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PubMed1987

Influence of fibronectin on the fibrillogenesis of type I and type III collagen.

The in vitro self-assembly of type I and type III calf skin collagen in the presence of fibronectin was studied turbidimetrically. Fibronectin delayed the fibrillogenesis of type III collagen but accelerated that of type I collagen. The effect of fibronectin was concentration-dependent. The lag phase was more altered than the growth phase in the presence of fibronectin while the final turbidity and the amount of fibrils formed were unmodified. Fibrils obtained in the presence of fibronectin all showed native banding pattern. Fibronectin bound partly to collagen fibrils; the amount of bound fibronectin was similar for the two types of collagen and tended to be constant at increasing fibronectin concentrations. It is suggested that the antithetic effect of fibronectin on type I and type III collagen fibrillogenesis may arise both from the different affinity of fibronectin to the two types of collagen and the different aggregation properties of each collagen type.

Animals↗
PubMed1997

Maternal plasma fibronectin: a predictor of preterm delivery.

OBJECTIVE: Current opinion holds that there are several distinct groups among patients with preterm labour: one of them is characterized by bacterial infection, another one by the presence of placental vascular abnormalities with endothelial damage. The aim of this study was to investigate plasma fibronectin, a suspected biochemical marker of endothelial damage, as an indicator for pregnancies with a high risk of preterm delivery. METHODS: Plasma fibronectin levels were measured in patients with preterm labour (n = 80) and in healthy pregnant women with uncomplicated (control) pregnancies (n = 64) between the 22nd and 36th week of gestation. Furthermore, the plasma concentrations of fibronectin in 15 newborns at term and ten babies born preterm were measured to study the relationship between preterm delivery and plasma fibronectin concentration in newborns. Fibronectin was measured by nephelometry. RESULTS: The mean concentration of fibronectin in patients with preterm labour was 0.44 g/l (S.D., 0.15) vs. 0.25 g/l (S.D., 0.12) in uncomplicated control pregnancies matched for gestational age. In control patients who actually delivered at term, fibronectin values were found to be lower than in control patients who underwent preterm delivery (0.25 g/l; S.D., 0.05; vs. 0.46 g/l; S.D., 0.15; P < 0.05). Particularly high values were detected in patients with preterm labour delivering before 32 weeks of gestation (0.60 g/l; S.D., 0.16). There was no significant difference between fibronectin concentrations in the umbilical arterial and venous blood of premature infants and mature infants. Leucocyte concentration, bacteriological smear and cervical dilatation did not correlate with fibronectin concentrations in patients with preterm delivery or controls. CONCLUSION: We conclude that the higher plasma concentrations of fibronectin in women with preterm labour may be a biochemical marker and a predictor of preterm delivery.

Adolescent↗
PubMed2001

Fibronectin in the vitreous body--distribution and possible functional role.

The presence of fibronectin in the bovine vitreous was demonstrated by immunohistochemical procedures which showed a uniform coating of the vitreous collagen network. A fractional extraction of bovine vitreous was carried out in order to determine the distribution of fibronectin and glycosaminoglycans as related to collagen fibers. About half of total fibronectin could be extracted with aqueous buffers with increasing concentrations of KCl, part of fibronectin remained however strongly associated with the insoluble collagen network even after a final extraction with 4 M urea and 0.05 M DTT. Total extractable fibronectin was of the order of 76 micrograms per vitreous, corresponding to approximately 0.17 nM fibronectin. Total quantity of GAG-s determined as uronic acid were of the order of 2200 micrograms/vitreous corresponding approximately to 4400 micrograms disaccharide units that is to about 11 nM disaccharide units of GAG per vitreous. The persistence of fibronectin, strongly associated with the collagen fibers even after repeated KCl and urea-DTT extractions was confirmed using immuno-gold labelling of vitreous collagen fibers. Gold particle density on the collagen fibers increased with the molarity of KCl used for the extractions. These findings suggest that KCl mainly removed fiber associated components probably GAG-s, which hindered the immune recognition of fiber-bound fibronectin. The strong association of fibronectin with vitreous collagen suggested a modified model for vitreous structure taking in account the binding of fibronectin both by collagen and GAG-s.

Animals↗
PubMed2000

Transactivation of EGF receptor induced by angiotensin II regulates fibronectin and TGF-beta gene expression via transcriptional and post-transcriptional mechanisms.

