Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.6.4 (chondroitinase)
2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metastatic spread of tumor cells occurs through a complex series of events, one of which involves the adhesion of tumor cells to extracellular matrix (ECM) components. Multiple interactions between cell surface receptors of an adherent tumor cell and the surrounding ECM contribute to cell motility and invasion. The current studies evaluate the role of a cell surface chondroitin sulfate proteoglycan (CSPG) in the adhesion, motility, and invasive behavior of a highly metastatic mouse melanoma cell line (K1735 M4) on type I collagen matrices. By blocking mouse melanoma cell production of CSPG with p-nitrophenyl beta-D-xylopyranoside (beta-D-xyloside), a compound that uncouples chondroitin sulfate from CSPG core protein synthesis, we observed a corresponding decrease in melanoma cell motility on type I collagen and invasive behavior into type I collagen gels. Melanoma cell motility on type I collagen could also be inhibited by removing cell surface chondroitin sulfate with chondroitinase. In contrast, type I collagen-mediated melanoma cell adhesion and spreading were not affected by either beta-D-xyloside or chondroitinase treatments. These results suggest that mouse melanoma CSPG is not a primary cell adhesion receptor, but may play a role in melanoma cell motility and invasion at the level of cellular translocation. Furthermore, purified mouse melanoma cell surface CSPG was shown, by affinity chromatography and in solid phase binding assays, to bind to type I collagen and this interaction was shown to be mediated, at least in part, by chondroitin sulfate. Additionally we have determined that mouse melanoma CSPG is composed of a 110-kD core protein that is recognized by anti-CD44 antibodies on Western blots. Collectively, our data suggests that interactions between a cell surface CD44-related CSPG and type I collagen in the ECM may play an important role in mouse melanoma cell motility and invasion, and that the chondroitin sulfate portion of the proteoglycan seems to be a critical component in mediating this effect.
...
PMID:A cell surface chondroitin sulfate proteoglycan, immunologically related to CD44, is involved in type I collagen-mediated melanoma cell motility and invasion. 173 Jul 66

The lymphocyte-high endothelial venule (HEV) cell interaction is an essential element of the immune system, as it controls lymphocyte recirculation between blood and lymphoid organs in the body. This interaction involves an 85-95-kD class of lymphocyte surface glycoprotein(s), CD44. A subset of lymphocyte CD44 molecules is modified by covalent linkage to chondroitin sulfate (Jalkanen, S., M. Jalkanen, R. Bargatze, M. Tammi, and E. C. Butcher. 1988. J. Immunol. 141:1615-1623). In this work, we show that removal of chondroitin sulfate by chondroitinase treatment of lymphocytes or incubation of HEV with chondroitin sulfate does not significantly inhibit lymphocyte binding to HEV, suggesting that chondroitin sulfate is not involved in endothelial cell recognition of lymphocytes. Affinity-purified CD44 antigen was, on the other hand, observed to bind native Type I collagen fibrils, laminin, and fibronectin, but not gelatin. Binding to fibronectin was studied more closely, and it was found to be mediated through the chondroitin sulfate-containing form of the molecule. The binding site on fibronectin was the COOH-terminal heparin binding domain, because (a) the COOH-terminal heparin-binding fragment of fibronectin-bound isolated CD44 antigen; (b) chondroitin sulfate inhibited this binding; and (c) finally, the ectodomain of another cell surface proteoglycan, syndecan, which is known to bind the COOH-terminal heparin binding domain of fibronectin (Saunders, S., and M. Bernfield. 1988. J. Cell Biol. 106: 423-430), inhibited binding of CD44 both to intact fibronectin and to its heparin binding domain. Moreover, inhibition studies showed that binding of a lymphoblastoid cell line, KCA, to heparin binding peptides from COOH-terminal heparin binding fragment of fibronectin was mediated via CD44. These findings suggest that recirculating lymphocytes use the CD44 class of molecules not only for binding to HEV at the site of lymphocyte entry to lymphoid organs as reported earlier but also within the lymphatic tissue where CD44, especially the subset modified by chondroitin sulfate, is used for interaction with extracellular matrix molecules such as fibronectin.
...
PMID:Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin. 173 Jul 78

