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PubMed1996

Embryonic expression patterns of Xenopus syndecans.

Syndecans are a family of heparan sulfate proteoglycans implicated in cell-cell and cell-matrix interactions. To investigate the roles of syndecans in early development, we identified three syndecan family members in Xenopus laevis: Xsyn-1, Xsyn-2, and Xsyn-3. Xsyn-1 and Xsyn-2 are maternal mRNAs localized to the animal pole in blastulae, and are expressed in the ectoderm of gastrulae. In neurulae, Xsyn-1 is restricted to non-neural ectoderm and Xsyn-2 is restricted to neural ectoderm. In tailbud embryos, the three syndecans are expressed in adjacent, non-overlapping patterns. Xsyn-2 is expressed in the heart while Xsyn-1 is expressed in the underlying anterior endoderm. Xsyn-3 is expressed in the hindbrain, midbrain, and forebrain, while Xsyn-2 is expressed in the intervening regions. These results suggest that different members of the syndecan family have distinct developmental roles, perhaps acting as barriers to define tissue boundaries.

Amino Acid Sequence↗
PubMed2002

Glycobiology of the synapse: the role of glycans in the formation, maturation, and modulation of synapses.

Synapses, which are the fundamental functional unit of the nervous system, are considered to be highly specialized cell adhesion structures. Studies since the 1960s demonstrated that various carbohydrates and glycoproteins are expressed in synapses in the central and peripheral nervous system. Although the functional roles of these synaptic carbohydrates and glycoproteins remain to be determined, rapidly accumulating data suggest that they may play critical roles in the formation, maturation, and functional modulation of synapses.

Agrin↗
PubMed2003

Association of the type 1 inositol (1,4,5)-trisphosphate receptor with 4.1N protein in neurons.

The type 1 inositol (1,4,5)-trisphosphate receptor (InsP(3)R1) is an intracellular calcium (Ca(2+)) release channel that plays an important role in neuronal function. In yeast two-hybrid screen of rat brain cDNA library with the InsP(3)R1 carboxy-terminal bait we isolated multiple clones of neuronal cytoskeletal protein 4.1N. We mapped the 4.1N-interaction site to a short fragment (50 amino acids) within the carboxy-terminal tail of the InsP(3)R1 and the InsP(3)R1-interaction site to the carboxy-terminal domain (CTD) of 4.1N. We established that InsP(3)R1 carboxy-terminal binds selectively to the CTDDelta alternatively spliced form of the 4.1N protein. In biochemical experiments we demonstrated that 4.1N and InsP(3)R1 specifically associate in vitro. We showed that both 4.1N and InsP(3)R1 were enriched in synaptic locations and immunoprecipitated the 4.1N-InsP(3)R1 complex from rat brain synaptosomes. In biochemical experiments we demonstrated a possibility of InsP(3)R1-4.1N-CASK-syndecan-2 quaternary complex formation. From our findings we hypothesize that InsP(3)R1-4.1N association may play a role in InsP(3)R1 localization or Ca(2+) signaling in neurons.

Alternative Splicing↗
PubMed1999

A role for a PDZ protein in the early secretory pathway for the targeting of proTGF-alpha to the cell surface.

In general, plasma membrane integral proteins, such as the membrane-anchored growth factor proTGF-alpha, are assumed to be transported to the cell surface via a nonregulated, constitutive pathway. proTGF-alpha C-terminal mutants are retained in an early secretory compartment. Here, using a two-hybrid screen, we identify two TACIPs (proTGF-alpha cytoplasmic domain-interacting proteins) that contain PDZ domains and do not interact with proTGF-alpha C-terminal mutants. The binding specificity of one of them, TACIP18 (previously identified and named Syntenin or mda-9), coincides with that of the component that possibly mediates the normal trafficking of proTGF-alpha. TACIP18 colocalizes and interacts specifically with immature, intracellular forms of proTGF-alpha. Therefore, it appears that the interaction of TACIP18 with proTGF-alpha in the early secretory pathway is necessary for the targeting of the latter to the cell surface.

Amino Acid Sequence↗
PubMed1998

Syndecan-1 is up-regulated in ras-transformed intestinal epithelial cells.

