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PubMed1988

Differential expression of fibronectin in a rat histiocytoma: possible role of fibronectin in tumor cell adhesion.

The specific role of fibronectin in tumor cells has been investigated using the transplantable histiocytic tumor line AK-5 [A. Khar (1986) J. Natl. Cancer Inst. 76, 871]. These cells, capable of growth as both ascites and solid tumors in rats, can be separated into four subpopulations by buoyant density centrifugation on Percoll. These subpopulations are shown to contain different amounts of fibronectin on the cell surface when studied by immunofluorescent staining followed by cytofluorometric analysis. Cells which contain high amounts of fibronectin can grow both as ascites and as solid tumors while those cells which contain low amounts of fibronectin cannot grow as solid tumors but can grow as ascitic tumors. Pretreatment of high-fibronectin-containing cells with anti-fibronectin antibody abolished their capacity to grow as solid tumors; however, the cells retained their capacity to grow as ascitic tumors. These results have been discussed with reference to the specific role of fibronectin in tumor-forming cells.

Animals↗
PubMed1986

Acylated fibronectin: a new type of posttranslational modification of cellular fibronectin.

Human fibroblasts were labelled with either [35S]methionine or [3H]palmitate and analyzed for the presence of 35S- or 3H-labelled fibronectin by immunoprecipitation and SDS-polyacrylamide gel electrophoresis. The majority of 35S-labelled fibronectin was found in the extracellular matrix of cells which could be removed quantitatively by mild trypsin treatment. In contrast, 3H-labelled fibronectin was found in a trypsin-resistant form. The 3H label of fibronectin could be identified predominantly as [3H]palmitate by HLPC analysis. The fatty acids remained stably associated with fibronectin during extraction and electrophoresis, indicating a covalent linkage. These results demonstrate that a subset of fibronectin different from extracellular matrix fibronectin is modified by acylation.

Acylation↗
PubMed1986

A weaker gelatin-binding affinity and increased glycosylation of amniotic fluid fibronectin than plasma fibronectin.

Human amniotic fluid fibronectin had different carbohydrate moieties from plasma fibronectin. Nearly 90% of glycopeptides released from amniotic fluid fibronectin was not bound by concanavalin A-Sepharose, whereas 75% of glycopeptides from plasma fibronectin was bound. Amniotic fluid fibronectin showed a significantly lower gelatin-binding affinity than plasma fibronectin at 25 degrees C. When the incubation temperature was lowered to 4 degrees C, no significant difference in this activity was found. Cell-attachment promoting activity of the two fibronectins was not significantly different.

Amniotic Fluid↗
PubMed1994

Forskolin induces the reorganization of extracellular matrix fibronectin and cytoarchitecture in 3T3-F442A adipocytes: its effect on fibronectin gene expression.

We studied the effect of forskolin on fibronectin and actin gene expression in 3T3-F442A adipogenic cell line. The structural organizations of extracellular matrix fibronectin and actin cytoskeleton were investigated in parallel. Immunofluorescence experiments showed that preadipocytes treated for 48 h with 10 microM forskolin exhibited an intensified network of both actin and fibronectin when compared to control. A similar picture was obtained with adipocytes given long-term exposure to forskolin. As determined by Western analysis, fibronectin protein levels were increased by 50-75% over control, both in preadipocytes and adipocytes. A parallel increase of fibronectin mRNA content was observed in forskolin-treated cells. In contrast, forskolin treatment of preadipocytes and adipocytes did not elicit any change in the steady-state level of either actin mRNA or protein. Nuclear run-on experiments showed that forskolin increased the fibronectin gene transcription rate but left that of the actin gene in adipocytes unchanged. These findings suggest the reorganization of the actin network in forskolin-treated adipocytes to be a consequence of fibronectin-enhanced biosynthesis and reorganization.

3T3 Cells↗
PubMed1995

Differential expression of fibronectin splice variants, oncofetal glycosylated fibronectin and laminin isoforms in nodular palmar fibromatosis.

