru-Dan Costache, and Irina-Iuliana Costache. "Syndecan-1: A Review on Its Role in Heart Failure and Chronic Liver Disease Patients’ Assessment." Cardiology Research and Practice 2019 (November 11, 2019): 1–7. http://dx.doi.org/10.1155/2019/4750580.

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The close connection and interaction between the cardiac and the liver functions are well-known, as cirrhotic cardiomyopathy is an important clinical entity which best describes the mutual pathogenical influence between these two organs. Due to the fact that cardiac dysfunction in patients with chronic hepatic disorders is oligosymptomatic or even asymptomatic, an early diagnosis represents a challenge for every physician. Syndecan-1—a transmembrane proteoglycan that exerts its functions mainly via its heparane sulfate chains—is a very promising biomarker, correlated not only with the degree of cardiac fibrosis but also with the severity of liver fibrosis. Many studies highlighted its role in the development of cardiac fibrosis or atherogenesis, being significantly correlated with the activity of angiotensin II. Multiple evidence revealed that syndecan-1 is also associated with tissue injury and may regulate inflammatory and regenerative responses, being considered a protective molecule that limits the inflammation and reduces cardiac remodelling and dysfunction after a myocardial infarction. Syndecan-1 may also be used as a reliable biomarker for the noninvasive assessment of liver fibrosis. Under various fibrogenetic conditions, shedding of syndecan’s extracellular domain took place, becoming a soluble form that binds different growth factors and inhibits further fibrosis. This complex molecule is also involved in the lipid metabolism, by altering the clearance of cholesterol particles, and in chronic hepatitis, by enhancing the viral invasion of hepatocytes. Due to the growing interest in this biomarker, multiple studies aimed at revealing syndecan-1’s potential benefits in the diagnosis and prognosis assessment in patients with heart failure or chronic liver disorders. In this review, we review the mechanisms by which syndecan-1 exerts its effects and the possible perspectives opened by its use as a dual cardio-hepatic biomarker.

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Slimani, Hocine, Nathalie Charnaux, Elisabeth Mbemba, Line Saffar, Roger Vassy, Claudio Vita, and Liliane Gattegno. "Interaction of RANTES with syndecan-1 and syndecan-4 expressed by human primary macrophages." Biochimica et Biophysica Acta (BBA) - Biomembranes 1617, no. 1-2 (October 2003): 80–88. http://dx.doi.org/10.1016/j.bbamem.2003.09.006.

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Kon, Shigeyuki, Masahiro Ikesue, Chiemi Kimura, Momoe Aoki, Yosuke Nakayama, Yoshinari Saito, Daisuke Kurotaki, et al. "Syndecan-4 protects against osteopontin-mediated acute hepatic injury by masking functional domains of osteopontin." Journal of Experimental Medicine 205, no. 1 (December 24, 2007): 25–33. http://dx.doi.org/10.1084/jem.20071324.

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Osteopontin (OPN) is a T helper type 1 immunoregulatory cytokine that plays a critical role in various inflammatory disorders. OPN exerts proinflammatory reactions through interaction with integrin receptors. OPN function can be modulated by protease digestion. However, the molecular mechanisms that regulate OPN function in vivo have not been elucidated. There are two putative heparin-binding domains (HBDs) within the OPN molecule, which may bind both heparin and heparin-like glycosaminoglycans such as syndecan. We show that expression of OPN and syndecan-4 is significantly up-regulated after concanavalin-A (ConA) injection. Syndecan-4 binds to one of the HBDs of OPN, which overlaps with the thrombin cleavage site of OPN. When OPN is associated with syndecan-4, syndecan-4 masks both the thrombin cleavage and the integrin binding sites within OPN. Importantly, syndecan-4–deficient (Syn4KO) mice are more susceptible to hepatic injury, and the thrombin-cleaved form of OPN is significantly elevated in Syn4KO mice as compared with wild-type mice after ConA injection. Finally, we demonstrate that administration of purified syndecan-4 protects mice from ConA-induced hepatic injury. Thus, syndecan-4 is a critical intrinsic regulator of inflammatory reactions via its effects on OPN function and is a potential novel therapeutic tool for treating inflammatory diseases.

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Imai, Shinji, Marko Kaksonen, Erkki Raulo, Tarja Kinnunen, Carole Fages, Xiaojuan Meng, Merja Lakso, and Heikki Rauvala. "Osteoblast Recruitment and Bone Formation Enhanced by Cell Matrix–associated Heparin-binding Growth-associated Molecule (HB-GAM)." Journal of Cell Biology 143, no. 4 (November 16, 1998): 1113–28. http://dx.doi.org/10.1083/jcb.143.4.1113.