The syndecans, a family of cell-surface heparan sulphate proteoglycans, have been proposed to mediate cellular interactions with extracellular effector molecules, such as growth factors and components of the extracellular matrix, during critical phases of development. Transcripts of all four syndecans are expressed at varying levels in the developing rat intestine and in a series of immature rat intestinal epithelial cell lines. In addition, we report the novel finding that, in the intestinal epithelial cell lines, expression of syndecan-1 transcript is up-regulated by transformation with activated H-ras. This is in contrast to other cell lines in which ras transformation is associated with a decrease in syndecan-1 levels. The observed increase in the syndecan-1 occurs as a result of increased transcription and can be correlated with the degree of transformation of the IEC-18 cells. Transformation is also associated with a decrease in apparent molecular weight and increased shedding of the proteoglycan into the culture medium. Increased shedding of syndecan-1 into the culture medium after transformation with H-ras may contribute to the disruption of proteoglycan interactions with the extracellular matrix, leading to alterations in cell adhesion and organization.

Aging↗
PubMed1995

Expression of a Xenopus counterpart of mammalian syndecan 2 during embryogenesis.

We have identified a Xenopus cDNA, XS-2, by screening a Xenopus embryonic stage-22-24 cDNA library with a DNA probe encoding the transmembrane and cytoplasmic domains of mouse syndecan 1. The 1.4 kb cDNA consists of an open reading frame of 642 nucleotides encoding a protein of 191 amino acids. The predicted protein of 20869 Da contains a 25-amino acid putative transmembrane domain and a 32-amino acid putative cytoplasmic domain, both of which are highly similar to the corresponding regions of rat syndecan 2 (92% identity) and to a lesser degree those of rat syndecans 1, 3 and 4 (62, 64 and 78% respectively). The putative N-terminal ectodomain contains a possible attachment site for heparan sulphate, identical with the comparable glycosaminoglycan-attachment sequence of rat syndecan 2. Polyclonal antisera raised against recombinant ectodomain of XS-2, expressed as a fusion protein, recognized a heparan sulphate proteoglycan in XTC cell-culture medium. This proteoglycan bound to DEAE-Sephacel and was eluted with 1 M NaCl; digestion with heparitinase but not chondroitinase ABC resulted in the identification of a 46 kDa protein by these antisera. Northern-blot analysis indicated that XS-2 identifies two Xenopus mRNA species approx. 4 and 2 kb in size in embryos ranging in maturation from the 64-cell stage to stage 54. These results demonstrate that a heparan sulphate proteoglycan, similar to syndecan 2, is expressed during Xenopus embryogenesis.

Amino Acid Sequence↗
PubMed2001

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

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

Animals↗
PubMed1997

Syntenin, a PDZ protein that binds syndecan cytoplasmic domains.

The syndecans are transmembrane proteoglycans that place structurally heterogeneous heparan sulfate chains at the cell surface and a highly conserved polypeptide in the cytoplasm. Their versatile heparan sulfate moieties support various processes of molecular recognition, signaling, and trafficking. Here we report the identification of a protein that binds to the cytoplasmic domains of the syndecans in yeast two-hybrid screens, surface plasmon resonance experiments, and ligand-overlay assays. This protein, syntenin, contains a tandem repeat of PDZ domains that reacts with the FYA C-terminal amino acid sequence of the syndecans. Recombinant enhanced green fluorescent protein (eGFP)-syntenin fusion proteins decorate the plasmamembrane and intracellular vesicles, where they colocalize and cosegregate with syndecans. Cells that overexpress eGFP-syntenin show numerous cell surface extensions, suggesting effects of syntenin on cytoskeleton-membrane organization. We propose that syntenin may function as an adaptor that couples syndecans to cytoskeletal proteins or cytosolic downstream signal-effectors.

Amino Acid Sequence↗
PubMed1998

Tyrosine phosphorylation of syndecan-1 and -4 cytoplasmic domains in adherent B82 fibroblasts.

The syndecans, a family of cell surface proteoglycans, have highly conserved cytoplasmic domains that bind proteins containing PDZ domains and co-localize with the actin cytoskeleton. The syndecan cytoplasmic domains contain four conserved tyrosine residues, two of which are located within favorable sequences for phosphorylation. Endogenous tyrosine phosphorylation of syndecans-1 and -4 is detected in adherent B82 fibroblasts. Approximately 1.5% of total syndecan is endogenously phosphorylated, while most, if not all, cell surface syndecan is phosphorylated following treatment with the tyrosine phosphatase inhibitor pervanadate. Syndecan phosphorylation is also detected in Raji-S1 and NMuMG cells, but only following treatment with vanadate or pervanadate, suggesting that endogenous phosphorylation is maintained in an "off" state in these cells. Endogenous syndecan phosphorylation in B82 cells is rapidly blocked by genistein (IC50 < 10 microM) confirming the presence of a constitutively active kinase and a corresponding tyrosine phosphatase. Phosphorylation is also inhibited by herbimycin A (IC50 < 1.0 microM) and staurosporine (IC50 < 1.0 nM), suggesting a role for Src family kinases in regulating syndecan phosphorylation. Together, these data suggest an important role for tyrosine phosphorylation of the syndecan cytoplasmic domains in regulating downstream signaling events in response to cell adhesion and/or growth factor activity.