The tissue formation process in nodular palmar fibromatosis (Morbus Dupuytren) was investigated by the demonstration of fibronectin splice variants (ED-A and ED-B fibronectin), de novo glycosylated fibronectin and laminin isoforms (A, M, B1, B2, s chains) in association to the proliferative activity (Ki-67 antigen) and the occurrence of myofibroblast phenotype (alpha-smooth muscle actin, desmin). The proliferative noduli of the fibromatosis were characterized by a diffuse immunostaining for alpha-smooth muscle actin, and single cells positive for desmin and the Ki-67 antigen. In contrast to the surrounding aponeurosis as extracellular matrix, components of the whole proliferative noduli were defined: ED-A, ED-B and de novo glycosylated fibronectin, B1 and B2 laminin chain, tenascin and collagen type IV. The demonstration of the A and M laminin chain was restricted to a few cells of the proliferative noduli. S laminin could be visualized in the majority of palmar aponeurotic fibroblasts. As revealed by mRNA, in situ hybridization a de novo synthesis of fibronectin could only be detected within proliferative noduli. There is a positive correlation between the myofibroblast phenotype formation, cellular proliferation and the occurrence of ED-A and ED-B containing fibronectin, as well as de novo glycosylated fibronectin in Dupuytren's disease. The ultrastructural irregularities of myofibroblastic basal lamina and the heterogeneity of the myofibroblast phenotype are equivalent to the variability of laminin isoform immunostaining.

Alternative Splicing↗
PubMed2002

The fibronectin-binding integrins alpha5beta1 and alphavbeta3 differentially modulate RhoA-GTP loading, organization of cell matrix adhesions, and fibronectin fibrillogenesis.

We have studied the formation of different types of cell matrix adhesions in cells that bind to fibronectin via either alpha5beta1 or alphavbeta3. In both cases, cell adhesion to fibronectin leads to a rapid decrease in RhoA activity. However, alpha5beta1 but not alphavbeta3 supports high levels of RhoA activity at later stages of cell spreading, which are associated with a translocation of focal contacts to peripheral cell protrusions, recruitment of tensin into fibrillar adhesions, and fibronectin fibrillogenesis. Expression of an activated mutant of RhoA stimulates alphavbeta3-mediated fibrillogenesis. Despite the fact that alpha5beta1-mediated adhesion to the central cell-binding domain of fibronectin supports activation of RhoA, other regions of fibronectin are required for the development of alpha5beta1-mediated but not alphavbeta3-mediated focal contacts. Using chimeras of beta1 and beta3 subunits, we find that the extracellular domain of beta1 controls RhoA activity. By expressing both beta1 and beta3 at high levels, we show that beta1-mediated control of the levels of beta3 is important for the distribution of focal contacts. Our findings demonstrate that the pattern of fibronectin receptors expressed on a cell dictates the ability of fibronectin to stimulate RhoA-mediated organization of cell matrix adhesions.

Actins↗
PubMedDate not supplied

Interactions of fibronectin with streptococci: the role of fibronectin as a receptor for Streptococcus pyogenes.

Current evidence suggests that lipoteichoic acid (LTA) on the surface of Streptococcus pyogenes is centrally involved in the adherence of these bacteria to the oral mucosa. The major receptor on the surface of buccal mucosal cells for S. pyogenes is fibronectin. Fibronectin is a complex glycoprotein found in blood, extracellular matrices, and saliva. Many species of streptococci bind to fibronectin, although the characteristics of these interactions are different. Furthermore, whereas LTA is an efficient inhibitor of the binding of fibronectin to group A streptococci, it has little ability to inhibit the binding of fibronectin to Streptococcus pneumoniae or Staphylococcus aureus. Studies conducted with fibronectin show that different bacteria bind to different sites. The ability of various bacteria to interact with different domains on the fibronectin molecule may play an important role in bacterial adherence and tissue tropism.

Animals↗
PubMed1983

[Distribution of fibronectin on the surface of single fibroblasts. The possible mechanism of the assembly of fibronectin structures].

Distribution of fibronectin on the surface of lamelloplasm and endoplasm of single cultured mouse embryo fibroblasts was studied by means of indirect immunofluorescence technique. Large fibronectin fibrillae were located on the surface of endoplasm mainly, while "spots" and "streaks" of fibronectin dominated on the surface of lamelloplasm. Colcemid-treated cells had approximately the same distribution whereas cytochalasin B-treated cells were characterized by a spotty fluorescence alone. In contrast, in dense cultures of colcemid-treated cells fibronectin network underwent tearing, while it remained unchanged in cytochalasin B-treated cells. The centripetal movement of the fibronectin--receptor complexes along the cell surface from lamelloplasm into endoplasm (or the natural capping of fibronectin receptors) seems to play an important role in the assembling of fibronectin fibrillae.