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Bone has an enormous capacity for growth, regeneration, and remodeling. This capacity is largely due to induction of osteoblasts that are recruited to the site of bone formation. The recruitment of osteoblasts has not been fully elucidated, though the immediate environment of the cells is likely to play a role via cell– matrix interactions. We show here that heparin-binding growth-associated molecule (HB-GAM), an extracellular matrix–associated protein that enhances migratory responses in neurons, is prominently expressed in the cell matrices that act as target substrates for bone formation. Intriguingly, N-syndecan, which acts as a receptor for HB-GAM, is expressed by osteoblasts/osteoblast precursors, whose ultrastructural phenotypes suggest active cell motility. The hypothesis that HB-GAM/N-syndecan interaction mediates osteoblast recruitment, as inferred from developmental studies, was tested using osteoblast-type cells that express N-syndecan abundantly. These cells migrate rapidly to HB-GAM in a haptotactic transfilter assay and in a migration assay where HB-GAM patterns were created on culture wells. The mechanism of migration is similar to that previously described for the HB-GAM–induced migratory response of neurons. Our hypothesis that HB-GAM/N-syndecan interaction participates in regulation of osteoblast recruitment was tested using two different in vivo models: an adjuvant-induced arthritic model and a transgenic model. In the adjuvant-induced injury model, the expression of HB-GAM and of N-syndecan is strongly upregulated in the periosteum accompanying the regenerative response of bone. In the transgenic model, the HB-GAM expression is maintained in mesenchymal tissues with the highest expression in the periosteum. The HB-GAM transgenic mice develop a phenotype characterized by an increased bone thickness. HB-GAM may thus play an important role in bone formation, probably by mediating recruitment and attachment of osteoblasts/osteoblast precursors to the appropriate substrates for deposition of new bone.

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HALDEN, Yvonne, Angelika REK, Werner ATZENHOFER, Laszlo SZILAK, Astrid WABNIG, and Andreas J. KUNGL. "Interleukin-8 binds to syndecan-2 on human endothelial cells." Biochemical Journal 377, no. 2 (January 15, 2004): 533–38. http://dx.doi.org/10.1042/bj20030729.

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Application of reverse transcription–PCR to total RNA prepared from TNF-α (tumour necrosis factor-α)-stimulated HUVECs (human umbilical vein endothelial cells) revealed that the syndecan-2 mRNA was up-regulated by this inflammatory stimulus. By immunoprecipitation using an anti-syndecan-2 antibody on TNF-α-stimulated HUVEC lysates, inflammation-induced interleukin-8 was found to be an interaction partner of this HS (heparan sulphate) proteoglycan, but not of any other syndecan on these cells. The glycosylated [Syn2ect(+HS)] and non-glycosylated [Syn2ect(−HS)] forms of Syn2ect (the syndecan-2 ectodomain) were purified from a stably transfected human cell line and from a bacterial expression system respectively. By CD spectroscopy, Syn2ect was found to adopt an all-β secondary structure. The dissociation constant of Syn2ect(+HS) with respect to interleukin-8 binding was determined by isothermal fluorescence titrations to be 23 nM. Despite its lack of HS chains, Syn2ect(−HS) exhibited significant binding to the chemokine, with a Kd of >1 µM. Thus, in addition to glycosaminoglycan binding, protein–protein contacts might also contribute to the chemokine–proteoglycan interaction.

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Bischof, Daniela, Sherine F. Elsawa, George Mantchev, Juhan Yoon, Grace E. Michels, Allan Nilson, Shari L. Sutor, et al. "Selective activation of TACI by syndecan-2." Blood 107, no. 8 (April 15, 2006): 3235–42. http://dx.doi.org/10.1182/blood-2005-01-0256.

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Abstract B-lymphocyte homeostasis and function are regulated by complementary actions of the TNFR family members TACI, BCMA, and BAFF-R, which are expressed by mature B cells. How these receptors are differentially activated is not entirely understood, because the primary ligand BAFF binds to all three. We searched for alternative ligands for TACI using recombinant TACI-Fc fusion protein as a probe and identified syndecan-2 as a new binding partner. TACI binding appears to require heparan sulfate posttranslational modifications of syndecan-2, because free heparin or pretreatment with heparitinase blocked the interaction. Syndecan-2 bound TACI but bound neither BAFF-R nor BCMA. Transfected cells expressing syndecan-2 activated signaling through TACI, as indicated by an NFAT-specific reporter. Syndecan-1 and syndecan-4 were also able to induce TACI signaling in a similar manner. This is the first identification of ligands that selectively activate TACI without simultaneously triggering BCMA or BAFF-R. This finding may help explain the alternative outcomes of signaling from this family of receptors in B cells.

