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PubMed2005

The interaction of versican with its binding partners.

Versican belongs to the family of the large aggregating chondroitin sulfate proteoglycans located primarily within the extracellular matrix (ECM). Versican, like other members of its family, has unique N- and C-terminal globular regions, each with multiple motifs. A large glycosaminoglycan-binding region lies between them. This review will begin by outlining these structures, in the context of ECM proteoglycans. The diverse binding partners afforded to versican by virtue of its modular design will then be examined. These include ECM components, such as hyaluronan, type I collagen, tenascin-R, fibulin-1, and -2, fibrillin-1, fibronectin, P- and L-selectins, and chemokines. Versican also binds to the cell surface proteins CD44, integrin beta 1, epidermal growth factor receptor, and P-selectin glycoprotein ligand-1. These multiple interactors play important roles in cell behaviour, and the roles of versican in modulating such processes are discussed.

Animals↗
PubMed2003

Hyaluronan, CD44 and versican in epidermal keratinocyte tumours.

BACKGROUND: The high molecular weight polysaccharide hyaluronan is a major component of the extracellular matrix between the vital cells of human skin epidermis. The levels of hyaluronan, and those of the hyaluronan receptor CD44 and the hyaluronan binding proteoglycan versican, correlate with the aggressiveness of different human carcinomas of epithelial origin. OBJECTIVES: To study skin keratinocyte tumours for the expression of hyaluronan, the hyaluronan receptor CD44 and the hyaluronan binding proteoglycan versican. METHODS: Paraffin-embedded sections of 114 basal cell carcinomas (BCC), 31 in situ carcinomas (ISC) and 35 squamous cell carcinomas (SCC) were stained with a hyaluronan specific probe, biotinylated hyaluronan binding complex, and with monoclonal antibodies against CD44 and versican. RESULTS: Compared with normal epidermis, ISC and well differentiated SCCs showed an enhanced hyaluronan signal on carcinoma cells while CD44 expression level resembled that of normal skin. Less differentiated SCCs showed reduced and irregular expression of both hyaluronan and CD44 on carcinoma cells. In BCCs, hyaluronan and CD44 signals were absent or very low on the surface of carcinoma cells. However, hyaluronan was frequently present on BCC cell nuclei, a feature completely absent in ISC, SCC and normal epidermis. An accumulation of hyaluronan in the connective tissue stroma around the tumour was more frequent in SCCs than BCCs. Versican staining was positive around hair follicles and dermal blood vessels of normal skin. Peritumoral versican signal was present in a part of the BCCs but not in other tumours. CONCLUSIONS: The completely different hyaluronan and CD44 expression patterns in BCC and SCC probably reflect the different origins of the tumours, with BCC an undifferentiated keratinocyte and SCC a keratinocyte at an early stage in the differentiation pathway. The difference in hyaluronan and CD44 expression between these tumours may also contribute to the difference in their capacity to metastasize.

Carcinoma↗
PubMed2002

Developmental changes and regional differences in histochemical localization of hyaluronan and versican in postnatal molar dental pulp.

AIM: The main aim of this study was to investigate the developmental changes in the distribution patterns of hyaluronan (HA) and versican in postnatal rat molar dental pulp, in order to confirm the hypothesis that the distribution of both molecules can vary with physiological conditions in the dental pulp. METHODOLOGY: Thirty postnatal Sprague-Dawley rats, 1, 7, 14, 21, 28, 35, 42 and 49 days old, were used for this study. Immunohistochemistry for versican with monoclonal antibodies 12C5 and CS-56 and histochemical staining for HA with HA-binding protein were applied to paraffin sections of the mandibular first molars at each age. RESULTS: At day 1, both molecules were evenly distributed in the interior parts of the pulp, but strong reactions for both molecules appeared in the subodontoblastic layer of the coronal pulp by the completion of crown formation. However, a strong reaction for HA and a weak reaction for versican were seen in the subodontoblastic layer of the radicular pulp. Furthermore, a versican-deficient, low-HA area first appeared in the interior of the coronal pulp at day 42 and expanded at day 49. CONCLUSIONS: Distribution of hyaluronan and versican in the dental pulp varied with age and also showed regional differences between the coronal and the radicular pulp, and this supports the hypothesis described above.

