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PubMed1994

Aggregation-induced association of syndecan-1 with microfilaments mediated by the cytoplasmic domain.

Expression of the transmembrane proteoglycan syndecan-1 in Schwann cells leads to enhanced spreading and cytoskeletal reorganization, but without an apparent stable association of syndecan-1 with cytoskeletal structures such as focal adhesions. Since cell surface oligomerization may be a mechanism for regulating the activities of transmembrane receptors, we wanted to investigate whether antibody-induced aggregation of the proteoglycan would promote its association with the cytoskeleton. When syndecan-1-expressing cells were incubated with anti-syndecan-1 and anti-IgG antibodies, clustering of proteoglycan on the cell surface was observed by immunofluorescence microscopy. The resulting pattern of syndecan-1 distribution was very similar to that of the underlying microfilament network, as visualized by fluorescent-phalloidin staining. In cells that were fixed briefly with paraformaldehyde before addition of the anti-IgG antibodies no such colocalization of syndecan-1 and microfilaments was observed. Additional findings supported the conclusion that this pattern of syndecan-1 distribution reflected an association with microfilaments: aggregated syndecan-1 was resistant to extraction by nonionic detergent; incubation of the cells with cytochalasin b, but not colchicine, altered the pattern of aggregated syndecan-1 distribution; antibody-induced clustering of syndecan-1 led to a reorganization of actin filaments. Syndecan-1 remained on the cell surface following antibody-induced clustering, as revealed by immunogold staining and transmission electron microscopy. A mutant form of syndecan-1 lacking most of the cytoplasmic domain failed to exhibit actin filament association or induce actin reorganization following antibody-mediated aggregation. These results suggest that transient associations of syndecan family proteoglycans with microfilaments may be important aspects of their biological functions.

Actin Cytoskeleton↗

PubMed1992

Syndecan-1, a cell-surface proteoglycan, changes in size and abundance when keratinocytes stratify.

In epidermis, keratinocytes in the basal cell layer differentiate, lose their attachment to the underlying extracellular matrix, and form extensive intercellular adhesions as they stratify. The alterations in cell-matrix and cell-cell adhesion required for keratinocyte stratification result from changes in the expression of numerous adhesion molecules. Syndecan-1, a member of a family of cell-surface proteoglycans, is known to bind cells to interstitial matrix. Syndecan-1 localizes to specific layers of mouse epidermal keratinocytes; its expression is modest in the basal layer, heavy in the suprabasal layers, but absent from the most superficial, terminally differentiated layers. This layer-specific difference suggests that syndecan-1 expression changes with keratinocyte differentiation. To assess this hypothesis, syndecan-1 expression was evaluated before and after calcium-induced stratification and differentiation. Cells growing as an unstratified monolayer express a higher molecular mass form of syndecan-1 than do stratified cells (modal relative mass of 160 kD versus 110 kD). This structural difference is due to larger and more heparan sulfate chains on syndecan-1 from monolayer cells. In addition, the amount of cell-surface syndecan-1 changes with stratification; stratified cultures show approximately 2.5 times more syndecan-1 per cell than do unstratified cultures, but do not significantly change the level of syndecan-1-specific mRNA. Thus, the structure and amount of syndecan-1 may be regulated to meet the changing adhesive requirements of stratifying keratinocytes.

Animals↗

PubMed1995

Loss of cell surface syndecan-1 causes epithelia to transform into anchorage-independent mesenchyme-like cells.