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Bespalov, Maxim M., Yulia A. Sidorova, Sarka Tumova, Anni Ahonen-Bishopp, Ana Cathia Magalhães, Evgeny Kulesskiy, Mikhail Paveliev, Claudio Rivera, Heikki Rauvala, and Mart Saarma. "Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin." Journal of Cell Biology 192, no. 1 (January 3, 2011): 153–69. http://dx.doi.org/10.1083/jcb.201009136.

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Glial cell line–derived neurotrophic factor (GDNF) family ligands (GFLs) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson’s disease. Soluble GFLs bind to a ligand-specific glycosylphosphatidylinositol-anchored coreceptor (GDNF family receptor α) and signal through the receptor tyrosine kinase RET. In this paper, we show that all immobilized matrix-bound GFLs, except persephin, use a fundamentally different receptor. They interact with syndecan-3, a transmembrane heparan sulfate (HS) proteoglycan, by binding to its HS chains with high affinity. GFL–syndecan-3 interaction mediates both cell spreading and neurite outgrowth with the involvement of Src kinase activation. GDNF promotes migration of cortical neurons in a syndecan-3–dependent manner, and in agreement, mice lacking syndecan-3 or GDNF have a reduced number of cortical γ-aminobutyric acid–releasing neurons, suggesting a central role for the two molecules in cortical development. Collectively, syndecan-3 may directly transduce GFL signals or serve as a coreceptor, presenting GFLs to the signaling receptor RET.

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Fages, C., M. Kaksonen, T. Kinnunen, E. L. Punnonen, and H. Rauvala. "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." Journal of Cell Science 111, no. 20 (October 15, 1998): 3073–80. http://dx.doi.org/10.1242/jcs.111.20.3073.

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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.

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Fages, Carole, Marko Kaksonen, Tarja Kinnunen, Eeva-Liisa Punnonen, and Heikki Rauvala. "Regulation of mRNA localization by transmembrane signalling: Local interaction of HB-GAM (heparin-binding growth-associated molecule) with the cell surface localizes β-actin mRNA." Journal of Cell Science 111, no. 20 (January 15, 1998): 3073–80. http://dx.doi.org/10.1242/jcs.20.111.3073.

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ABSTRACT 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 β-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 β- 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 β-actin mRNA.

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Wang, Haiyao, LuAnn Leavitt, Ravishankar Ramaswamy, and Alan C. Rapraeger. "Interaction of Syndecan and α6β4 Integrin Cytoplasmic Domains." Journal of Biological Chemistry 285, no. 18 (February 24, 2010): 13569–79. http://dx.doi.org/10.1074/jbc.m110.102137.

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Verderio, Elisabetta, and Alessandra Scarpellini. "Significance of the Syndecan-4-Transglutaminase-2 Interaction." Scientific World JOURNAL 10 (2010): 1073–77. http://dx.doi.org/10.1100/tsw.2010.102.

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Elhassan, AKB, AM Suleiman, NIA El Dawi, and Sofia B. Mohamed. "Detection of Micro-invasion in Sudanese Oral Verrucous Carcinoma Samples Using Syndecan-1 Stain." Biomarkers in Cancer 11 (January 2019): 1179299X1986195. http://dx.doi.org/10.1177/1179299x19861957.

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Aim: Verrucous carcinoma (VC) is a low-grade rare variant of squamous cell carcinoma (SCC). Syndecan-1 (CD138) is a heparan sulfate proteoglycan which participates in cell-to-cell adhesion and cell-matrix interaction. Being misled by the apparent non-aggressive nature of VC, some clinicians and pathologists believe that this tumor is not an aggressive tumor, not realizing the fact that some of these lesions may contain nests or foci of well-differentiated SCC. This study aimed to assess syndecan-1 expression of VC and detection of micro-invasion in VC using syndecan-1 immunohistochemical (IHC) stain. Methods: Observational analytical study of 34 paraffin block of VC cases and 24 cases of variable grades of oral epithelial dysplasia. Cases were stained by hematoxylin and eosin (H&E) and then IHC stain for syndecan-1 was applied. Nine paraffin blocks from specimens of normal oral mucosa were used as the reference group for syndecan-1 stain positivity. Results: In this study, we found that 32 (94.1%) out of 34 of verrucous carcinoma cases showed loss of syndecan-1 expression. Moreover, highly statistically significant association was found between the presence of suggestive micro-invasion in H&E and loss of syndecan-1 expression in micro-invasive area in the same case. Conclusions: In conclusion, syndecan-1 stain can be used as a biomarker in detection of micro-invasion in verrucous carcinoma.