Amino Acid Sequence↗
PubMed2003

Laminin alpha 3 LG4 module induces matrix metalloproteinase-1 through mitogen-activated protein kinase signaling.

The LG4 module of the laminin alpha 3 chain (alpha 3 LG4), a component of epithelial-specific laminin-5, has cell attachment activity and binds syndecan (Utani, A., Nomizu, M., Matsuura, H., Kato, K., Kobayashi, T., Takeda, U., Aota, S., Nielsen, P. K., and Shinkai, H. (2001) J. Biol. Chem. 276, 28779-28788). Here, we show that recombinant alpha 3 LG4 and a 19-mer synthetic peptide (A3G756) within alpha 3 LG4 active for syndecan binding increased the expression of matrix metalloproteinase-1 (MMP-1) in keratinocytes and fibroblasts. This induction was inhibited by heparin and required de novo synthesis of proteins. In keratinocytes, A3G756 up-regulated interleukin (IL)-1 beta and MMP-1 expression and an IL-1 receptor antagonist thoroughly inhibited A3G756-mediated induction of MMP-1. A3G756 also activated p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-related kinase (Erk). Studies with specific inhibitors of MAPKs showed that p38 MAPK activation was necessary for both IL-1 beta and MMP-1 induction, but Erk activation was required only for MMP-1 induction. In fibroblasts, IL-1 receptor antagonist did not block A3G756-mediated induction of MMP-1. These results indicated that induction of MMP-1 by alpha 3 LG4 is mediated through the IL-1 beta autocrine loop in keratinocytes but the mechanism of the induction in fibroblasts is different. Our study suggests that the laminin alpha 3 LG4 module may play an important role in tissue remodeling by inducing MMP-1 expression during wound healing.

Animals↗
PubMedDate not supplied

Time-dependent increases in syndecan-1 and fibroglycan messenger RNA expression in the infarct zone after experimentally induced myocardial infarction in rats.

BACKGROUND: Syndecan-1 and fibroglycan, heparan sulphate proteoglycans, play important roles in extracellular matrix formation via their biological functions. OBJECTIVE: To examine experimentally the sequential changes in syndecan-1 and fibroglycan messenger RNA (mRNA) expression after acute myocardial infarction. MATERIALS AND METHODS: The left coronary arteries of male Sprague-Dawley rats were ligated and the hearts were excised on days 1-14, 28 and 42. Syndecan-1 and fibroglycan mRNA expression in the infarct and non-infarct zones and in sham-operated hearts was determined by reverse transcriptase-polymerase chain reaction. Amplified products were quantified by densitometry of the electrophoresed bands stained with ethidium bromide and standardized relative to the glyceraldehyde 3-phosphate dehydrogenase or beta-actin mRNA expression. Northern hybridization was also performed in the infarct and non-infarct zones on day 3. RESULTS: Expression both of syndecan-1 and of fibroglycan mRNA began to increase on day 2. The expression attained maximum levels on day 3. The maximum levels of syndecan-1 and fibroglycan expression were, respectively, sevenfold and fivefold the preligation level and the level in the sham-operated hearts. The levels remained elevated until day 14, whereupon they declined gradually, returning to the control levels by around day 42. Northern blotting also demonstrated that there was an increased expression both of syndecan-1 and of fibroglycan mRNA in the infarct compared with that in the non-infarct zone on day 3. CONCLUSION: Our results demonstrated that there are sequential increases in the expression both of syndecan-1 and of fibroglycan mRNA in the infarct zone after experimentally induced myocardial infarction in rats, suggesting that these proteoglycans play some role in the pathological course of infarction.

Animals↗
PubMed2002

Proteolysis-inducing factor differentially influences transcriptional regulation in endothelial subtypes.