Simple epithelial cells are polygonal in shape, polarized in an apical-basal orientation, and organized into closely adherent sheets, characteristics that result from a variety of cellular specializations and adhesive proteins. These characteristics are lost when the epithelia transform during embryogenesis into mesenchymal cells or after neoplasia into invasive carcinoma cells. Of the syndecan family of transmembrane heparan sulfate proteoglycans, simple epithelia produce predominantly syndecan-1, which is found at basolateral surfaces and within adhesive junctions. To elucidate the function of this syndecan-1, normal murine mammary gland epithelia were made deficient in syndecan-1 by transfection with an expression vector containing the syndecan-1 cDNA in the antisense configuration. Several independently derived clones of stable transfectants contained the antisense cDNA in their genome and expressed the antisense transcript. These grew either as epithelial islands of closely adherent polygonal cells, identical to both the parental cells and the vector-only control transfectants, or as individual elongated fusiform cells that invaded and migrated within collagen gels, like mesenchymal cells, but were anchorage-independent for growth. The clones that retained epithelial characteristics were moderately deficient in cell surface syndecan-1 (greater than 48% of control levels) but did not differ from control cells in expression of beta 1-integrins and E-cadherin, or in F-actin organization. However, the clones of fusiform cells were severely deficient in cell surface syndecan-1 (less than 12% of control levels) and showed rearranged beta 1-integrins, markedly reduced E-cadherin expression, and disorganized F-actin filaments, but retained mammary epithelial markers. Therefore, depleting epithelia of cell surface syndecan-1 alters cell morphology and organization, the arrangement and expression of adhesion molecules, and anchorage-dependent growth controls. Thus, cell surface syndecan-1 is required to maintain the normal phenotype of simple epithelia.

Actins↗

PubMed1995

Elevated levels of syndecan-1 expression confer potent serum-dependent growth in human 293T cells.

Syndecan-1 is the best studied integral membrane proteoglycan and functions to modulate epithelial cell attachment and physiology. Extracellularly, syndecan-1 binds both growth factors and extracellular matrix components, and intracellularly, its cytoplasmic portion interacts with cytoskeletal components. To investigate the possible role of syndecan-1 in epithelial cell transformation that is characterized by alteration in extracellular matrix interactions and cytoskeleton architecture, we established stable transfectants of syndecan-1 in a highly transformed human renal epithelial line expressing two viral oncogenes, adenovirus E1a and SV40 large T antigen (293T cell line). Expression of syndecan-1 core protein and appropriate posttranslational attachment of glycosaminoglycan chains was confirmed by enzymatic digestion and Western blot analysis. Overexpresser cells grew at a significantly faster rate than the vector-transfected control cells in serum-rich media but showed a proliferative disadvantage in serum-reduced media. In addition to this serum dependency, syndecan-1 overexpression caused a partial reversal of the transformed phenotype with the expressing clones becoming more anchorage dependent and less motile than the vector-transfected counterparts. Surprisingly, the overexpressers were more tumorigenic when injected s.c. into nude mice. These results indicate that syndecan-1 expression plays a role in the control of cell proliferation and suggest that serum-dependent growth may be the more reflective of tumorigenicity in nude mice.

Animals↗

PubMed1994

Analysis of transport and targeting of syndecan-1: effect of cytoplasmic tail deletions.

Madin-Darby canine kidney (MDCK) cells and Chinese hamster ovary (CHO) cells were transfected with wild-type and cytoplasmic deletion mutants of mouse syndecan-1 to study the requirements for transport and polarized expression of this proteoglycan. Expression in MDCK cells revealed that wild-type syndecan-1 is directed to the basolateral surface via a brefeldin A-insensitive route. A deletion of the last 12 amino acids of the syndecan-1 cytoplasmic tail (CT22) was sufficient to result in the appearance of mutant proteoglycans at both the basolateral and apical cell surfaces. Treatment with brefeldin A was able to prevent apical transport of the mutants. We thus propose that the C-terminal part of the cytoplasmic tail is required for steady-state basolateral distribution of syndecan-1. In CHO cells a deletion of the last 25 or 33 amino acids of the 34-residue cytoplasmic domain (CT9 and CT1, respectively) resulted in partial retention of the mutants in the endoplasmic reticulum (ER). A deletion mutant lacking the last 12 amino acids (CT22) was not retained. Interestingly, the unglycosylated core proteins of the CT9 and CT1 mutants showed a significantly lower apparent molecular weight when analyzed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis than wild-type syndecan-1. However, when CHO transfectants expressing the CT1 mutant were incubated with brefeldin A, causing fusion of the ER and Golgi, CT1 ran with an almost equally high apparent molecular weight as the wild-type molecule. This would suggest that syndecan-1 undergoes extensive posttranslational modifications or forms an SDS-resistant dimer/complex after transit from the ER.