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Jang, Bohee, Ayoung Kim, Yejin Lee, Jisun Hwang, Jee-Young Sung, Eun-Ju Jang, Yong-Nyun Kim, et al. "Substituted Syndecan-2-Derived Mimetic Peptides Show Improved Antitumor Activity over the Parent Syndecan-2-Derived Peptide." International Journal of Molecular Sciences 23, no. 11 (May 24, 2022): 5888. http://dx.doi.org/10.3390/ijms23115888.

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We previously showed that a synthetic peptide (S2-P) corresponding to a portion of the human syndecan-2 (SDC2) sequence can bind to the pro-domain of matrix metalloproteinase-7 (MMP-7) to inhibit colon cancer activities. Since S2-P had a relatively weak binding affinity for the MMP-7 pro-domain, we herein modified the amino acid sequence of S2-P to improve the anticancer potential. On the basis of the interaction structure of S2-P and MMP-7, four peptides were generated by replacing amino acids near Tyr 51, which is critical for the interaction. The SDC2-mimetic peptides harboring an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-D) or with an Ala-to-Phe substitution at the N-terminal side of Tyr 51 and an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-FE) showed improved interaction affinities for the MMP-7 pro-domain. Compared to S2-P, S2-FE was better able to inhibit the SDC2–MMP-7 interaction, the cell surface localization of MMP-7, the gelatin degradation activity of MMP-7, and the cancer activities (cell migration, invasion, and colony-forming activity) of human HCT116 colon cancer cells in vitro. In vivo, S2-FE inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a xenograft mouse model. Together, these data suggest that S2-FE could be useful therapeutic anticancer peptides for colon cancer.

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Kim, Minseon, and Yongae Kim. "NMR Structural Study of Syndecan-4 Transmembrane Domain with Cytoplasmic Region." Molecules 28, no. 23 (November 29, 2023): 7855. http://dx.doi.org/10.3390/molecules28237855.

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Syndecan-4 (SDC4) consists of transmembrane heparan sulfate proteoglycan (HSPG) belonging to the syndecan family. It is present in most cell types of Mammalia. Its structure contains a heparan-sulfate-modified extracellular domain, a single transmembrane domain, and a short C-terminal cytoplasmic domain. Regarding the overall cellular function of SDC4, other cells or ligands can bind to its ecto-domain. In addition, 4,5-bisphosphate phosphatidylinositol (PIP2) or protein kinase Cα can bind to its cyto-domain to activate downstream signaling pathways. To understand the signal transduction mechanism of syndecan, it is important to know the interactions between their actual structure and function in vivo. Therefore, it is important to identify the structure of SDC4 to understand the ligand binding behavior of SDC4. In this study, expression and purification were performed to reveal structures of the short ecto-domain, the transmembrane domain, and the cytoplasmic domain of Syd4-eTC (SDC4). Solution-state NMR spectroscopy and solid-state NMR spectroscopy were used to study the structure of Syd4-eTC in membrane environments and to demonstrate the interaction between Syd4-eTC and PIP2.

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Couchman, J. R., and A. Woods. "Syndecan-4 and integrins: combinatorial signaling in cell adhesion." Journal of Cell Science 112, no. 20 (October 15, 1999): 3415–20. http://dx.doi.org/10.1242/jcs.112.20.3415.

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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(α) 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.

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Whiteford, James R., Xiaojie Xian, Claire Chaussade, Bart Vanhaesebroeck, Sussan Nourshargh, and John R. Couchman. "Syndecan-2 is a novel ligand for the protein tyrosine phosphatase receptor CD148." Molecular Biology of the Cell 22, no. 19 (October 2011): 3609–24. http://dx.doi.org/10.1091/mbc.e11-02-0099.