We report herein identification of a novel ligand for CD44, a cell surface glycoprotein implicated in tumor metastasis, lymphocyte differentiation and homing. A mouse T cell line CTLL-2 transfected with cDNA encoding a hemopoietic form of mouse CD44 exhibited a new self-adhesive phenotype, forming large aggregates. The aggregation was blocked by anti-CD44 mAb but little affected by hyaluronidase, indicating the involvement of CD44 and its non-hyaluronate ligand in the cell aggregation. The ability to induce CD44-dependent aggregation was observed in culture supernatants of CTLL-2 and its CD44 transfectants. Immunoprecipitation analysis using a CD44-Ig chimeric molecule indicated that CTLL-2 and its transfectants synthesized a macromolecule (gp600) which bound specifically to CD44. gp600 was readily labeled with radioactive sulfate and treatment of gp600 with chondroitinase ABC or AC II generated a lower molecular weight species (18-22 kDa), suggesting that gp600 consists of a small core protein heavily modified with chondroitin sulfate glycosaminoglycan side chains. However, when binding of CD44 was tested in vitro to chondroitinase-sensitive purified glycosaminoglycans, such as chondroitin-4-sulfate, chondroitin-6-sulfate and dermatan sulfate, no binding was demonstrable, suggesting either that a novel type of chondroitinase-sensitive glycosaminoglycan is recognized by CD44 or that association of the glycosaminoglycan with a core protein is required for recognition by CD44.
...
PMID:A novel ligand for CD44 is sulfated proteoglycan. 751 79

We have identified a novel ligand for CD44, a cell surface glycoprotein implicated in tumor metastasis and lymphocyte homing. When the mouse T cell line CTLL-2 was transfected with cDNA encoding a hemopoietic form of mouse CD44, CTLL-2 cells exhibited a new self-adhesive phenotype, forming large aggregates. The aggregation was blocked by neutralizing anti CD44 monoclonal antibody but unaffected by hyaluronidase, indicating the involvement of CD44 and its non-hyaluronate ligand in the cell aggregation. The ability to induce CD44-dependent aggregation was found in culture supernatants of CTLL-2 and its CD44 transfectants. The use of CD44-immunoglobulin chimeric protein revealed that CTLL-2 and its transfectants synthesized a large-molecular weight protein (gp600) which bound specifically to CD44. The gp600 was readily labeled with radioactive sulfate, and treatment of gp600 with chondroitinase ABC or ACII generated a lower molecular weight species (18-22 kDa), suggesting that gp600 consists of a small core protein with chondroitin sulfate glycosaminoglycan side chains. However, binding of CD44 to glycosaminoglycans such as chondroitin 4-sulfate, chondroitin 6-sulfate, and dermatan sulfate was undetectable, suggesting either that a novel chondroitin-type glycosaminoglycan is recognized by CD44 or that a particular configuration of the glycosaminoglycan is required for recognition by CD44.
...
PMID:A sulfated proteoglycan as a novel ligand for CD44. 2292 40

CD44 is a major cell surface receptor for the extracellular matrix glycosaminoglycan hyaluronan (HA). However, the ability of CD44 to bind ligand is strictly regulated. Three activation states of CD44 have been demonstrated: (a) inactive; (b) inducible (by certain CD44-specific mAb); and (c) constitutively active. Starting with two parental cell lines expressing CD44 in the inactive state, a pre-B cell (RAW 253) and a fibroblast (L cells), we used fluorescence-activated cell sorting with fluorescein-conjugated hyaluronan in the presence of inducing mAb to derive variant cell lines with CD44 in the inducible state. Constitutively active derivatives were isolated from the inducible variants by a further round of fluorescence-activated cell sorting in the absence of inducing antibody. However, constitutively active variants could not be isolated directly from parental cells expressing CD44 in the inactive state. These results suggest that two genetic events must occur to obtain an active CD44-HA receptor from an inactive receptor. Variant and parental cell-derived CD44 molecules exhibited differences in migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis that were partly attributable to differences in N-linked glycosylation. Furthermore, culture in tunicamycin for 2-3 d converted parental and inducible cell lines into cells showing constitutive CD44-mediated HA binding. Also, removal of cell surface glycosaminoglycan chains by culture of cells in p-nitrophenyl beta-D-xylopyranoside or treatment with chondroitinase ABC resulted in conversion of cells with an inactive CD44 receptor to an inducible state. These results indicate that carbohydrate side chains of CD44 and/or other molecules on the cell surface that interact with CD44 are potentially involved in regulating the HA-binding function of CD44 on the cell surface.
...
PMID:Variant cell lines selected for alterations in the function of the hyaluronan receptor CD44 show differences in glycosylation. 754 38