The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of growth factor, and recent evidence indicates transactivation of epidermal growth factor receptor (EGF-R) by G protein-coupled receptors. Here, we report the involvement of EGF-R in Ang II-induced synthesis of fibronectin and TGF-beta in cardiac fibroblasts. Ang II stimulated fibronectin mRNA levels dose-dependently with a maximal increase (approximately 5-fold) observed after 12 h of incubation. Ang II-, or calcium ionophore-induced fibronectin synthesis was completely abolished by tyrosine kinase inhibitors and intracellular Ca2+ chelating agents. Ang II-induced fibronectin mRNA was not affected by PKC inhibitors or PKC depletion, whereas specific inhibition of EGF-R function by a dominant negative EGF-R mutant and tyrphostin AG1478 abolished induction of fibronectin mRNA. We isolated the rat fibronectin gene including the 5'-flanking region and found that the AP-1 binding site present in the promoter region was responsible for the Ang II responsiveness of this gene. Gel retardation assay revealed the binding of nuclear protein to the AP-1 site, which was supershifted with anti-c-fos and anti-c-jun but not anti-ATF-2 antibodies. Conditioned medium from Ang II-treated cells contained TGF-beta bioactivity and addition of neutralizing TGF-beta antibody modestly (46%) inhibited induction of fibronectin. Ang II-induced synthesis of TGF-beta was also abolished by inhibition of EGF-R function. The effect of TGF-beta was exerted by stabilizing fibronectin mRNA without affecting the promoter activity and required de novo protein synthesis. We concluded that Ang II-induced expression of fibronectin and TGF-beta is mediated by downstream signaling of EGF-R transactivated by Ca2+-dependent tyrosine kinase, and that Ang II-induced fibronectin mRNA expression is regulated by two different mechanisms; transcriptional control by binding of c-fos/c-jun complex to the AP-1 site, and post-transcriptional control by mRNA stabilization due to autocrine and/or paracrine effects of TGF-beta. Thus, this study suggested that the action of Ang II on extracellular matrix formation should be interpreted in association with the EGF-R signaling cascade.

Angiotensin II↗
PubMed1980

Circulating immunoreactive and bioassayable opsonic plasma fibronectin during experimental tumour growth.

Immunoreactive and bioassayable plasma fibronectin (opsonic α(2) surface-binding (SB) glycoprotein) was measured during experimental Sarcoma-180 tumour growth in mice. Male C57BL/6 mice were challenged s.c. with 2 × 10(6) viable Sarcoma-180 tumour cells and evaluated sequentially in parallel with saline-injected controls over a 21-day experimental period. Before challenge, immunoreactive plasma fibronectin was 1050-1150 μg/ml. Minimal tumour growth occurred until 6 days after tumour challenge. There was then a rapid increase in primary tumour size, especially over the 7-14-day interval, with a plateau of growth over the 18-21-day interval. Immunoreactive plasma fibronectin was significantly (P < 0·05) raised at 3 and 7 days after tumour challenge. A rapid rise (P < 0·001) to 2816·6 ± 158·9 μg/ml was observed at 14 days followed by a modest decline at 21 days. Bioassayable opsonic activity increased (P < 0·5) with the rise in immunoreactive fibronectin 3 and 7 days after tumour challenge, but the rapid rise in immunoreactive fibronectin over the 7-14-day interval was associated with a significant (P < 0·5) fall in bioassayable opsonic activity. Thus, the rapid rise in immunoreactive plasma fibronectin parallels the rapid rate of tumour growth, but is associated with a fall in opsonically active plasma fibronectin. Dissociation between immunoreactive and opsonically active plasma fibronectin may be mediated by inhibition and/or alteration of circulating fibronectin during rapid tumour growth. Alternatively, it may reflect increased release of antigenically related protein (i.e. cell-surface fibronectin) during rapid tumour growth, which may have limited biological opsonic activity.

Animals↗
PubMed1999

Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinoma.