Age Factors↗
PubMed2001

A comparative analysis of the differential spatial and temporal distributions of the large (aggrecan, versican) and small (decorin, biglycan, fibromodulin) proteoglycans of the intervertebral disc.

This study provides a comparative analysis of the temporal and spatial distribution of 5 intervertebral disc (IVD) proteoglycans (PGs) in sheep. The main PGs in the 2 and 10 y old sheep groups were polydisperse chondroitin sulphate and keratan sulphate substituted species. Their proportions did not differ markedly either with spinal level or disc zone. In contrast, the fetal discs contained 2 slow migrating (by composite agarose polyacrylamide gel electrophoresis, CAPAGE), relatively monodisperse chondroitin sulphate-rich aggrecan species which were also identified by monoclonal antibody 7-D-4 to an atypical chondroitin sulphate isomer presentation previously found in chick limb bud, and shark cartilage. The main small PG detectable in the fetal discs was biglycan, whereas decorin predominated in the 2 and 10 y old IVD samples; its levels were highest in the outer annulus fibrosus (AF). Versican was most abundant in the AF of the fetal sheep group; it was significantly less abundant in the 2 and 10 y old groups. Furthermore, versican was immunolocalised between adjacent layers of annular lamellae suggesting that it may have some role in the provision of the viscoelastic properties to this tissue. Versican was also diffusely distributed throughout the nucleus pulposus of fetal IVDs, and its levels were significantly lower in adult IVD specimens. This is the first study to identify versican in ovine IVD tissue sections and confirmed an earlier study which demonstrated that ovine IVD cells synthesised versican in culture (Melrose et al. 2000). The variable distribution of the PGs identified in this study provides further evidence of differences in phenotypic expression of IVD cell populations during growth and development and further demonstrates the complexity of the PGs in this heterogeneous but intricately organised connective tissue.

Aggrecans↗
PubMed1995

The versican C-type lectin domain recognizes the adhesion protein tenascin-R.

The core proteins of large chondroitin sulfate proteoglycans contain a C-type lectin domain. The lectin domain of one of these proteoglycans, versican, was expressed as a recombinant 15-kDa protein and shown to bind to insolubilized fucose and GlcNAc. The lectin domain showed strong binding in a gel blotting assay to a glycoprotein doublet in rat brain extracts. The binding was calcium dependent and abolished by chemical deglycosylation treatment of the ligand glycoprotein. The versican-binding glycoprotein was identified as the cell adhesion protein tenascin-R, and versican and tenascin-R were both found to be localized in the granular layer of rat cerebellum. These results show that the versican lectin domain is a binding domain with a highly targeted specificity. It may allow versican to assemble complexes containing proteoglycan, an adhesion protein, and hyaluronan.

Acetylglucosamine↗
PubMed1999

Fibulin-1 is a ligand for the C-type lectin domains of aggrecan and versican.

The aggregating proteoglycans (aggrecan, versican, neurocan, and brevican) are important components of many extracellular matrices. Their N-terminal globular domain binds to hyaluronan, but the function of their C-terminal region containing a C-type lectin domain is less clear. We now report that a 90-kDa protein copurifies with recombinant lectin domains from aggrecan and versican, but not from the brain-specific neurocan and brevican. Amino acid sequencing of tryptic peptides from this protein identified it as fibulin-1. This extracellular matrix glycoprotein is strongly expressed in tissues where versican is expressed (blood vessels, skin, and developing heart), and also expressed in developing cartilage and bone. It is thus likely to interact with these proteoglycans in vivo. Surface plasmon resonance measurements confirmed that aggrecan and versican lectin domains bind fibulin-1, whereas brevican and neurocan do not. As expected for a C-type lectin, the interactions with fibulin-1 are Ca2+-dependent, with KD values in the low nanomolar range. Using various deletion mutants, the binding site for aggrecan and versican lectin domains was mapped to the epidermal growth factor-like repeats in domain II of fibulin-1. No difference in affinity was found for deglycosylated fibulin-1, indicating that the proteoglycan C-type lectin domains bind to the protein part of fibulin-1.