Animals↗
PubMed2001

Fibronectin-binding protein A of Staphylococcus aureus has multiple, substituting, binding regions that mediate adherence to fibronectin and invasion of endothelial cells.

Invasive Staphylococcus aureus infection frequently involves bacterial seeding from the bloodstream to other body tissues, a process necessarily involving interactions between circulating bacteria and vascular endothelial cells. Staphylococcus aureus fibronectin-binding protein is central to the invasion of endothelium, fibronectin forming a bridge between bacterial fibronectin-binding proteins and host cell receptors. To dissect further the mechanisms of invasion of endothelial cells by S. aureus, a series of truncated FnBPA proteins that lacked one or more of the A, B, C or D regions were expressed on the surface of S. aureus and tested in fibronectin adhesion, endothelial cell adhesion and invasion assays. We found that this protein has multiple, substituting, fibronectin-binding regions, each capable of conferring both adherence to fibronectin and endothelial cells, and endothelial cell invasion. By expressing S. aureus FnBPA on the surface of the non-invasive Gram-positive organism Lactococcus lactis, we have found that no other bacterial factor is required for invasion. Furthermore, we have demonstrated that, as with other cell types, invasion of endothelial cells is mediated by integrin alpha5beta1. These findings may be of relevance to the development of preventive measures against systemic infection, and bacterial spread in the bacteraemic patient.

Adhesins, Bacterial↗
PubMed1995

Vitamin E succinate induction of HL-60 cell adhesion: a role for fibronectin and a 72-kDa fibronectin-binding molecule.

HL-60 cells, growing as single cells in suspension, exhibit marked cell-cell adhesion when treated for 24 hours with 10 micrograms/ml RRR-alpha-tocopheryl succinate, also called vitamin E succinate (VES). VES-induced cell-cell adhesion is dependent on divalent cations and a functional cytoskeleton and is protein mediated. Cell adhesion molecules CD11a/CD18, CD11b/CD18, CD29, and CD54 do not appear to be mediating VES-induced cell adhesion. HL-60 cells treated with VES adhere to fibronectin-coated plastic and secrete elevated levels of fibronectin. A 72-kDa fibronectin-binding membrane molecule was detected on VES-treated HL-60 cells, and antibodies to fibronectin were shown to inhibit VES-induced cell aggregation. VES induction of HL-60 cell-cell adhesion is proposed to result from increased amounts of extracellular fibronectin binding to VES-induced cell surface fibronectin-binding molecules.

Antibodies↗
PubMed1992

Epidermal growth factor stimulates corneal epithelial cell attachment to fibronectin through a fibronectin receptor system.

Epidermal growth factor (EGF) stimulates corneal epithelial migration in vivo and in vitro. Antibody against fibronectin inhibits this effect in vitro, suggesting that a fibronectin-dependent mechanism in involved. To elucidate the action of EGF, we placed rabbit corneal epithelial cells, preincubated in the absence or presence of EGF (10 ng/ml), into wells coated with fibronectin. After 45 minutes of incubation, the numbers of cells attached to the wells were counted. Preincubation with EGF for 6 hr was not effective, but preincubation for 9 hr significantly increased the numbers of cells attached to the wells. These numbers were not increased further by additional preincubation. When concentrations of EGF were reduced, numbers of attached cells decreased proportionally, but remained significantly higher than the numbers obtained with cells not exposed to EGF. The EGF-stimulated attachment to the fibronectin matrix was inhibited in a dose-dependent fashion by antifibronectin IgG and by GRGDSP, a synthetic peptide that mimics the amino acid sequence of the cell-binding domain of fibronectin. The authors conclude that a fibronectin/fibronectin receptor system mediates EGF-induced stimulation of cellular attachment. These findings suggest that EGF may increase the expression of fibronectin receptors.

Amino Acid Sequence↗
PubMed1991

Fibronectin binding determinants of the Staphylococcus aureus fibronectin receptor.