The expression of laminin and fibronectin isoforms varies with cellular maturation and differentiation and these differences may well influence cellular processes such as adhesion and motility. The basement membrane (BM) of fetal oral squamous epithelium contains the laminin chains, alpha2, alpha3, alpha5, beta1, beta2, beta3, gamma1 and gamma2. The BM of adult normal oral squamous epithelium comprises the laminin chains, alpha3, alpha5, beta1, beta3, gamma1 and gamma2. A re-expression of the laminin alpha2 and beta2 chains could be shown in adult hyperproliferative, dysplastic and carcinomatous lesions. In dysplasia and oral squamous cell carcinoma (OSCC), multifocal breaks of the BM are present as indicated by laminin chain antibodies. These breaks correlate to malignancy grade in their extent. Moreover, in the invasion front the alpha3 and gamma2 chain of laminin-5 can immunohistochemically be found outside the BM within the cytoplasm of budding carcinoma cells and in the adjacent stroma. The correlation between the morphological pattern of invasive tumour clusters and a laminin-5 immunostaining in the adjacent stroma may suggest, first, that a laminin-5 deposition outside the BM is an immunohistochemical marker for invasion and second, that OSCC invasion is guided by the laminin-5 matrix. Expression of oncofetal fibronectins (IIICS de novo glycosylated fibronectin and ED-B fibronectin) could be demonstrated throughout the stromal compartment. However, the ED-B fibronectin synthesizing cells (RNA/RNA in situ hybridization) are confined to small stroma areas and to single stroma and inflammatory cells in the invasion front. A correlation of the number of ED-B fibronectin synthesizing cells to malignancy grade could not be seen. ED-B fibronectin mRNA-positive cells seem to be concentrated in areas of fibrous stroma recruitment with a linear alignment of stromal fibro-/myofibroblasts (desmoplasia). Double staining experiments (ED-B fibronectin in situ hybridization and alpha-smooth muscle actin immunohistochemistry) indicated that the stroma myofibroblasts are a preferential source of ED-B fibronectin. In conclusion, in OSCC, a fetal extracellular matrix conversion is demonstrable. Tumour cells (laminin alpha2 and beta2 chain) and recruited stromal myofibroblasts (oncofetal ED-B fibronectin) contribute to the fetal extracellular matrix milieu.

Adult↗
PubMed2004

Interactions with fibronectin attenuate the virulence of Streptococcus pyogenes.

Fibronectin-binding surface proteins are found in many bacterial species. Most strains of Streptococcus pyogenes, a major human pathogen, express the fibronectin-binding protein F1, which promotes bacterial adherence to and entry into human cells. In this study, the role of fibronectin in S. pyogenes virulence was investigated by introducing the protein F1 gene in an S. pyogenes strain lacking this gene. Furthermore, transgenic mice lacking plasma fibronectin were used to examine the relative contribution of plasma and cellular fibronectin to S. pyogenes virulence. Unexpectedly, protein F1-expressing bacteria were less virulent to normal mice, and virulence was partly restored when these bacteria were used to infect mice lacking plasma fibronectin. Dissemination to the spleen of infected mice was less efficient for fibronectin-binding bacteria. These bacteria also disseminated more efficiently in mice lacking plasma fibronectin, demonstrating that plasma fibronectin bound to the bacterial surface downregulates S. pyogenes virulence by limiting bacterial spread. From an evolutionary point of view, these results suggest that reducing virulence by binding fibronectin adds selective advantages to the bacterium.

Adhesins, Bacterial↗
PubMed2005

HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1.

The matrix fibronectin protein is a multifunctional adhesive molecule that promotes migration and invasiveness of many tumors including melanomas. Increased fibronectin synthesis has been associated with the metastatic potential of melanoma cells; however, the molecular mechanisms underlying fibronectin overexpression during melanoma development are poorly understood. We report that hepatocyte growth factor/scatter factor (HGF) induces fibronectin expression and its extracellular assembly on the surface of melanoma cells through activation of mitogen-activated protein (MAP) kinase pathway, and induction and transcriptional activation of Early growth response-1 (Egr-1). Inhibition of B-RAF/MAP kinase pathway by dominant-negative mutants and by U0126-abrogated HGF-induced Egr-1, and chromatin immunoprecipitation showed that Egr-1 is bound to the fibronectin promoter in response to HGF. Exogenously expressed Egr-1 increased fibronectin levels, while blockage of Egr-1 activation by expression of the Egr-1 corepressor NAB2 interfered with the upregulation of fibronectin synthesis induced by HGF, indicating that Egr-1 exerts a significant role in fibronectin expression in response to HGF. Finally, analysis of the expression pattern of fibronectin in melanoma cells demonstrated that fibronectin levels are correlated with constitutive MAP kinase signaling. Our data define a novel mechanism that might have important implications in regulation of melanoma progression by autocrine HGF signaling or by constitutive activation of MAP kinase pathway.