Aggrecans↗
PubMed2000

Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44.

Here we show that a large chondroitin sulfate proteoglycan, versican, derived from a renal adenocarcinoma cell line ACHN, binds L-selectin, P-selectin, and CD44. The binding was mediated by the interaction of the chondroitin sulfate (CS) chain of versican with the carbohydrate-binding domain of L- and P-selectin and CD44. The binding of versican to L- and P-selectin was inhibited by CS B, CS E, and heparan sulfate (HS) but not by any other glycosaminoglycans tested. On the other hand, the binding to CD44 was inhibited by hyaluronic acid, chondroitin (CH), CS A, CS B, CS C, CS D, and CS E but not by HS or keratan sulfate. A cross-blocking study indicated that L- and P-selectin recognize close or overlapping sites on versican, whereas CD44 recognizes separate sites. We also show that soluble L- and P-selectin directly bind to immobilized CS B, CS E, and HS and that soluble CD44 directly binds to immobilized hyaluronic acid, CH, and all the CS chains examined. Consistent with these results, structural analysis showed that versican is modified with at least CS B and CS C. Thus, proteoglycans sufficiently modified with the appropriate glycosaminoglycans should be able to bind L-selectin, P-selectin, and/or CD44.

Animals↗
PubMed2001

The proteoglycans aggrecan and Versican form networks with fibulin-2 through their lectin domain binding.

Aggrecan, versican, neurocan, and brevican are important components of the extracellular matrix in various tissues. Their amino-terminal globular domains bind to hyaluronan, but the function of their carboxyl-terminal globular domains has long remained elusive. A picture is now emerging where the C-type lectin motif of this domain mediates binding to other extracellular matrix proteins. We here demonstrate that aggrecan, versican, and brevican lectin domains bind fibulin-2, whereas neurocan does not. As expected for a C-type lectin, the interactions are calcium-dependent, with K(D) values in the nanomolar range as measured by surface plasmon resonance. Solid phase competition assays with previously identified ligands demonstrated that fibulin-2 and tenascin-R bind the same site on the proteoglycan lectin domains. Fibulin-1 has affinity for the common site on versican but may bind to a different site on the aggrecan lectin domain. By using deletion mutants, the interaction sites for aggrecan and versican lectin domains were mapped to epidermal growth factor-like repeats in domain II of fibulin-2. Affinity chromatography and solid phase assays confirmed that also native full-length aggrecan and versican bind the lectin domain ligands. Electron microscopy confirmed the mapping and demonstrated that hyaluronan-aggrecan complexes can be cross-linked by the fibulins.

Aggrecans↗
PubMed2006

Versican G3 domain promotes blood coagulation through suppressing the activity of tissue factor pathway inhibitor-1.

We have detected versican, a member of the large chondroitin sulfate proteoglycans, and its degraded C-terminal G3 fragments in human plasma and observed that the versican G3 domain promoted blood coagulation. Silencing G3 expression with small interfering RNA reduced the effect of G3 on coagulation. Plasma coagulation assays suggest that G3 enhances coagulation irrespective of its actions on platelets and white blood cells. To examine how versican affected blood coagulation, we used normal human plasma and different types of coagulation factor-deficient plasmas. The experiments indicated that versican enhanced coagulation through the extrinsic pathway, and that Factor VII was the target molecule. FVII activity assays showed that G3 activated FVII in the presence of plasma but not with purified FVII directly. Yeast two-hybrid, immunoprecipitation, and gel co-migration assays showed that G3 interacted with the tissue factor pathway inhibitor-1 (TFPI-1). TFPI-1 activity assays suggested that G3 inhibited TFPI-1 activity, allowing FVIIa and FXa to facilitate the coagulation process. G3-induced blood coagulation was further confirmed with a mouse model in a real-time manner. Taken together, these results indicate that versican may represent a new target for the development of therapies against atherosclerosis.