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Syndecan-2 is a heparan sulfate proteoglycan that has a cell adhesion regulatory domain contained within its extracellular core protein. Cell adhesion to the syndecan-2 extracellular domain (S2ED) is β1 integrin dependent; however, syndecan-2 is not an integrin ligand. Here the protein tyrosine phosphatase receptor CD148 is shown to be a key intermediary in cell adhesion to S2ED, with downstream β1 integrin–mediated adhesion and cytoskeletal organization. We show that S2ED is a novel ligand for CD148 and identify the region proximal to the transmembrane domain of syndecan-2 as the site of interaction with CD148. A mechanism for the transduction of the signal from CD148 to β1 integrins is elucidated requiring Src kinase and potential implication of the C2β isoform of phosphatidylinositol 3 kinase. Our data uncover a novel pathway for β1 integrin–mediated adhesion of importance in cellular processes such as angiogenesis and inflammation.

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Hsueh, Yi-Ping, Fu-Chia Yang, Viktor Kharazia, Scott Naisbitt, Alexandra R. Cohen, Richard J. Weinberg, and Morgan Sheng. "Direct Interaction of CASK/LIN-2 and Syndecan Heparan Sulfate Proteoglycan and Their Overlapping Distribution in Neuronal Synapses." Journal of Cell Biology 142, no. 1 (July 13, 1998): 139–51. http://dx.doi.org/10.1083/jcb.142.1.139.

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

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Horowitz, Arie, Eugene Tkachenko, and Michael Simons. "Fibroblast growth factor–specific modulation of cellular response by syndecan-4." Journal of Cell Biology 157, no. 4 (May 13, 2002): 715–25. http://dx.doi.org/10.1083/jcb.200112145.

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Proteoglycans participate in growth factor interaction with the cell surface through their heparan sulfate chains (HS), but it is not known if they are otherwise involved in growth factor signaling. It appears now that the syndecan-4 core protein, a transmembrane proteoglycan shown previously to bind phosphatidylinositol 4,5-bisphosphate (PIP2) and activate PKCα, participates in mediating the effects of fibroblast growth factor (FGF)2 on cell function. Mutations in the cytoplasmic tail of syndecan-4 that either reduced its affinity to PIP2 (PIP2−) or disrupted its postsynaptic density 95, disk large, zona occludens-1 (PDZ)-dependent binding (PDZ−) produced a FGF2-specific dominant negative phenotype in endothelial cells as evidenced by the marked decline of their migration and proliferation rates and the impairment of their capacity to form tubes. In both cases, the molecular mechanism was determined to consist of a decrease in the syndecan-4–dependent activation of PKCα. This decrease was caused either by inhibition of FGF2-induced syndecan-4 dephosphorylation in the case of the PDZ− mutation or by disruption of basolateral targeting of syndecan-4 and its associated PDZ-dependent complex in the case of the PIP2− mutation. These results suggest that PKCα activation and PDZ-mediated formation of a serine/threonine phosphatase-containing complex by syndecan-4 are downstream events of FGF2 signaling.

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Sun, Zheng, Shihao Li, Fuhua Li, and Jianhai Xiang. "Bioinformatic Prediction of WSSV-Host Protein-Protein Interaction." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/416543.

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WSSV is one of the most dangerous pathogens in shrimp aquaculture. However, the molecular mechanism of how WSSV interacts with shrimp is still not very clear. In the present study, bioinformatic approaches were used to predict interactions between proteins from WSSV and shrimp. The genome data of WSSV (NC_003225.1) and the constructed transcriptome data ofF. chinensiswere used to screen potentially interacting proteins by searching in protein interaction databases, including STRING, Reactome, and DIP. Forty-four pairs of proteins were suggested to have interactions between WSSV and the shrimp. Gene ontology analysis revealed that 6 pairs of these interacting proteins were classified into “extracellular region” or “receptor complex” GO-terms. KEGG pathway analysis showed that they were involved in the “ECM-receptor interaction pathway.” In the 6 pairs of interacting proteins, an envelope protein called “collagen-like protein” (WSSV-CLP) encoded by an early virus gene “wsv001” in WSSV interacted with 6 deduced proteins from the shrimp, including three integrin alpha (ITGA), two integrin beta (ITGB), and one syndecan (SDC). Sequence analysis on WSSV-CLP, ITGA, ITGB, and SDC revealed that they possessed the sequence features for protein-protein interactions. This study might provide new insights into the interaction mechanisms between WSSV and shrimp.

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Chaves, Maria, Matheus Mendes, Maximilian Schwermann, Raquel Queiroz, Regina Coelho, Francisco Salmito, Gdayllon Meneses, Alice Martins, Ana Moreira, and Alexandre Libório. "Angiopoietin-2: A Potential Mediator of the Glycocalyx Injury in Adult Nephrotic Patients." Journal of Clinical Medicine 7, no. 11 (October 31, 2018): 401. http://dx.doi.org/10.3390/jcm7110401.