Autocrine Communication↗
PubMed1980

Polypeptide heterogeneity of hamster and calf fibronectins.

The adhesive glycoprotein fibronectin has been isolated from fresh hamster plasma by affinity chromatography on gelatin coupled to Sepharose beads by the method of Engvall & Ruoslahti [Int. J. Cancer (1979) 20, 1-5]. Polyacrylamide-gel electrophoresis of material heated in sodium dodecyl sulphate and 2-mercaptoethanol shows two prominent polypeptide subunits of approx. mol.wts. 215 000 and 200 000, with variable amounts of lower-molecular-weight fragments. The unexpected polypeptide heterogeneity of different preparations of hamster fibronectins and bovine serum fibronectin is shown to be partly an artefact and is generated during isolation and storage of purified fibronectin. Treatment of each hamster fibronectin subunit or a smaller fragment of approx. mol.wt. 140 000 with thermolysin or trypsin after radioiodination produces similar patterns of tyrpsine-containing peptides, indicating similar primary amino-acid sequences. Antibodies raised against the major subunits of hamster plasma fibronectin were coupled to Sepharose beads and used in conjunction with gelatin affinity chromatography to isolate fibronectins extracted with urea from baby-hamster kidney (BHK) cells and present in the long-term culture medium of these cells. The cell and medium fibronectins are similar to hamster plasma fibronectin in amino-acid and carbohydrate composition and also produce very similar peptide 'maps'. We conclude that the various forms of hamster fibronectins are structurally analogous in agreement with indistinguishable biological properties in mediating the substance adhesion of BKH cells [Pena & Hughes (1978) Cell Biol. Int. Rep. 3, 339-344].

Amino Acids↗
PubMed1982

A fibronectin-binding glycoprotein from human platelet membranes.

Fibronectin ('cold-insoluble globulin') has been suggested as a possible mediator of platelet adhesion. A fibronectin-binding protein as partially purified from washed solubilized human platelet membranes by affinity chromatography on fibronectin-Sepharose. The isolated protein migrated as a single band on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis with an Mr (relative molecular mass) of approx. 125 000 under reducing conditions. The protein migrated as a dimer in non-reduced gels. The purified protein did not react with immunoglobulins against fibrinogen or fibronectin when tested in crossed immunoelectrophoresis or electroimmunoassay. The protein and purified fibronectin formed a complex that had a significantly faster mobility in crossed immunoelectrophoresis than did native fibronectin. The presence of heparin in the binding-protein-fibronectin mixture resulted in an even faster mobility of the complex, whereas the mobility of native fibronectin was unaffected. Crossed affinoimmunoelectrophoresis of the complex using different lectins suggested that the binding protein is a glycoprotein containing N-acetylglucosamine residues. The complex, but not purified fibronectin, bound to phenyl-Sepharose on crossed hydrophobic-interaction immunoelectrophoresis. The results strongly suggest the presence of a fibronectin-binding glycoprotein in the platelet membrane.

Blood Platelets↗
PubMed1989

Evidence for a role of dipeptidyl peptidase IV in fibronectin-mediated interactions of hepatocytes with extracellular matrix.

Dipeptidyl peptidase IV (DPP IV) is a cell surface glycoprotein which has been implicated in hepatocyte-extracellular matrix interactions [Hixson, DeLourdes, Ponce, Allison & Walborg (1984) Exp. Cell Res. 152, 402-414; Walborg, Tsuchida, Weeden, Thomas, Barrick, McEntire, Allison & Hixson (1985) Exp. Cell Res. 158, 509-518; Hanski, Huhle & Reutter (1985) Biol. Chem. Hoppe-Seyler 366, 1169-1176]. However, its proteolytic substrate(s) and/or binding protein(s) which mediate this influence have not been conclusively identified. Nitrocellulose binding assays using 125I-labelled DPP IV that was purified to homogeneity from rat hepatocytes revealed a direct interaction of DPP IV with fibronectin. Although fibronectin could mediate an indirect binding of DPP IV to collagen, no evidence was found for a direct binding of DPP IV to native or denatured Type I collagen. Fibronectin appeared to bind DPP IV at a site distinct from its exopeptidase substrate recognition site since protease inhibitors such as competitive peptide substrates and phenylmethanesulphonyl fluoride enhanced binding, possibly as a result of an altered conformation of DPP IV. To determine if fibronectin binding to DPP IV is involved in the interaction of fibronectin with the hepatocyte surface, the effect of various DPP IV inhibitors on 125I-fibronectin binding to isolated hepatocytes in suspension was examined. Kinetic studies revealed that inhibitors of DPP IV which enhanced fibronectin binding in vitro accelerated the initial binding of fibronectin to the cell surface where it was subsequently cross-linked (presumably by tissue transglutaminase) to as yet undefined components. Immunolocalization of fibronectin and DPP IV in normal rat liver sections showed that both proteins were present along the hepatocyte sinusoidal membrane. These observations, coupled with previous results showing that DPP IV is tightly bound to biomatrix isolated from rat liver (Hixson et al., 1984; Walborg et al., 1985), suggest that DPP IV binding to fibronectin may play a role in interactions of hepatocytes with extracellular matrix in vivo and possibly in matrix assembly.