Amino Acid Sequence↗

PubMed1995

Heparan sulfate-mediated cell aggregation. Syndecans-1 and -4 mediate intercellular adhesion following their transfection into human B lymphoid cells.

Because syndecans are present at sites of cell-cell contact in vivo it has been hypothesized that they play a role in mediating cell-cell adhesion. However, there has been no direct evidence to support this notion. To address this question, B lymphoid (ARH-77) cells were transfected with the cDNA for murine syndecan-1. Unlike the parental cells, the transfectants form large multicellular aggregates in suspension cultures and stain intensely for syndecan-1 at sites of cell-cell contact. Using rotation-mediated aggregation assays, we find that aggregation of syndecan-1-transfected cells is dependent on divalent cations and is inhibited by the following: (i) addition of heparin and heparin-like glycosaminoglycans, (ii) removal of heparan sulfate from the cell surface, or (iii) addition of exogenous purified syndecan-1. Mixing of syndecan-1-transfected and control-transfected cells results in aggregates containing both cell types indicating that aggregation occurs through a heterophilic adhesion mechanism in which heparan sulfate chains bind to a counter-receptor present on these cells. Importantly, syndecan-4-transfected cells also aggregate in a heparan sulfate-dependent manner, while in contrast, betaglycan-transfected cells aggregate poorly. Thus, syndecans may be important mediators of cell-cell adhesion, but this function may not be common to all transmembrane heparan sulfate-bearing proteoglycans.

Animals↗

PubMed1994

Interactions of syndecan-1 and heparin with human collagens.

Glycosaminoglycan (GAG)-collagen interactions play important roles in cell adhesion and extracellular matrix assembly; however, the chemical bases for these interactions are not fully understood. We have used affinity co-electrophoresis (ACE) (Lee, M.K. and Lander, A.D., Proc. Natl. Acad. Sci, USA, 88, 2768-2772, 1991) to study the binding of the heparan sulphate proteoglycan syndecan-1 and heparin to human collagens. [35S]Syndecan-1 [from normal murine mammary gland (NMuMG) epithelial cells] and low-M(r) (approximately 6 kDa) [125I]heparin were subjected to electrophoresis through agarose gel lanes containing human collagens at various concentrations, and binding affinities were measured from shifts in migration of the labelled materials. Results demonstrate that the affinities of each collagen for syndecan-1 and low-M(r) heparin were similar, and followed the order: type V >> type IV approximately type III approximately type I > type VI >> type II, and ranged in Kd from approximately 10(-8) to approximately 3 x 10(-6) M. These data suggest that syndecan-1 and heparin may contain similar collagen-binding determinants. It was also found that the same heparin subpopulation was selectively bound with high affinity by each of the collagens. The published amino acid sequences of the six collagens were examined for what are thought to be heparin-binding consensus sequences (Cardin, A.D. and Weintraub, H.J.R., Arteriosclerosis, 9, 21-32, 1989). The presence of such sequences did not correlate with affinity for heparin or syndecan-1, and collagens I, II and III lacked such sequences entirely. The data suggest that collagens may use novel types of binding sites to interact with GAGs.

Animals↗

PubMed1995

Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis.