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Introduction: Glomerulopathy is a group of diseases that affect mainly young adults between the ages of 20 and 40 years. Recently, it has been demonstrated that syndecan-1, a biomarker of endothelial glycocalyx damage, is increased in nephrotic patients with near-normal renal function and it is important to endothelial dysfunction in these patients. Angiopoietin-2 (AGPT2) is an endothelial growth factor that promotes cell derangement. Here we evaluated AGPT2 levels in patients with nephrotic syndrome, near-normal renal function and the possible interaction of AGPT2 with endothelial glycocalyx derangement. Methods: This was a cross-sectional study performed from January through November 2017. Adult patients (age > 18 years) with nephrotic syndrome and without immunosuppression were included. Blood samples were drawn after a 12 h fast for later measurement of syndecan-1 and AGPT2. Mediation analyses were performed to assess the hypothesized associations of nephrotic syndrome features and AGPT2 with syndecan-1. Results: We included 65 patients, 37 (56.9%) of them female, with primary glomerular disease. Syndecan-1 in nephrotic patients was higher than in control individuals (102.8 ± 36.2 vs. 28.2 ± 9.8 ng/mL, p < 0.001). Correlation of syndecan-1 with the main features of nephrotic syndrome after adjustment for age and estmmated glomerular filtration rate (eGFR) demonstrated that syndecan-1 was significantly associated with 24-h urinary protein excretion, total cholesterol, LDL (low density lipoprotein)-cholesterol, HDL (high-density lipoprotein)-cholesterol, and triglycerides. Angiopoietin-2 was independently associated with serum albumin, 24 h urinary protein excretion, total cholesterol, and LDL-cholesterol, in addition to being strongly associated with syndecan-1 (0.461, p < 0.001). The results of the mediation analyses showed that the direct association between LDL-cholesterol and syndecan-1 was no longer significant after AGPT-2 was included in the mediation analysis. AGPT2 explained 56% of the total observed association between LDL-cholesterol and syndecan-1. Conclusion: The association between LDL-cholesterol and glycocalyx derangement in nephrotic patients is possibly mediated by AGPT2.

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Watson, L. N., M. Sasseville, R. B. Gilchrist, and D. L. Russell. "118. CHARACTERISATION OF HEPARAN SULPHATE PROTEOGLYCANS IN THE MATURING CUMULUS OOCYTE COMPLEX." Reproduction, Fertility and Development 21, no. 9 (2009): 37. http://dx.doi.org/10.1071/srb09abs118.

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Many growth factors including members of the transforming growth factor beta (TGFβ) superfamily and epidermal growth factor (Egf)-like ligands signal via interactions with heparan sulphate proteoglycans (HSPGs). Cell surface HSPGs can act by sequestering ligands at their site of action, by presenting a ligand to its signalling receptor, or by preventing ligand-receptor interaction. The oocyte secreted factors (OSF) growth differentiation factor 9 and bone morphogenetic protein 15 are members of the TGFβ superfamily that act selectively on cumulus cells. Conversely Egf-like ligands are secreted by mural granulosa cells and transmit LH-induced signals to cumulus cells. We investigated the possibility that HSPGs contribute to the spatially restricted responses these signals exert on cumulus cells. Syndecan-1 and Glypican-1 are cell surface HSPGs that are involved in numerous biological processes, including growth factor regulation, cell proliferation and differentiation. Microarray analysis showed Syndecan-1 and Glypican-1 mRNA expression induced 6-fold (P=10-9) and 3-fold (P=10-7) respectively in Egf+FSH stimulated cumulus oocyte complexes (COCs). Furthermore, Syndecan-1 and Glypican-1 mRNA were induced 27- and 16-fold respectively in COCs after hCG treatment of mice. Syndecan-1 and Glypican-1 protein was localised specifically to the COC through immunohistochemical analysis. In Vitro Maturation (IVM) of oocytes is a valuable alternative to gonadotropin mediated superovulation, but IVM COCs are less competent than those matured in vivo. Several components of the COC have been shown to be altered in IVM, including the chondroitin sulphate proteoglycan Versican. COCs from mice that underwent IVM in the presence of Egf+FSH and cilostamide for 16 hours had >16 fold reduced mRNA for Syndecan-1 when compared with In Vivo matured COCs. The lack of Syndecan-1 in IVM COCs could reduce signalling capacity of growth factors including OSFs. This may contribute to the reduced capacity of IVM oocytes to fertilise and produce a healthy embryo, and ultimately, a healthy offspring.