Animals↗
PubMed1997

Influence of fibronectin on the motility of human spermatozoa.

The objective of the present study was to scrutinize the concentration of seminal fibronectin and the potential effects of exogenous fibronectin on human sperm motility. In addition, variability in the localization of fibronectin on human spermatozoa from andrological patients was studied, at both the light and electron microscopic levels. A total of 58 freshly ejaculated semen samples from patients attending for infertility treatment were submitted to sperm motility analysis and ELISA quantification of seminal plasma and cell-bound fibronectin. Immunofluorescence and immunoelectron microscopy revealed a relatively broad distribution pattern of fibronectin immunoreactivity on sperm heads and testicular spermatids. Addition of a fibronectin antiserum to vital spermatozoa in vitro at a moderate dilution (1:50) resulted in a significant increase in sperm motility. Purified plasma fibronectin, added at various concentrations to a preparation of live spermatozoa, was found to inhibit sperm motility in a dose-dependent manner. At concentrations from 0.18 to 0.5 mg fibronectin per ml ejaculate, no motile spermatozoa were recorded. Seminal plasma fibronectin ranged between 0.8 and 1000 micrograms/ml in infertility patients. There was a significant inverse correlation between sperm motility and seminal fibronectin in patients with oligo-astheno-teratozoospermia. In a preliminary study in patients with varicocele or hypogonadism, no such correlation was found.

Blotting, Western↗
PubMed2000

Co-operative binding of human fibronectin to Sfbl protein triggers streptococcal invasion into respiratory epithelial cells.

Streptococcal fibronectin binding protein I (SfbI) mediates adherence to and invasion of Streptococcus pyogenes into human epithelial cells. In this study, we analysed the binding activity of distinct domains of SfbI protein towards its ligand, the extracellular matrix component fibronectin, as well as the biological implication of the binding events during the infection process. By using purified recombinant SfbI derivatives as well as in vivo expressed SfbI domains on the surface of heterologous organism Streptococcus gordonii, we were able to dissociate the two major streptococcal target domains on the human fibronectin molecule. The SfbI repeat region exclusively bound to the 30 kDa N-terminal fragment of fibronectin, whereas the SfbI spacer region exclusively bound to the 45 kDa collagen-binding fragment of fibronectin. In the case of native surface-expressed SfbI protein, an induced fit mode of bacteria-fibronectin interaction was identified. We demonstrate that binding of the 30 kDa fibronectin fragment to the repeat region of SfbI protein co-operatively activates the adjacent SfbI spacer domain to bind the 45 kDa fibronectin fragment. The biological consequence arising from this novel mode of fibronectin targeting was analysed in eukaryotic cell invasion assays. The repeat region of SfbI protein is mediating adherence and constitutes a prerequisite for subsequent invasion, whereas the SfbI spacer domain efficiently triggers the invasion process of streptococci into the eukaryotic cell. Thus, we were able to dissect bacterial adhesion from invasion by manipulating one protein. SfbI protein therefore represents a highly evolved prokaryotic molecule that exploits the host factor fibronectin not only for extracellular targeting but also for its subsequent activation that leads to efficient cellular invasion.

Adhesins, Bacterial↗
PubMed1999

Renal proximal tubular cell fibronectin accumulation in response to glucose is polyol pathway dependent.