Midkine (MK) and heparin binding-growth associated molecule (HB-GAM or pleiotrophin), constitute a new family of heparin-binding proteins implicated in the regulation of growth and differentiation (T. Muramatsu (1993) Int. J. Dev. Biol. 37, 183-188). We used affinity-purified antibodies against MK and HB-GAM to analyze their distribution during mouse embryonic development. From 9 to 14.5 day post-coitum (dpc), both proteins were detected in central and peripheral nervous systems, facial processes, limb buds, sense organs, respiratory, digestive, urogenital, and skeletal systems. MK and HB-GAM were often localized on the surface of differentiating cells and in basement membranes of organs undergoing epithelial-mesenchymal interactions. The level of MK protein decreased considerably in the 16.5 dpc embryo, whereas HB-GAM staining persisted in many tissues. Our in situ hybridization results revealed a widespread expression of MK transcripts that was not always consistent with the distribution of MK protein in developing tissues. In many epithelio-mesenchymal organs MK and HB-GAM were codistributed with syndecan-1, a cell surface proteoglycan. In limb buds and facial processes, MK, HB-GAM, and syndecan-1 were localized to the apical epithelium and the adjacent proliferating mesenchyme. Both MK and HB-GAM bound syndecan-1 in solid-phase assays in a heparan sulfate-dependent manner. The biological effects of MK and HB-GAM on limb and facial mesenchyme were studied in vitro by application of beads preloaded with the proteins. Neither MK nor HB-GAM stimulated mesenchymal cell proliferation or induced syndecan-1 expression. Taken together these results indicate that MK and HB-GAM may play regulatory roles in differentiation and morphogenesis of the vertebrate embryo, particularly in epithelio-mesenchymal organs, and suggest molecular interactions with syndecan-1.

Animals↗

PubMed1995

Expression of proteoglycans and hyaluronan during wound healing.

We investigated the expression of proteoglycans (PGs) and hyaluronan (HA) during healing of human mucosal wounds. Biopsy specimens of experimental wounds were taken 1, 3, and 7 days after wounding. Frozen sections were used for immunolocalization of CD44, syndecan-1, basement membrane-associated heparan sulfate proteoglycan (BM-HSPG), decorin, and biglycan. HA was localized in paraffin sections with a specific HA-binding probe. Epithelium showed first signs of migration on Day 1, more progressive migration on Day 3, and epithelial sheets confronted on Day 7. CD44 surrounded migrating keratinocytes at all stages of wound healing. In epithelium, CD44 and HA remarkably localized to the same region. Expression of syndecan-1 was switched from the suprabasal cell layer of unwounded epithelium to the basal cell layer of the migrating wound epithelium. BM-HSPG was absent under migrating keratinocytes. It started to reappear at the basement membrane zone on Day 7. The area under the wound epithelium containing newly synthesized collagen fibers first became positive for decorin on Day 7, whereas staining of biglycan was negative. Granulation tissue was also strongly positive for CD44 and hyaluronan. Our results indicate that migrating keratinocytes express both CD44 and syndecan-1 but not BM-HSPG. During differentiation of keratinocytes, expression of CD44 preceded that of syndecan-1. The results suggest that different HSPGs have multiple functions in keratinocyte migration and differentiation during reepithelialization.

Basement Membrane↗

PubMed1995

Modulated glycosylation of proteoglycans during differentiation of human B lymphocytes.

Proteoglycans are mediators of cellular adhesion and regulate growth factor activities. Proteoglycans of B lymphocytes undergo structural changes during B cell ontogeny which may correspond to the specific requirements of the respective microenvironment of the maturing cell. We analyzed three human B cell lines representing pre-B cells (Nalm-6), activated B cells (Jok-1) and plasma cells (U266) for their cellular proteoglycans. Gel filtration of the 35S-labeled macromolecules of the three cell lines revealed an increase in size in the order Nalm-6 < Jok-1 < U266. In Jok-1 and U266 cells the major pool of proteoglycans consisted of proteochondroitin sulfates of 50 to 90 kDa. These proteolglycans carried a protein core of approx. 30 kDa to which 1 to 3 glycosaminoglycan chains in the range of 28 to 32 kDa were attached. In Nalm-6 cells only free chondroitin sulfate chains of 23 kDa, but no intact proteoglycans, were detected. Chondroitin sulfate chains were predominantly composed of chondroitin-4-sulfate, those of Nalm-6 and U266 cells additionally contained 10-20% of unsulfated disaccharides. In U266 cells 30% of glycosaminoglycans consisted of heparan sulfate either bound to pure proteoheparan sulfate or to chondroitin sulfate/heparan sulfate hybrid-proteoglycans. Earlier, syndecan-1 was described as a hybrid proteoglycan containing heparan sulfate/chondroitin sulfate chains which is transcribed by murine B cells at early and late maturation stages. In order to see whether syndecan is transcribed by the human B cell lines used here, we measured expression of syndecan mRNA by the reverse transcriptase polymerase chain reaction. Similar to murine lymphocytes, syndecan-specific mRNA was detected in Nalm-6 and U266 cells, equivalent to early and late B cells, but not in lymphoblastoid Jok-1 cells. However, Nalm-6 cells do not produce proteoheparan sulfate. In these cells, syndecan synthesis may be blocked at the translational level. Also, the proteoglycans of U266 are different from syndecan-1 in their composition of glycosaminoglycans and in size of protein cores. Together, these results indicate that the major pool of proteoglycans produced by human B cells consists of proteochondroitin sulfate and additionally in later stages of a smaller proportion of proteoheparan sulfate which is not identical to syndecan-1. During distinct phases of B cell differentiation, modulations in the glycosaminoglycan moiety concerning size and sulfation of glycosaminoglycan chains were also found.