Proteolysis-inducing factor (PIF) is a novel sulfated glycoprotein initially identified as a protein capable of triggering muscle proteolysis during the process of cancer cachexia. Only skeletal muscle and liver exhibit substantial binding of PIF in adult tissue. Here, we demonstrate that PIF induces transcriptional regulation in both the liver endothelial cell line SK-HEP-1 and in human umbilical vein endothelial cells (HUVECs) but not in pulmonary artery endothelial cells. PIF differentially induces activation of nuclear factor-kappaB, resulting in the induction of proinflammatory cytokines [interleukin (IL)-8 and IL-6] and increased expression of the cell surface proteins intercellular adhesion molecule-1 and vascular cell adhesion molecule in SK-HEP-1 and HUVECs only. In addition, PIF induces the shedding of syndecans from the cell surface. Syndecans are involved in wound repair, metastasis of cancers, and embryonic development. These results suggest that PIF may play additional roles in the proinflammatory response observed in cancer cachexia but may also have a role without the cachectic process.

Blood Proteins↗
PubMed2003

Left-right asymmetry: nodal points.

The striking left-right asymmetry of visceral organs is known to depend on left- and right-side-specific cascades of gene expression during early embryogenesis. Now, developmental biologists are characterizing the earliest steps in asymmetry determination that dictate the sidedness of asymmetric gene expression. The proteins and structures involved control fascinating physiological processes, such as extracellular fluid flow and membrane voltage potential and yet little is known about how their activities are coordinated to control laterality. By analogy with intercellular signalling in certain epithelial and endothelial cells, however, it is reasonable to speculate that at least three of these players, monocilia, gap junction communication and the Ca2+ channel polycystin-2, participate in a signalling pathway that propagates left-right cues through multicellular fields.

Animals↗
PubMed2003

Analyses of beta-1 syntrophin, syndecan 2 and gem GTPase as candidates for chicken muscular dystrophy.

Despite intensive studies of muscular dystrophy of chicken, the responsible gene has not yet been identified. Our recent studies mapped the genetic locus for abnormal muscle (AM) of chicken with muscular dystrophy to chromosome 2q using the Kobe University (KU) resource family, and revealed the chromosome region where the AM gene is located has conserved synteny to human chromosome 8q11-24.3, where the beta-1 syntrophin (SNTB1), syndecan 2 (SDC2) and Gem GTPase (GEM) genes are located. It is reasonable to assume those genes might be candidates for the AM gene. In this study, we cloned and sequenced the chicken SNTB1, SDC2 and GEM genes, and identified sequence polymorphisms between parents of the resource family. The polymorphisms were genotyped to place these genes on the chicken linkage map. The AM gene of chromosome 2q was mapped 130 cM from the distal end, and closely linked to calbindin 1 (CALB1). SNTB1 and SDC2 genes were mapped 88.5 cM distal and 27.6 cM distal from the AM gene, while the GEM gene was mapped 18.5 cM distal from the AM gene and 9.1 cM proximal from SDC2. Orthologues of SNTB1, SDC2 and GEM were syntenic to human chromosome 8q. SNTB1, SDC2 and GEM did not correspond to the AM gene locus, suggesting it is unlikely they are related to chicken muscular dystrophy. However, this result also suggests that the genes located in the proximal region of the CALB1 gene on human chromosome 8q are possible candidates for this disease.

Amino Acid Sequence↗
PubMed1999

Heparan sulfate proteoglycan expression is induced during early erythroid differentiation of multipotent hematopoietic stem cells.

Heparan sulfate (HS) proteoglycans of bone marrow (BM) stromal cells and their extracellular matrix are important components of the microenvironment of hematopoietic tissues and are involved in the interaction of hematopoietic stem and stromal cells. Although previous studies have emphasized the role of HS proteoglycan synthesis by BM stromal cells, we have recently shown that the human hematopoietic progenitor cell line TF-1 also expressed an HS proteoglycan. Immunochemical, reverse transcriptase-polymerase chain reaction (RT-PCR), and Northern blot analysis of this HS proteoglycan showed that it was not related to the syndecan family of HS proteoglycans or to glypican. To answer the question of whether the expression of HS proteoglycans is associated with the differentiation state of hematopoietic progenitor cells, we have analyzed the proteoglycan synthesis of several murine and human hematopoietic progenitor cell lines. Proteoglycans were isolated from metabolically labeled cells and purified by several chromatographic steps. Isolation and characterization of proteoglycans from the cell lines HEL and ELM-D, which like TF-1 cells have an immature erythroid phenotype, showed that these cells synthesize the same HS proteoglycan, previously detected in TF-1 cells, as a major proteoglycan. In contrast, cell lines of the myeloid lineage, like the myeloblastic/promyelocytic cell lines B1 and B2, do not express HS proteoglycans. Taken together, our data strongly suggest that expression of this HS proteoglycan in hematopoietic progenitor cell lines is associated with the erythroid lineage. To prove this association we have analyzed the proteoglycan expression in the nonleukemic multipotent stem cell line FDCP-Mix-A4 after induction of erythroid or granulocytic differentiation. Our data show that HS proteoglycan expression is induced during early erythroid differentiation of multipotent hematopoietic stem cells. In contrast, during granulocytic differentiation, no expression of HS proteoglycans was observed.