Microvascular endothelial cell invasion into the fibrin provisional matrix is an integral component of angiogenesis during wound repair. Cell surface receptors which interact with extracellular matrix proteins participate in cell migration and invasion. Malignant cells use CD44-related chondroitin sulfate proteoglycan (CSPG) as a matrix receptor to mediate migration and invasion. In this study, we examine whether cell surface CSPG can mediate similar events in nonmalignant wound microvascular endothelial cells or whether use of CSPG for migration and invasion is a property largely restricted to malignant cells. After inhibiting CSPG synthesis with p-nitrophenyl beta-d xylopyranoside (beta-d xyloside), wound microvascular endothelial cells were capable of attaching and spreading on the surface of a fibrin gel; however, their ability to invade the fibrin matrix was virtually eliminated. To begin to examine the mechanism by which endothelial cells use CSPG to invade fibrin matrices, cell adhesion and migration on fibrinogen was examined. Endothelial cell adhesion and migration on fibrinogen were inhibited by both beta-d xyloside and after cleavage of chondroitin sulfate from the core protein by chondroitinase ABC. We have determined that wound microvascular endothelial cells express the majority of their proteoglycan as CSPG and that the CSPG core protein is immunologically related to CD44. PCR studies show that these cells express both the "standard" (CD44H) isoform and an isoform containing the variably spliced exon V3. In addition, anti-CD44 antibody blocks endothelial cell migration on fibrinogen. Affinity chromatography studies reveal that partially purified microvascular endothelial cell CSPG binds fibrinogen. These findings suggest that CD44-related CSPG, a molecule implicated in the invasive behavior of tumor cells, is capable of binding fibrinogen/fibrin, thereby mediating endothelial cell migration and invasion into the fibrin provisional matrix during wound repair.
...
PMID:CD44-related chondroitin sulfate proteoglycan, a cell surface receptor implicated with tumor cell invasion, mediates endothelial cell migration on fibrinogen and invasion into a fibrin matrix. 864 47

We have previously suggested that sulfated polysaccharides could be used in a vaginal formulation to inhibit infection by human immunodeficiency virus (HIV-1). This supposition was based on studies in which we developed and employed an in vitro model to simulate the mechanism of HIV-1 transmission during coitus. We found that adhesion of mononuclear cells to epithelia was the initial step in infection and speculated that blocking adhesion would prevent HIV-1 transmission. We observed that certain sulfated polysaccharides prevented adhesion of lymphoma cell lines to epithelial cell lines, which were derived from the genital tract, in concentrations of a few milligrams per milliliter; and we theorized that sulfated polysaccharides could thus be used as active ingredients in a topical "microbicide." In the present in vitro study, evidence is presented that a number of sulfated polysaccharides, including carrageenan, dextran sulfate, heparin, fucoidan, and pentosan polysulfate, are capable of blocking infection by mechanisms other than adhesion at concentrations of a thousand times lower than the dosages that are needed to block cell adhesion. One of these compounds, iota carrageenan, is capable not only of blocking infection of epithelia at concentrations of 1-2 micrograms, but of blocking adhesion to a far greater extent than the other sulfated polysaccharides tested. For this reason, as well as for considerations of safety, stability, and gelling properties, we suggest that iota carrageenan may be the best choice of the sulfated polysaccharides tested for use as a vaginal microbicide. The same in vitro model was employed to decipher the cell surface molecules involved in lymphocyte-to-epithelial adhesion. To accomplish this, we screened for the presence of cell adhesion molecules (CAMs), carbohydrates, proteoglycans, and carbohydrate-binding sites. HIV-1-infected lymphocytic cells expressed a CAM profile typical of activated, infected cells (e.g., HLA-DR+, CD4-, LFA-1+, ICAM-1+, LFA-3+, CD2+) whereas epithelia expressed few CAMs (LFA-3, ICAM-1, VLA-5, CD44, CD26, sLEX). Both cell types expressed heparan sulfate and chondroitin sulfate proteoglycans. A variety of sugars (mannose, fucose, galactose, Nac-galactosamine, Nac-glucosamine) were also present, but these cells expressed few carbohydrate-binding sites; lymphocytes bound beta-galactose. We were unable to block the adhesion with anti-CAM antibodies or with exogenous sugars. When enzymes were used against sulfated cell surface molecules, chondroitinase was found to block the adhesion. Our evidence suggests that this CAM-independent adhesion may be a lectin-glycosaminoglycan interaction.
...
PMID:Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of human immunodeficiency virus-1. 883 15