B-Lymphocytes↗

PubMed1995

Repetitive Ser-Gly sequences enhance heparan sulfate assembly in proteoglycans.

We showed previously that the synthesis of heparan sulfate on betaglycan occurs at a Ser-Gly dipeptide flanked by a cluster of acidic residues and an adjacent tryptophan (Zhang, L., and Esko, J.D. (1994) J. Biol. Chem. 269, 19295-19299). A survey of the protein data base revealed that most heparan sulfate proteoglycans contain repetitive (Ser-Gly)n segments (n = 2) and a nearby cluster of acidic residues. To study the role of these amino acid sequences in controlling heparan sulfate synthesis, we have examined the assembly of glycosaminoglycans on Chinese hamster ovary (CHO) cell syndecan-1. The glycosylation sites were mapped by making chimeric proteoglycans containing segments of CHO syndecan-1 cDNA fused to Protein A. Two sites near the transmembrane domain (-EGS205GEQ- and -ETS215GEN-) were used solely for chondroitin sulfate synthesis, whereas three sites near the N terminus (-DGS35GDDSDNFS45GS47GTG-) supported both heparan sulfate and chondroitin sulfate synthesis. The strongest sites for heparan sulfate synthesis consisted of the repeat unit, -S45GS47G-. An unusual coupling phenomenon occurred across the adjacent SG dipeptides, leading to a greater proportion of heparan sulfate than predicted by the behavior of each site acting independently. The clusters of acidic residues adjacent to the heparan sulfate sites play important roles as well. These sequence motifs suggest a set of rules for predicting whether heparan sulfate assembles at glycosylation sites in proteoglycan core proteins.

Amino Acid Sequence↗

PubMed1995

Androgen and fibroblast growth factor (FGF) regulation of FGF receptors in S115 mouse mammary tumor cells.