Amino Acid Motifs↗
PubMed2004

Versican V1 isoform induces neuronal differentiation and promotes neurite outgrowth.

The chondroitin sulfate proteoglycan versican is one of the major extracellular components in the developing and adult brain. Here, we show that isoforms of versican play different roles in neuronal differentiation and neurite outgrowth. Expression of versican V1 isoform in PC12 cells induced complete differentiation, whereas expression of V2 induced an aborted differentiation accompanied by apoptosis. V1 promoted neurite outgrowth of hippocampal neurons, but V2 failed to do so. V1 transfection enhanced expression of epidermal growth factor receptor and integrins, and facilitated sustained extracellular signal-regulated kinase/MAPK phosphorylation. Blockade of the epidermal growth factor receptor, beta1 integrin, or Src significantly inhibited neuronal differentiation. Finally, we demonstrated that versican V1 isoform also promoted differentiation of neural stem cells into neurons. Our results have implications for understanding how versican regulates neuronal development, function, and repair.

Animals↗
PubMed2005

The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis.

Versican is a large chondroitin sulfate proteoglycan belonging to the lectican family. Alternative splicing of versican generates at least four isoforms named V0, V1, V2, and V3. We have shown that the versican V1 isoform not only enhanced cell proliferation, but also modulated cell cycle progression and protected the cells from apoptosis. Futhermore, the V1 isoform was able to not only activate proto-oncogene EGFR expression and modulate its downstream signaling pathway, but also induce p27 degradation and enhance CDK2 kinase activity. As well, the V1 isoform down-regulated the expression of the proapoptotic protein Bad. By contrast, the V2 isoform exhibited opposite biological activities by inhibiting cell proliferation and down-regulated the expression of EGFR and cyclin A. Furthermore, V2 did not contribute apoptotic resistance to the cells. In light of these results, we are reporting opposite functions for the two versican isoforms whose expression is differentially regulated. Our studies suggest that the roles of these two isoforms are associated with the subdomains CSbeta and CSalpha, respectively. These results were confirmed by silencing the expression of versican V1 with small interfering RNA (siRNA), which abolished V1-enhanced cell proliferation and V1-induced reduction of apoptosis.

Animals↗
PubMed1999

Identification and characterization of ligands for L-selectin in the kidney. I. Versican, a large chondroitin sulfate proteoglycan, is a ligand for L-selectin.

Ligands for a leukocyte adhesion molecule, L-selectin, are expressed not only in the specific vascular endothelium in lymph nodes and Peyer's patches but also in the extravascular tissues such as the brain white matter, choroid plexus and the kidney distal straight tubuli. However, the biological significance of these extravascular ligands is currently unknown. We now report the purification and characterization of a novel extravascular ligand for L-selectin in the kidney using a tubule-derived cell line, ACHN. Binding of L-selectin-IgG chimera (LEC-IgG) to the isolated ligand was specifically blocked with either (i) anti-L-selectin mAb, (ii) EDTA, (iii) fucoidan, (iv) chondroitin sulfate (CS) B or CS E, or (v) treatment with chondroitinases. Partial amino acid sequencing, Western blotting and immunoprecipitation analyses showed that a major ligand for L-selectin in ACHN cells is versican of 1600 kDa. Histochemical as well as biochemical analyses verified that a versican subspecies in the kidney was indeed reactive with L-selectin. Studies with cell lines including those derived from the kidney indicated that a certain glycoform and/or splice form of versican is reactive with L-selectin. Under pathological conditions such as those induced by unilateral ureteral obstruction, versican was shed from the distal straight tubuli and became localized in the adjacent vascular bundles around which a substantial leukocyte infiltration was concomitantly observed. Possible involvement of versican in leukocyte trafficking into the kidney under diseased conditions is discussed.

Animals↗
PubMed1996

Differential expression of versican isoforms in brain tumors.