CD44 is an integral membrane glycoprotein that is a principal receptor for hyaluronan and plays a role in cell-extracellular matrix interactions. Recent studies of melanomas in mouse models have suggested that increased CD44 expression by these tumors may relate to metastatic potential. Immunohistochemical expression of CD44 (standard [s] and variant [v6]) in benign and malignant nevomelanocytic lesions was assessed in formalin-fixed, paraffin-embedded tissue and was correlated with histological parameters and prognostic factors. Cases included benign nevi (three junctional, four compound, five intradermal, five blue, six Spitz, one deep penetrating), architecturally disordered (dysplastic) nevi (three, and primary (22) and metastatic melanomas (eight). All of the benign lesions showed diffuse and essentially uniform membrane staining of CD44s in nevomelanocytic cells, regardless of lesion size, depth, or extent of dermal involvement. In contrast, semiquantitative analysis (0 to 3+) of the primary melanomas showed heterogeneous and decreased staining of CD44s, which inversely correlated with lesion size (-0.569) and depth of invasion (-0.622 and -0.617 for Breslow's depth and Clark's level, respectively). These results were significant at P < .05. CD44s expression in metastases paralleled that of their respective primaries. None of the benign nevomelanocytic lesions showed CD44v6 staining. In contrast, all of the malignant nevomelanocytic lesions showed cytoplasmic staining of the tumor cells. Pretreatment with chondroitinase did not alter CD44s staining. CD44s expression by immunohistochemical determination is uniform in benign nevomelanocytic lesions. Malignant melanomas show decreased, heterogeneous staining that inversely correlates with increasing size, depth, and level of invasion. CD44 expression may be a prognostic indicator in malignant melanomas. Tumor staining with anti-chondroitin sulfate monoclonal antibodies suggests that CD44s may be expressed as a chondroitin sulfate proteoglycan in primary melanomas.
...
PMID:CD44 expression in benign and malignant nevomelanocytic lesions. 895

Collagen XIV, a fibril-associated collagen with interrupted triple helices, is expressed in differentiated soft connective tissues and in cartilage. However, a cellular receptor for this protein has not been identified. Here we show that human placental collagen XIV, isolated by a mild and simple two-step method, serves as adhesive protein for a variety of mesenchymal and some epithelial cells. Cell adhesion could be inhibited by preincubation of the collagen XIV substrate with heparin or with the chondroitin/dermatan sulfate proteoglycan decorin and by pretreatment of cells with chondroitinase ABC or heparinase III, suggesting a cell membrane proteoglycan as receptor. Affinity chromatography of 125I-labeled fibroblast cell surface proteins on collagen XIV-Sepharose yielded a chondroitin/dermatan sulfate proteoglycan with a molecular mass of 97-105 kDa after chondroitinase ABC digestion and of 60-70 kDa after further treatment with N-glycosidase F. The eluates contained also some high-molecular-weight material that was susceptible to digestion with heparinase but no detectable integrins. Immunoprecipitation with a specific monoclonal antibody identified the prominent chondroitin/dermatan sulfate proteoglycan as a member of the CD44 family. The interaction between collagen XIV and cells appears to be finely tuned, since matrix-associated glycosaminoglycans, and particularly proteoglycans like decorin, could compete with cells for the binding site(s) on collagen XIV under physiological conditions.
...
PMID:A chondroitin/dermatan sulfate form of CD44 is a receptor for collagen XIV (undulin). 898 22

CD44 is a group of cell surface glycoproteins that is generated from a single gene by mRNA splice variation. Its functions in matrix adhesion and tumor invasion are strongly influenced by glycosylation. We studied the glycosylated tissue forms of CD44 from extracts of normal adult human epidermis by using western blotting and immunoprecipitation from short-term skin organ cultures. An antibody for CD44 (Hermes 3) precipitated 7-17% of all 35SO4-labeled proteoglycans (PGs) synthesized in epidermis. Immunoprecipitates digested with heparitinase lost 40-68% of incorporated 35SO4 and 24-40% of [3H]glucosamine, indicating that heparan sulfate was the predominant glycosaminoglycan in epidermal CD44. Chondroitinase ABC released 10-25% and 6-12% of 35SO4 and [3H]glucosamine, respectively. Less than 5% of both isotopes were susceptible to keratanase. Five to 33% of 35SO4 and 26-37% of [3H]glucosamine, however, was released by endo-beta-galactosidase, implying marked substitution by oligosaccharides with N-acetyllactosamine repeats. Heparitinase pretreatment retarded, whereas endo-beta-galactosidase enhanced the mobility of the > or = 180-kDa polydisperse CD44 on agarose gel electrophoresis. On SDS-polyacrylamide gel electrophoresis, however, western blotting and fluorographs of 35SO4-labeled immunoprecipitates showed the main CD44 isoform at > or = 250 kDa and a shift to 180-200 kDa after heparitinase treatment. Keratanase, keratanase II, and chondroitinase ABC had minor effects. A less abundant form of CD44, with a core of 100 kDa, partly substituted with chondroitinase ABC- and endo-beta-galactosidase-sensitive chains, was also present. Therefore, the large heparan sulfate-substituted CD44 forms a significant part of all proteoglycans in normal human epidermis. Both the large and the 100-kDa variant of epidermal CD44 contain endo-beta-galactosidase-sensitive oligosaccharides not previously noted in other cells or tissues.
...
PMID:CD44 substituted with heparan sulfate and endo-beta-galactosidase-sensitive oligosaccharides: a major proteoglycan in adult human epidermis. 924 10


1 2 3 Next >>

---