We studied the androgen regulation of fibroblast growth factor (FGF) receptors (FGFRs) in the Shionogi 115 (S115) mouse mammary tumor cell line and its genetic variant Clone 22. In S115 cells, androgen maintains a transformed morphology, rate of proliferation, and serum and anchorage independence. Similar effects were induced by treatment of the cells with FGF-2 or a heparin-binding growth factor (HBGF) fraction prepared from the medium conditioned by the cells. The effects of androgen and FGF-2 could be partly reversed with a specific anti-FGF-2 immunoglobulin G or by suramin, which inhibits binding of FGFs to their high affinity receptors. Testosterone and FGF-2 increased the expression of FGFR-1 messenger RNA (mRNA) and, to a lesser extent, FGFR-3 mRNA, but down-regulated FGFR-2 mRNA in S115 cells. No FGFR-4 mRNA was detected. FGF-2 also down-regulated the expression of syndecan-1, a heparan sulfate proteoglycan that binds FGF with low affinity. The binding of radiolabeled FGF-2 to FGFRs was lower in the cells cultured with testosterone or in the presence of the HBGFs from androgen-treated cells, presumably because of the autocrine production of FGF-like factors. In Clone 22 cells, FGFRs and syndecan-1 responded to androgen as in S115 cells, but they were less sensitive to FGF-2. Androgen or FGF-2 could not induce morphological transformation, although both stimulated proliferation. Androgen-increased proliferation was not, however, decreased by anti-FGF-2 immunoglobulin G in Clone 22 cells. These data suggest that of the HBGFs produced, FGF-2 is required in androgen induction of morphological change, whereas the effect on proliferation involves other factors as well (perhaps mostly FGF-8). The results show that androgen differentially regulates the expression of the high and low affinity FGF receptors, which could mediate androgen induction of the transformed phenotype in S115 cells by an autocrine mechanism. The differential responses of the Clone 22 variant cells to androgen and FGF-2 suggest that the pathways of steroid induction of different parameters of the transformed phenotype, such as transition to fibroblastic morphology and stimulation of proliferation, are divergent.

Animals↗

PubMed1994

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

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

Animals↗

PubMed1995

Chondroitin sulfate proteoglycans in the developing cerebral cortex: the distribution of neurocan distinguishes forming afferent and efferent axonal pathways.

The first thalamocortical axons to arrive in the developing cerebral cortex traverse a pathway that is separate from the adjacent intracortical pathway for early efferents, suggesting that different molecular signals guide their growth. We previously demonstrated that the intracortical pathway for thalamic axons is centered on the subplate (Bicknese et al. [1994] J. Neurosci. 14:3500-3510), which is rich in chondroitin sulfate proteoglycans (CSPGs; Sheppard et al. [1991] J. Neurosci. 11:3928-3942), whereas efferent axons cross the subplate to exit in a zone containing much less CSPG. To define the molecular composition of the subplate further, we used antibodies against CSPG core proteins and chondroitin sulfate disaccharides in an immunohistochemical analysis of their distribution in the developing neocortex of the rat. Immunolabeling for neurocan, a central nervous system-specific CSPG (Rauch et al. [1992] J. Biol. Chem. 267:19537-19547), and for chondroitin 6-sulfate and unsulfated chondroitin becomes prominent in the subplate before the arrival of thalamic afferents. Immunolabeling is initially sparse in the cortical plate but appears later in maturing cortical layers. A postnatal decline in immunolabeling occurs uniformly for most proteoglycans, but, in the somatosensory cortex, labeling for neurocan, phosphacan, and chondroitin 4- and 6-sulfate declines in the centers of the whisker barrels before the walls. In contrast to neurocan, immunolabeling for other proteoglycans is either uniformly distributed (syndecan-1, N-syndecan, 5F3, phosphacan, chondroitin 4-sulfate), restricted to axons (PGM1), distributed exclusively on nonneuronal elements (2D6, NG2, and CD44), or undetectable (9.2.27, aggrecan, decorin). Thus, neurocan is a candidate molecule for delineating the intracortical pathway of thalamocortical axons and distinguishing it from that of cortical efferents.

Afferent Pathways↗

PubMed1995

Effect of transforming growth factor-beta 1 and basic fibroblast growth factor on the expression of cell surface proteoglycans in human lung fibroblasts. Enhanced glycanation and fibronectin-binding of CD44 proteoglycan, and down-regulation of glypican.