BACKGROUND: Thickening and reduplication of the tubular basement membrane have been reported as early events in diabetic nephropathy. In this study, we have examined the polar requirements of proximal tubular cells for the d-glucose-stimulated accumulation of fibronectin and the mechanism by which this occurred, with particular emphasis on the polyol pathway. METHODS: To determine the polarity of fibronectin generation in response to glucose, LLC-PK1 cells were grown on porous tissue culture inserts. Monolayer confluence was determined by serial measurement of transepithelial resistance. Confluent cells were growth arrested by serum deprivation, and all experiments were performed under serum-free conditions. RESULTS: Application of 25 mm d-glucose to either the apical or basolateral aspect of LLC-PK1 cells led to fibronectin accumulation in the basolateral compartment. This reached statistical significance 24 hours following apical addition of glucose (2.6-fold increase compared with 5 mm d-glucose, P = 0.0025, N = 6 vs. N = 4 controls) and 12 hours after the basolateral addition of glucose (2.5-fold increase compared with 5 mm d-glucose, P = 0.03, N = 6 vs. N = 4 controls). Exposure of cells to glucose at either their apical or basolateral aspect leads to accumulation of intracellular glucose and polyol pathway activation, as assessed by sorbitol accumulation. The increase in fibronectin concentration in response to glucose was inhibited by the aldose reductase inhibitor sorbinil. At a dose of 100 micron sorbinil, there was a 59% inhibition of fibronectin accumulation in response to apical glucose (P = 0.004, N = 3 sorbinil vs. N = 4 controls) and a 66% inhibition in response to basolateral glucose (P = 0.008, N = 3 sorbinil vs. N = 4 controls) 48 hours after the addition of the inhibitor. Furthermore, fibronectin accumulation was also demonstrated following both the apical and basolateral addition of 1 mm sorbitol, but not following the addition of 25 mm galactose to either aspect of the cells. Following the addition of sorbitol, there was a 2. 8-fold increase in fibronectin 48 hours after apical stimulation (P = 0.01, N = 3 treated vs. N = 4 control) and a 2.27-fold increase following basolateral stimulation (P = 0.04, N = 3 treated vs. N = 4 control) at 24 hours. CONCLUSIONS: In summary, these data demonstrate that fibronectin generation in response to glucose was nonpolar in terms of application of glucose but was polar in terms of fibronectin accumulation. The mechanisms of glucose-induced modulation of fibronectin were mediated by polyol pathway activation and were more specifically related to the metabolism of sorbitol to fructose.

Aldehyde Reductase↗
PubMed2000

Stimulation of integrin-mediated cell contractility by fibronectin polymerization.

Ligation of integrins with extracellular matrix molecules induces the clustering of actin and actin-binding proteins to focal adhesions, which serves to mechanically couple the matrix with the cytoskeleton. During wound healing and development, matrix deposition and remodeling may impart additional tensile forces that modulate integrin-mediated cell functions, including cell migration and proliferation. We have utilized the ability of cells to contract floating collagen gels to determine the effect of fibronectin polymerization on mechanical tension generation by cells. Our data indicate that fibronectin polymerization promotes cell spreading in collagen gels and stimulates cell contractility by a Rho-dependent mechanism. Fibronectin-stimulated contractility was dependent on integrin ligation; however, integrin ligation by fibronectin fragments was not sufficient to induce either tension generation or cell spreading. Furthermore, treatment of cells with polyvalent RGD peptides or pre-polymerized fibronectin did not stimulate cell contractility. Fibronectin-induced contractility was blocked by agents that inhibit fibronectin polymerization, suggesting that the process of fibronectin polymerization is critical in triggering cytoskeletal tension generation. These data indicate that Rho-mediated cell contractility is regulated by the process of fibronectin polymerization and suggest a novel mechanism by which extracellular matrix fibronectin regulates cytoskeletal organization and cell function.

Amino Acid Sequence↗
PubMed2005

Fibrin but not adsorbed fibrinogen supports fibronectin assembly by spread platelets. Effects of the interaction of alphaIIb beta3 with the C terminus of the fibrinogen gamma-chain.