Cell Differentiation↗
PubMedDate not supplied

Growth factors regulate the expression profile of their syndecan co-receptors and the differentiation of mesothelioma cells.

BACKGROUND: Diffuse malignant pleural mesotheliomas are locally aggressive and highly lethal tumors that are becoming more common. The tumor derives from pluripotential mesothelial stem cells, which differentiate into epithelial or mesenchymal elements. Tumors with a predominantly epithelial growth pattern have a better prognosis than the sarcomatous and mixed types, the phenotype being important for the biology of the tumor. We have previously shown that mesotheliomas express a wide range of cell surface heparan sulfate proteoglycans (HSPGs), particularly syndecans, which interact with growth factors and matrix components. MATERIALS AND METHODS: This study was undertaken to examine the epithelial-mesenchymal transition of mesothelioma cells by exposing epithelially-differentiated cells to an array of growth factors. Following substitution with TGF-beta 2, EGF, FGF-2, IGF-I and PDGF-BB, the expression levels of syndecans-1, -2 and -4 were monitored at selected times (30 minutes, 6 hours and 18 hours) by semi-quantitative RT-PCR and FACS analysis. The morphological appearance and proliferation rate of the treated cells was correlated to the PG profile obtained and to the subcellular compartmentalization of PGs. RESULTS: An early response was obtained only for syndecan-4. Changes in the differentiation pattern appeared later. Exposure to EGF and IGF-I induced a fibroblast-like morphology, simultaneously with a reduced expression of syndecans-1 and 2. TGF-beta 2 enhanced the focal contacts and showed a marked up-regulation of syndecan-4 and down-regulation of syndecan-1. Interestingly, TGF-beta 2 delayed the nuclear transport of syndecan-1 concomitantly with an antiproliferative effect. CONCLUSION: Growth factor signalling seems to be delicately controlled by an autoregulatory loop involving the syndecan expression levels and amounts of soluble HS chains shed into the medium.

Cell Differentiation↗
PubMed1993

Differential expression of transmembrane proteoglycans in vascular smooth muscle cells.

Rat aortic vascular smooth muscle (VSM) cells synthesize the transmembrane proteoglycan syndecan (Cizmeci-Smith, G., Asundi, V., Stahl, R. C., Teichman, L. J., Chernousov, M., Cowan, K., and Carey, D. J. (1992) J. Biol. Chem. 267, 15729-15736). The present work demonstrated that VSM cells synthesize the related transmembrane proteoglycan fibroglycan and that increased expression of these two proteoglycans is stimulated under different conditions. Fibroglycan synthesis by cultured rat aortic VSM cells was demonstrated by Northern blot analysis with a rat fibroglycan cDNA probe and immunoblot analysis with anti-rat fibroglycan antibodies. Effects of growth factors and vasoactive substances on syndecan and fibroglycan expression were examined by Northern blot analysis. Syndecan mRNA levels increased in response to stimulation of VSM cells with serum, platelet-derived growth factor, or angiotensin II. VSM cells stimulated with platelet-derived growth factor contained more syndecan core protein and processed syndecan than control cells. Fibroglycan mRNA levels either decreased or remained unchanged in response to these agents. Fibroglycan mRNA levels increased following transforming growth factor-beta stimulation, while syndecan mRNA levels decreased. Other agents, including basic fibroblast growth factor, endothelin, and carbacyclin did not alter the expression of either proteoglycan. Syndecan and fibroglycan mRNA levels also varied as a function of cell density. These data demonstrate that syndecan and fibroglycan expression are regulated differently in VSM cells and lend support to the hypothesis that these proteoglycans carry out distinct physiological functions.

Angiotensin II↗