We have tested the effects of transforming growth factor-beta 1 (TGF-beta 1), basic fibroblast growth factor (bFGF) and TGF-beta 1 + bFGF on the expression of the cell surface proteoglycans (CD44, syndecans and glypican) in cultures of human lung fibroblasts (HLF). Cell surface proteoglycan expression was monitored by quantitative immunoprecipitation from metabolically labelled cells. Western and Northern blotting and evaluation of the glycanation of the proteoglycans. Stimulation of the cells with TGF-beta 1 increased the length of the chondroitin sulphate (CS) chains on CD44 (approximately 1.6-fold). bFGF, administered solely, also increased the length of the CS chains on CD44 (approximately 1.4-fold), whereas the combination of TGF-beta 1 + bFGF nearly doubled both the length and the number of the CS chains on CD44. None of these treatments lead to changes in CD44 message or core-protein expression. This enhanced glycanation of CD44 after the TGF-beta 1, bFGF and combined treatments correlated with a 2-fold increase in the affinity of the proteoglycan for fibronectin but had no influence on the binding to type I collagen. TGF-beta 1, alone or in combination with bFGF, also stimulated the CS content of syndecan-1, but none of the other syndecans was significantly affected by any of the factors or combinations tested. The expression of glypican however was significantly decreased (nearly halved) by the combination of TGF-beta 1 + bFGF, less so by TGF-beta 1 and not at all by bFGF. This decrease occurred both at the level of the message and of the core protein. These data demonstrate specific and differential effects of TGF-beta 1 and bFGF on the structure, expression and interactions of the cell surface proteoglycans of HLF.

Base Sequence↗

PubMed1995

Regulation of organogenesis. Common molecular mechanisms regulating the development of teeth and other organs.

Vertebrate organs develop from epithelial and mesenchymal tissues, and during their early development they share common morphological features. These include condensation of the mesenchymal cells and thickening, folding or branching of epithelial sheets. Sequential and reciprocal interactions between the epithelial and mesenchymal tissues play central roles in regulation of the morphogenesis of all organs. During recent years increasing amounts of molecular data have accumulated from studies describing developmental changes in expression patterns of molecules, as well as from functional in vitro studies and from the generation of transgenic mice. In this review article, we discuss common features in the molecular regulation that appear to be shared by the developing tooth and other organs. Several growth factors have been shown to act as inductive signals mediating epithelial-mesenchymal interactions in different organs. The early signals are proposed to regulate the expression of master regulatory genes, such as transcription factors. In early tooth germ, bone morphogenetic proteins BMP-2 and BMP-4 regulate expression of the homeobox containing genes Msx-1 and Msx-2. These may specify early patterning of organs through regulation of molecules at the cell surface and the extracellular matrix, such as syndecan-1 and tenascin. Changes in cell adhesion and matrix remodelling, particularly in the organ-specific mesenchyme and in basement membrane contribute to formation of mesenchymal cell condensations and to epithelial morphogenesis. Several growth factors and their receptors, particularly in the TGF beta-, FGF- and EGF- families, have been implicated in formation of mesenchymal condensates and in epithelial morphogenesis of many organs, including the tooth. It is apparent that molecules which regulate morphogenesis in different organs are potential candidate genes for congenital malformation syndromes in which several organs are affected.

Animals↗

PubMed1989

B lymphocytes express and lose syndecan at specific stages of differentiation.

Lymphopoietic cells require interactions with bone marrow stroma for normal maturation and show changes in adhesion to matrix during their differentiation. Syndecan, a heparan sulfate-rich integral membrane proteoglycan, functions as a matrix receptor by binding cells to interstitial collagens, fibronectin, and thrombospondin. Therefore, we asked whether syndecan was present on the surface of lymphopoietic cells. In bone marrow, we find syndecan only on precursor B cells. Expression changes with pre-B cell maturation in the marrow and with B-lymphocyte differentiation to plasma cells in interstitial matrices. Syndecan on B cell precursors is more heterogeneous and slightly larger than on plasma cells. Syndecan 1) is lost immediately before maturation and release of B lymphocytes into the circulation, 2) is absent on circulating and peripheral B lymphocytes, and 3) is reexpressed upon their differentiation into immobilized plasma cells. Thus, syndecan is expressed only when and where B lymphocytes associate with extracellular matrix. These results indicate that B cells differentiating in vivo alter their matrix receptor expression and suggest a role for syndecan in B cell stage-specific adhesion.

Animals↗

PubMed2026

SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear. OBJECTIVE: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME. DESIGN: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways. RESULTS: We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis. CONCLUSIONS: Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Humans↗