We investigated the assembly of soluble fibronectin by lysophosphatidic acid-activated platelets adherent to fibrinogen or fibrin. More fibronectin was assembled by activated platelets spread on fibrin matrices than by platelets spread on adsorbed fibrinogen. The difference between platelets adherent to fibrinogen and fibrin occurred under both static and flow conditions. Similar differences were seen in binding of the 70-kDa N-terminal fragment of fibronectin that recognizes fibronectin assembly sites on adherent cells. Antibody and peptide blocking studies demonstrated that alphaIIb beta3 integrin mediates platelet adhesion to fibrinogen, whereas both alphav beta3 and alphaIIb beta3 mediate platelet adhesion to fibrin. The hypothesis that engagement of the C-terminal QAGDV sequence of the fibrinogen gamma-chain by alphaIIb beta3 inhibits the ability of the platelet to assemble fibronectin was tested by several experiments. Activated platelets adherent to adsorbed mutant fibrinogen lacking the QAGDV sequence (gammadelta5FG) were assembly-competent, as were platelets adherent to adsorbed normal fibrinogen that had been pretreated with the 7E9 antibody to the C terminus of the gamma-chain. Moreover, adsorbed normal fibrinogen but not gammadelta5FG suppressed the ability of co-adsorbed fibronectin to direct assembly of soluble fibronectin by spread platelets. The suppressive effect was lost when a surface of co-adsorbed fibronectin and fibrinogen was pretreated with 7E9. These results support a model in which the engagement of alphaIIb beta3 by the C-terminal sequence of the fibrinogen gamma-chain initiates signals that suppress subsequent fibronectin assembly by spread platelets. This interaction is less dominant when platelets adhere to fibrin, resulting in enhanced fibronectin assembly.

Adsorption↗
PubMed1984

Determination of activated plasma fibronectin using radioactive labelled collagen I.

The plasma concentration of biological active fibronectin was assayed by a protein binding assay using 125I-collagen I as ligand and heparin as activator. The standard curve is linear for a fibronectin range of 1.1-11 pmol (0.5-5.0 micrograms) and the coefficient of variation was less than 10%. The active or activable fibronectin was compared to the immunoreactive fibronectin in plasma from patients with various bacterial diseases. Similar concentrations were detected by the two assays suggesting that all the circulating fibronectin was functionally active. The assay was also applied to determine the structure-function relationship of heparin and heparansulphate in activation of fibronectin. Low-sulphated heparansulphate from umbilical cords and heparin-activated fibronectin but the effect was uncorrelated to anticoagulation activity. Only a small fraction of the heparin was actually capable of activating fibronectin. It is concluded that the assay is very convenient to detect biological active fibronectin and to elucidate the structure-function relationship of heparin and heparansulphate in activating fibronectin.

Adult↗
PubMed2001

Fibronectin is a marker for organ involvement and may reflect the severity of preeclampsia.

OBJECTIVE: We have studied whether plasma fibronectin is related to a rise in blood pressure during normal pregnancy, whether it can be used for the early prediction of preeclampsia, and whether plasma fibronectin is a marker for organ involvement in preeclampsia. STUDY DESIGN: Two hundred twenty-eight healthy pregnant nullipara women were examined prospectively during pregnancy. Analyses of fibronectin in plasma were performed in pregnancy weeks 16, 24, 28, 32, and 36. During the same period, 177 patients with suspected preeclampsia and/or intrauterine growth retardation (IUGR) were tested for plasma fibronectin, mainly in the third trimester. RESULTS: In the normal population of pregnant women (n=222/228), fibronectin levels were 0.35 +/- 0.06 g/L in pregnancy week 16 and 0.43 +/- 0.12 g/L in week 36. These levels showed a positive correlation to blood pressure elevation during pregnancy (r=0.21, p=0.006). The six patients in this group (n=6/228) who later developed preeclampsia had higher fibronectin values 0.42 +/- 0.07 g/L already in week 16 (p=0.023). In the population of women with suspected preeclampsia (preeclampsia, n=129; IUGR alone, n=17; hypertension or proteinuria during pregnancy, n=31), fibronectin values were significantly higher, 0.75 +/- 0.27 g/L than in the normal population. Patients with preeclampsia and laboratory signs of organ involvement (n=56) showed significantly higher fibronectin values (0.85 +/- 0.27 g/L) compared to preeclampsia without organ involvement (n=73) [0.76 +/- 0.22 g/L (p=0.03)]. CONCLUSION: Our data show that fibronectin is related to blood pressure in pregnancy. Fibronectin values in women who develop preeclampsia are elevated already in pregnancy week 16 and were higher in those with laboratory signs of organ involvement.

Adolescent↗