Versican is a member of the family of large aggregating chondroitin sulfate proteoglycans which are one of the major constituents of brain extracellular matrix (ECM). We examined the expression of versican splice variants at mRNA and protein levels in normal human brain and in gliomas, medulloblastomas, schwannomas, neurofibromas, and meningiomas. RT-PCR revealed transcripts for V0 and V1 in all tissues. V2 mRNA was restricted to gliomas and normal brain, while V3 mRNA was detected in all tissues except for medulloblastomas. Immunohistochemistry using antibodies to the glycosaminoglycan (GAG)-alpha attachment domain of versican (present in V0 and V2) revealed decreased staining of most glioma ECMs compared to normal neuropil, while some abnormal tumor vessels, but not normal cerebral vessels, were GAG-alpha-positive. Expression of the GAG-beta attachment domain (present in V0 and V1) was faint in normal neuropil and cerebral vessels, but increased in tumor vessels and was absent in most glioma ECMs. Both GAG-alpha and GAG-beta were expressed in connective tissue of all nonglial tumors. Our data suggest that V2 is the major versican isoform of normal neuropil and glioma ECM. Furthermore, increased expression in tumor vessels and decreased expression in glioma ECM of the anti-adhesive versican may be related to marked local invasivity and rarity of extracranial metastasis of gliomas.

Base Sequence↗
PubMed2001

Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries: correlation to patency.

BACKGROUND: Matrix proteoglycans versican, biglycan and decorin are important determinants of vessel-wall structure and pathology. Thickened myxoid intimas typical of restenosis and early atherosclerosis are enriched in versican and biglycan, proteoglycans that promote proliferation and migration of smooth muscle cells and bind lipoproteins. In contrast, compact fibrous intimas are characterized by decorin. OBJECTIVE: To compare the distribution patterns of these matrix proteoglycans, and changes induced by organ culture in coronary artery, saphenous vein, internal thoracic artery (ITA), and radial artery, and correlate differences to patency. METHODS: Vessels were collected at the time of bypass surgery and heart transplantation and either fixed for immunohistochemistry or prepared for organ culture. Vessels in culture were labelled with [3H]-glucosamine and processed for autoradiography and immunohistochemistry. Distribution patterns for proteoglycans and radio-labelling were determined morphometrically. RESULTS: Distribution profiles in coronary artery and saphenous vein were similar, with relatively high levels of subendothelial versican and biglycan and low levels of decorin. In culture subendothelial incorporation of [3H]-glucosamine and immunostaining for versican and biglycan, but not decorin, were significantly increased. In contrast, the thin intima of the ITA was relatively enriched in decorin compared with the medial layers and in culture intimal staining for decorin increased markedly compared with a modest increase for biglycan and no change for versican. There was an even distribution in radial artery of all three proteoglycans across the intima without subendothelial accumulations. In culture there was an increase in staining intensity for proteoglycans of the radial artery. Neither the ITA nor radial artery exhibited an increase in subendothelial incorporation of [3H]-glucosamine in culture. CONCLUSIONS: The distributions of proteoglycans, and responses to culture correlate to the known differences in patency between grafted saphenous vein and ITA and predict that the radial artery will outperform the saphenous vein but might not be as good as the ITA for long-term patency.

Adult↗
PubMed2005

Identification of versican as an isolectin B4-binding glycoprotein from mammalian spinal cord tissue.

Nociceptors are specialized nerve fibers that transmit noxious pain stimuli to the dorsal horn of the spinal cord. A subset of nociceptors, the nonpeptidergic C-fibers, is characterized by its reactivity for the plant isolectin B4 (IB4) from Griffonia simplicifolia. The molecular nature of the IB4-reactive glycoconjugate, although used as a neuroanatomical marker for more than a decade, has remained unknown. We here present data which strongly suggest that a splice variant of the extracellular matrix proteoglycan versican is the IB4-reactive glycoconjugate associated with these nociceptors. We isolated (by subcellular fractionation and IB4 affinity chromatography) a glycoconjugate from porcine spinal cord tissue that migrated in SDS/PAGE as a single distinct protein band at an apparent molecular mass of > 250 kDa. By using MALDI-TOF/TOF MS, we identified this glycoconjugate unambiguously as a V2-like variant of versican. Moreover, we demonstrate that the IB4-reactive glycoconjugate and the versican variant can be co-released from spinal cord membranes by hyaluronidase, and that the IB4-reactive glycoconjugate and the versican variant can be co-precipitated by an anti-versican immunoglobulin and perfectly co-migrate in SDS/PAGE. Our findings shed new light on the role of the extracellular matrix, which is thought to be involved in plastic changes underlying pain-related phenomena such as hyperalgesia and allodynia.