Synthetic peptide analogs mimicking a repeated motif within the Staphylococcus aureus fibronectin receptor inhibit binding of the bacteria to fibronectin (Signäs, C., Raucci, G., Jonsson, K., Lindgren, P. E., Anantharamaiah, G. M., Höök, M., and Lindberg, M. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 699-703). In this study, we have further localized the fibronectin-binding determinant within the 37 amino acid D3 peptide. Chemical modification of the carboxyl side chains of the glutamic and aspartic residues in D3 abolished fibronectin-binding activity, whereas modifications of lysine or tyrosine residues had little effect. An active peptide encompassing residues 15-36 was isolated from a trypsin digest of D3, and a synthetic peptide S16-36 had activity comparable with that of intact D3. Scrambling the amino acid sequence of S16-36 or replacing the aspartic and glutamic residues with asparagine and glutamine resulted in loss of activity. Therefore, one or more of the acidic residues are essential for activity. However, additional sequence is required. Reduction in the size of S16-36 from either the N- or C-terminal end resulted in peptides with greatly diminished activity. These data suggest that the amino acids essential for binding fibronectin are contained within residues 21-33 of the D3 peptide and that the flanking N- and C-terminal amino acids are necessary for the peptide to acquire a conformation that is favorable for fibronectin binding.

Amino Acid Sequence↗
PubMed1985

Comparisons of evolutionarily distinct fibronectins: evidence for the origin of plasma and fibroblast cellular fibronectins from a single gene.

Plasma and fibroblast cellular fibronectins from three different species were compared for structural similarities and differences. Partial tryptic digestion of either human or chicken plasma and cellular fibronectins yields homologous protease-resistant domains within a species but few homologies between species regardless of the source. Within a species, human or chicken plasma and fibroblast cellular fibronectins are immunologically indistinguishable as determined by the ELISA technique. There is limited immunological cross-reactivity between species. Two-dimensional tryptic peptide maps of fibroblast cellular and plasma fibronectins from the same species are also very similar: 85-95% of the spots on such maps comigrate. When peptide maps from different species are compared, no more than 10% of the spots comigrate. Three models for the genetic origin of cellular and plasma fibronectins in vertebrates are considered. A model in which both fibroblast cellular and plasma fibronectins arise from the same gene is the simplest that is consistent with the data.

Animals↗
PubMed1985

Human keratinocytes that have not terminally differentiated synthesize laminin and fibronectin but deposit only fibronectin in the pericellular matrix.

Fibronectin and laminin production by human keratinocytes cultured in serum-free, low-calcium medium without a fibroblast feeder layer were examined by several techniques. By indirect immunofluorescence, fibronectin but not laminin appeared as short radial fibrils between the cells and the substratum, and in the pericellular matrix. Synthesis of fibronectin and laminin by 7-day keratinocyte cultures was determined by 18 hr 35S-methionine metabolic labeling followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Fibronectin accounted for 2.9% of total synthesized protein, 26.5% of fluid phase protein secretion, and 4.3% of deposited ECM protein. In contrast, only 0.1% of the total synthesized protein was laminin, little (6.3%) of this product was secreted, and none of this product was deposited in the ECM. Our results indicate that human keratinocytes under culture conditions that prevent terminal differentiation in vitro can synthesize, secrete, and deposit fibronectin in the extracellular matrix. Although these cells synthesize laminin, they secrete very little and deposit no detectable laminin in the matrix under these culture conditions. From these data we believe that fibronectin may play an important role in the interaction of epidermal cells with connective tissue matrix during wound healing or morphogenesis in in vivo situations in which the epidermis is not terminally differentiated.

Autoradiography↗
PubMed1992

Basolateral distribution of fibronectin matrix assembly sites on vascular endothelial monolayers is regulated by substratum fibronectin.

Endothelial cells exhibit binding sites for the amino terminus of fibronectin that participate in subendothelial fibronectin matrix assembly. These binding sites, termed matrix assembly sites, are localized on the basolateral surface of confluent endothelial monolayers (Kowalczyk et al. Blood, 75:2335, 1990). The present study investigates the role of cell-cell and cell-substratum interactions in the localization of matrix assembly sites to the basal surface of endothelial cells. Cells were cultured in Transwell culture inserts and matrix assembly sites were detected by binding assays using an iodinated 70 Kd amino-terminal fibronectin fragment. Integrity of intercellular junctions was monitored by measuring protein flux across Transwell filters. Time course experiments demonstrated that matrix assembly site expression on the basolateral cell surface preceded intercellular junction formation. Transfer of confluent monolayers to calcium-free medium resulted in the loss of junctions and in an increase in 125I-70 kD binding from the apical medium. The increased 125I-70 kD binding resulted from increased access of 125I-70 kD to basolateral matrix assembly sites and not from the relocation of binding sites to the apical membrane. To determine the effect of matrix composition on matrix assembly site expression and localization, cells were seeded onto vitronectin- or fibronectin-coated substrates. Fibronectin increased the expression of matrix assembly sites on the apical surface within 24 hours. By 48 hours, matrix assembly sites were located only on the basolateral surface. Vitronectin had no effect on the expression or localization of matrix assembly sites. These results indicate that the expression and localization of matrix assembly sites on the surface of vascular endothelial cells can be regulated by substratum fibronectin.