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Hohenester, E., S. Hussain, and J. A. Howitt. "Interaction of the guidance molecule Slit with cellular receptors." Biochemical Society Transactions 34, no. 3 (May 22, 2006): 418–21. http://dx.doi.org/10.1042/bst0340418.

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Slits are large secreted glycoproteins characterized by an unusual tandem of four LRR (leucine-rich repeat) domains in their N-terminal half. Slit proteins were initially described as repulsive guidance cues in neural development, but it has become clear that they have additional important functions, for instance in the vasculature and immune system. Genetic studies have identified two types of cellular receptors for Slits: Robos (Roundabout) and the HS (heparan sulphate) proteoglycan syndecan. The intracellular signalling cascade downstream of Robo activation is slowly being elucidated, but the mechanism of transmembrane signalling by Robo has remained obscure. No active signalling role for syndecan has yet been demonstrated. Slit–HS interactions may be important for shaping the presumed Slit gradient or presenting Slit at its target cell surface. Recent studies have mapped the binding sites for Robos and HS/heparin to discrete Slit domains. Robos bind to the second LRR domain of Slit, whereas HS/heparin binds with very high affinity to the C-terminal portion of Slit. Slit activity is likely to be modulated by physiological proteolytic cleavage in the region separating the Robo and HS/heparin-binding sites.

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Horiguchi, Kotaro, Tom Kouki, Ken Fujiwara, Takehiro Tsukada, Floren Ly, Motoshi Kikuchi, and Takashi Yashiro. "Expression of the proteoglycan syndecan-4 and the mechanism by which it mediates stress fiber formation in folliculostellate cells in the rat anterior pituitary gland." Journal of Endocrinology 214, no. 2 (May 29, 2012): 199–206. http://dx.doi.org/10.1530/joe-12-0156.

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Folliculostellate (FS) cells in the anterior pituitary gland appear to have multifunctional properties. FS cells connect to each other at gap junctions and thereby form a histological and functional network. We have performed a series of studies on network formation in FS cells and recently reported that FS cells markedly prolong their cytoplasmic processes and form numerous interconnections with neighboring FS cells in the presence of laminin, an extracellular matrix (ECM) component of the basement membrane. In this study, we investigated the mechanism of this extension of FS cell cytoplasmic processes under the influence of laminin and found that laminin promoted stress fiber formation within FS cells. Next, we noted that formation of stress fibers in FS cells was mediated by syndecan-4, a transmembrane proteoglycan that binds ECM and soluble factors via their extracellular glycosaminoglycan chain. We then observed that expressions of syndecan-4 and α-actinin (a microfilament bundling protein that cross-links actin stress fibers in FS cells) were upregulated by laminin. Using specific siRNA of syndecan-4, actin polymerization of FS cells was inhibited. Our findings suggest that FS cells received a signal from laminin–syndecan-4 interaction, which resulted in morphological changes, and that the formation of a morphological and functional network in FS cells was transduced by a syndecan-4-dependent mechanism in the presence of ECM.

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Urbinati, Chiara, Maria Milanesi, Nicola Lauro, Cinzia Bertelli, Guido David, Pasqualina D’Ursi, Marco Rusnati, and Paola Chiodelli. "HIV-1 Tat and Heparan Sulfate Proteoglycans Orchestrate the Setup of in Cis and in Trans Cell-Surface Interactions Functional to Lymphocyte Trans-Endothelial Migration." Molecules 26, no. 24 (December 10, 2021): 7488. http://dx.doi.org/10.3390/molecules26247488.

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HIV-1 transactivating factor Tat is released by infected cells. Extracellular Tat homodimerizes and engages several receptors, including integrins, vascular endothelial growth factor receptor 2 (VEGFR2) and heparan sulfate proteoglycan (HSPG) syndecan-1 expressed on various cells. By means of experimental cell models recapitulating the processes of lymphocyte trans-endothelial migration, here, we demonstrate that upon association with syndecan-1 expressed on lymphocytes, Tat triggers simultaneously the in cis activation of lymphocytes themselves and the in trans activation of endothelial cells (ECs). This “two-way” activation eventually induces lymphocyte adhesion and spreading onto the substrate and vascular endothelial (VE)-cadherin reorganization at the EC junctions, with consequent endothelial permeabilization, leading to an increased extravasation of Tat-presenting lymphocytes. By means of a panel of biochemical activation assays and specific synthetic inhibitors, we demonstrate that during the above-mentioned processes, syndecan-1, integrins, FAK, src and ERK1/2 engagement and activation are needed in the lymphocytes, while VEGFR2, integrin, src and ERK1/2 are needed in the endothelium. In conclusion, the Tat/syndecan-1 complex plays a central role in orchestrating the setup of the various in cis and in trans multimeric complexes at the EC/lymphocyte interface. Thus, by means of computational molecular modelling, docking and dynamics, we also provide a characterization at an atomic level of the binding modes of the Tat/heparin interaction, with heparin herein used as a structural analogue of the heparan sulfate chains of syndecan-1.