Amino Acid Sequence↗
PubMed2002

Human coronary smooth muscle cells internalize versican-modified LDL through LDL receptor-related protein and LDL receptors.

Versican-like proteoglycans are the main component of the intimal extracellular matrix interacting with low density lipoprotein (LDL). The aim of this study has been to investigate the receptors involved in versican-modified LDL uptake by human vascular smooth muscle cells (VSMCs). We have found that versican-LDL interaction leads to the following: (1) monomeric LDL particles that are similar in size and electrophoretic mobility to native LDL but that have a higher capacity to induce intracellular cholesteryl ester (CE) accumulation and (2) fused LDL particles similar in size to those obtained by vortexing. The precipitable fraction of versican-LDL, composed of 50% monomeric and 50% fused LDL particles, induced a dose-response increase in the CE content of VSMCs. Anti-LDL receptor antibody decreased the CE accumulation derived from monomeric LDL particles by 88 +/- 3% and that derived from the total precipitable fraction by 45 +/- 3%. Inhibition of LDL receptor-related protein expression by antisense oligodeoxynucleotides reduced the CE accumulation derived from the precipitable fraction by 65 +/- 2.8%, whereas it did not produce any effect on the CE accumulation derived from monomeric LDL. These results suggest that versican-LDL induces CE accumulation in human VSMCs by the LDL receptor (monomeric particles) and LDL receptor-related protein (fused LDL).

Cell Membrane↗
PubMed2000

Brain derived versican V2 is a potent inhibitor of axonal growth.

In this paper, we identify the chondroitin sulfate proteoglycan versican V2 as a major inhibitor of axonal growth in the extracellular matrix of the mature central nervous system. In immunohistochemical and in situ hybridization experiments we show that this tissue-specific splice variant of versican is predominantly present in myelinated fiber tracts of the brain and in the optic nerve, most likely being expressed by oligodendrocytes. We demonstrate that isolated versican V2 strongly inhibits neurite outgrowth of central and peripheral neurons in stripe-choice assays using laminin-1 as permissive substrate. The inhibitory character of versican V2 is maintained after removal of chondroitin sulfate and N- and O-linked oligosaccharide side chains, but it is abolished after core protein digestion with proteinase-K. Our data support the notion, that intact versican V2 prevents excessive axonal growth during late phases of development and hereby participates in the structural stabilization of the mature central nervous system.

Animals↗
PubMed2003

Distribution of versican and hyaluronan in the mouse uterus during decidualization.

Preparation for embryo implantation requires extensive adaptation of the uterine microenvironment. This process consists of cell proliferation and cell differentiation resulting in the transformation of endometrial fibroblasts into a new type of cell called decidual cell. In the present study, we followed the space-time distribution of versican and hyaluronan (HA) in different tissues of the uterus before and after embryo implantation. Fragments of mouse uteri obtained on the fourth, fifth, sixth and seventh days of pregnancy were fixed in Methacarn, embedded in Paraplast and cut into 5-microm thick sections. HA was detected using a biotinylated fragment of the proteoglycan aggrecan, which binds to this glycosaminoglycan with high affinity and specificity. Versican was detected by a polyclonal antibody. Both reactions were developed by peroxidase methods. Before embryo implantation, both HA and versican were present in the endometrial stroma. However, after embryo implantation, HA disappeared from the decidual region immediately surrounding the implantation chamber, whereas versican accumulated in the same region. The differences observed in the expression of HA and versican suggest that both molecules may participate in the process of endometrial decidualization and/or embryo implantation.

Animals↗