Animals↗
PubMed1990

Expression of fibronectin and type I collagen by human dental pulp cells and gingiva fibroblasts grown on fibronectin substrate.

Specific antibodies and indirect immunoperoxidase labelling were used to study the intracellular production of collagen and fibronectin by cells grown on fibronectin-coated glass; the same cell populations seeded on uncoated glass were used as controls. Strong intracellular staining for type I collagen was seen in all cases, but immunostaining for fibronectin was very faint or negative in both gingival and pulp cells grown on the fibronectin substrate, in contrast to control cells. Thus, fibronectin substrate inhibited fibronectin synthesis by the cultured cells, but did not seem to influence type I collagen synthesis.

Cells, Cultured↗
PubMed1987

Heterogeneity of fibronectin reactivity among streptococci as revealed by binding of fibronectin fragments.

Streptococci belonging to serological groups A, B, C, G, L and U were studied for their interaction with 125I-labelled fibronectin and its fragments. Fibronectin purified from humans plasma by affinity chromatography on gelatin-agarose and heparin-agarose was cleaved by thrombin into a 29,000 Dalton and a 210,000 Dalton fragments. Terminal analysis of purified fragments indicated that 29,000 fragment was from amino-terminal and 210,000 fragment from carboxyl-terminal domain of fibronectin. Binding of fibronectin was observed in all streptococci except those of group B. Streptococci of groups A, G, L, U and S. equisimilis reacted only with 29,000 Dalton fragment whereas S. dysgalactiae, S. zooepidermicus and S. equi reacted only with 210,000 Dalton fragment. The streptococcal binding sites for these two fragments were distinct from each other. Fibrinogen blocked the binding of 210,000 Dalton fragment but not of 29,000 Dalton fragment. Trypsinization of streptococci did not affect their binding sites for 210,000 Dalton fragment but destroyed those for 29,000 Dalton fragment. The results indicate that the streptococci of group A and G as well as S. equisimilis which are mainly pathogenic in humans bind amino-terminal fragment of fibronectin. This may facilitate the adherence of these pathogens. On the other hand, the streptococci isolated from animal infections had different binding sites recognized only by carboxyl-terminal part of fibronectin.

Binding Sites↗
PubMed1995

Topical fibronectin ophthalmic solution in the treatment of persistent defects of the corneal epithelium. Chiron Vision Fibronectin Study Group.

PURPOSE: We sought to evaluate the efficacy of topical fibronectin ophthalmic solution, containing 3.5 mg/ml of human fibronectin, in the treatment of persistent epithelial defects of the cornea. METHODS: In a double-masked, randomized clinical trial, patients with a persistent, corneal epithelial defect of at least 14 days in duration, and at least 2 mm in width along the larger axis, were sought from the practices of 38 clinical investigators. After a 14-day washout period, 65 patients were randomly assigned to one of three treatment groups. One group (n = 20) received fibronectin drops; the second (n = 23) received drops of the vehicle from the fibronectin solution; and the third (n = 22) received a placebo. RESULTS: After 21 days of treatment, there was no difference in percentage reduction of the corneal epithelial defect size; the average percentage of reduction of defect area ranged from 46.5% to 54.3%. Fibronectin treatment showed a beneficial effect for patients with larger baseline defects (10 mm2 or greater in area); however, no such effect was observed among patients with smaller defects. Defect duration before treatment had a significant effect on outcome (P = .007); defects of longer duration were less likely to decrease in size over the course of the study. CONCLUSIONS: All three treatment groups showed similar reductions in defect size; therefore, this study provides no support for the efficacy of fibronectin treatment of persistent, corneal epithelial defects. Defect duration showed a negative association with reduction in defect size. Because strict control of topical applications during the washout and treatment periods resulted in beneficial responses, physicians should carefully consider the topical medications used by patients who have persistent, corneal epithelial defects.

Administration, Topical↗