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Zimmermann, Pascale, Zhe Zhang, Gisèle Degeest, Eva Mortier, Iris Leenaerts, Christien Coomans, Joachim Schulz, Francisca N’Kuli, Pierre J. Courtoy, and Guido David. "Syndecan Recyling Is Controlled by Syntenin-PIP2 Interaction and Arf6." Developmental Cell 9, no. 3 (September 2005): 377–88. http://dx.doi.org/10.1016/j.devcel.2005.07.011.

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Zimmermann, Pascale, Zhe Zhang, Gisèle Degeest, Eva Mortier, Iris Leenaerts, Christien Coomans, Joachim Schulz, Francisca N’Kuli, Pierre J. Courtoy, and Guido David. "Syndecan Recycling Is Controlled by Syntenin-PIP2 Interaction and Arf6." Developmental Cell 9, no. 5 (November 2005): 721. http://dx.doi.org/10.1016/j.devcel.2005.10.011.

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Zhao, Tingting, Li Cui, Xiangqian Yu, Zhonghai Zhang, Qi Chen, and Xiuguo Hua. "Proteome Analysis Reveals Syndecan 1 Regulates Porcine Sapelovirus Replication." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4386. http://dx.doi.org/10.3390/ijms21124386.

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Porcine sapelovirus A (PSV) is a single stranded, positive-sense, non-enveloped RNA virus that causes enteritis, pneumonia, polioencephalomyelitis, and reproductive disorders in pigs. Research on PSV infection and interaction with host cells is unclear. In this study, we applied tandem mass tag proteomics analysis to investigate the differentially expressed proteins (DEPs) in PSV-infected pig kidney (PK)-15 cells and explored the interactions between PSV and host cells. Here we mapped 181 DEPs, including 59 up-regulated and 122 down-regulated DEPs. Among them, osteopontin (SPP1), induced protein with tetratricopeptide repeats 5 (IFIT5), ISG15 ubiquitin-like modifier (ISG15), vinculin (VCL), and syndecan-1 (SDC1) were verified significantly changed using RT-qPCR. Additionally, overexpression of SDC1 promoted PSV viral protein (VP)1 synthesis and virus titer, and silencing of SDC1 revealed the opposite results. Our findings show that SDC1 is a novel host protein and plays crucial roles in regulating PSV replication.

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Arnold, Katelyn, Yongmei Xu, Erica M. Sparkenbaugh, Miaomiao Li, Xiaorui Han, Xing Zhang, Ke Xia, et al. "Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure." Science Translational Medicine 12, no. 535 (March 18, 2020): eaav8075. http://dx.doi.org/10.1126/scitranslmed.aav8075.

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Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and N-acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of N-acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N-acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.

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Keller-Pinter, A., L. Mendler, and L. Dux. "EM.P.1.05 Heparan sulfate-dependent interaction of myostatin and syndecan-4." Neuromuscular Disorders 19, no. 8-9 (September 2009): 550. http://dx.doi.org/10.1016/j.nmd.2009.06.026.

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Kim, Heeyoun, Jiho Yoo, Inhwan Lee, Ying Jin Kang, Hyun-Soo Cho, and Weontae Lee. "Crystal structure of syndesmos and its interaction with Syndecan-4 proteoglycan." Biochemical and Biophysical Research Communications 463, no. 4 (August 2015): 762–67. http://dx.doi.org/10.1016/j.bbrc.2015.06.010.

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Fan, Shilong, Yingang Feng, Zhiyi Wei, Bin Xia, and Weimin Gong. "Solution Structure of Synbindin Atypical PDZ Domain and Interaction with Syndecan-2." Protein & Peptide Letters 16, no. 2 (February 1, 2009): 189–95. http://dx.doi.org/10.2174/092986609787316342.

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Journal articles on the topic 'Syndecan interaction'

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