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PubMed1995

Alpha v beta 1 is a receptor for vitronectin and fibrinogen, and acts with alpha 5 beta 1 to mediate spreading on fibronectin.

We have shown previously that VUP was the only line out of ten human melanoma lines that failed to express the vitronectin receptor alpha v beta 3, but instead expressed alpha v beta 1. Levels of alpha v beta 1 expression were low on parental VUP cells so that iterative sorting by FACS, using an anti-alpha v antibody (13C2), was utilised to derive sublines with 8- to 10-fold higher amounts of cell surface alpha v beta 1. There was little difference between low (V-) and high (V+) alpha v beta 1-expressing sublines with regard to adherence to collagen type I, collagen type IV or laminin substrata. However, adherence to vitronectin and fibrinogen correlated closely with alpha v beta 1 expression (35-42% adhesion for V(+) lines versus 6-8% adhesion for V- lines on vitronectin, for example). Utilising a high alpha v beta 1-expressing subline (V + B2) we have shown that binding to vitronectin and fibrinogen was inhibited specifically by function-blocking antibodies to alpha v (17E6 and 14D9) and beta 1 (A11B2). V(+) sublines spread more compared with V(-) sublines on both vitronectin and fibronectin. However, neither alpha 5- nor alpha v-blocking antibodies had any effect on attachment or spreading of V + B2 on fibronectin whereas the combination of alpha 5 (PID6)- and alpha v(17E6)-blocking antibodies abrogated binding to fibronectin almost completely. This is the first report of an alpha v beta 1 integrin able to recognize vitronectin and fibrinogen, and also cooperate with alpha 5 beta 1 to mediate attachment to and spreading on fibronectin.

Antibodies↗
PubMed2002

Foxa (HNF3) up-regulates vitronectin expression during retinoic acid-induced differentiation in mouse neuroblastoma Neuro2a cells.

Accumulation of vitronectin protein increased in the conditioned medium of mouse neuroblastoma Neuro2a cells during retinoic acid-induced differentiation. To study the regulatory mechanism of the increase in vitronectin expression during the differentiation, the activity of the -527/+95 vitronectin promoter was observed in Neuro2a cells with or without retinoic acid treatment. The result showed that the -527/+95 promoter activity increased 2.7-fold with retinoic acid, and despite deletion of regions from -527 to -49 and +54 to +95 base pairs (bp), the -48/+53 promoter preserved the retinoic acid response. We recently showed that the -48/+53 region has two transcription factor Foxa (HNF3)-binding sites (site A from -34 to -25 bp and site B from +15 to +26 bp), suggesting that Foxa may up-regulate the vitronectin expression. Therefore, we examined the change of Foxa expression in Neuro2a cells during the differentiation. The expression of Foxa1 protein was increased during the differentiation, but the expression of Foxa2 protein was not detected. In addition, overexpression of Foxa1 increased the amount of vitronectin protein in the conditioned medium of Foxa1-overexpressed Neuro2a cells, but overexpression of Foxa2 only weakly increased it. The site-A and -B double mutation of the -527/+95 promoter remarkably reduced the promoter activity induced by Foxa overexpression, indicating that Foxa-binding sites in the -527/+95 region are located only on sites A and B. The mutation of site A in the -48/+53 promoter did not affect the retinoic acid response, but the site-B mutation abolished the constitutive promoter activity and remarkably reduced the promoter activity with retinoic acid. These results demonstrate that Foxa up-regulates the vitronectin expression during the retinoic acid-induced differentiation in Neuro2a cells.

Animals↗
PubMed2006

Haemophilus influenzae surface fibrils contribute to serum resistance by interacting with vitronectin.

Vitronectin inhibits the membrane attack complex of the complement system and is found both in plasma and the extracellular matrix. In this study, we have identified the outer membrane protein Haemophilus surface fibrils (Hsf) as the major vitronectin-binding protein in encapsulated H. influenzae type b. A H. influenzae mutant devoid of Hsf showed a significantly decreased binding to both soluble and immobilized vitronectin as compared with the wild-type counterpart. Moreover, Escherichia coli-expressing Hsf at the surface strongly adhered to immobilized vitronectin. Importantly, the H. influenzae Hsf mutant had a markedly reduced survival as compared with the wild-type bacterium when incubated with normal human serum. A series of truncated Hsf fragments were recombinantly manufactured in E. coli. The vitronectin binding regions were located within two separate binding domains. In conclusion, Hsf interacts with vitronectin and thereby inhibits the complement-mediated bactericidal activity, and thus is a major H. influenzae virulence factor.

Adhesins, Bacterial↗
PubMed1999

Changes of hepatic vitronectin levels in patients with chronic hepatitis C treated with interferon alpha.

Hepatic vitronectin expression was assessed in 27 patients with chronic hepatitis C before and after interferon alpha treatment and in 7 control patients. Before interferon therapy, vitronectin was localized in the hepatocytes and in the portal and central venous regions. A high correlation was found for the vitronectin expression level with the histological grading and staging scores in the hepatocytes as well as in the portal region. After interferon therapy, the hepatic vitronectin was significantly decreased in the sustained and transient responders, but it was not as markedly decreased in the nonresponders and the non-treated group. A good correlation was found for the vitronectin expression with the staging scores but not with the grading scores in the portal region. These findings suggest that hepatic vitronectin is influenced by interferon therapy and that it may play an important role as a hepatic adhesion molecule through the improvement of inflammation, necrosis and fibrogenesis.

Antiviral Agents↗
PubMed1990

The presence of methionine or threonine at position 381 in vitronectin is correlated with proteolytic cleavage at arginine 379.

Vitronectin (serum spreading factor, complement S protein, epibolin) is a glycoprotein that mediates cell adhesion and interacts with components of the complement, coagulation, and fibrinolytic systems. It circulates in plasma as a 75-kDa single chain polypeptide and as a two-chain form consisting of 65- and 10-kDa polypeptides linked by a disulfide bond. An individual may have a predominance of the single chain or the two-chain form inherited as a Mendelian trait or have approximately equal amounts of both forms. Inspection of published cDNA sequences suggests that either methionine or threonine can occur at position 381, which is adjacent to the presumed site of proteolytic cleavage (Arg379-Ala380) that gives rise to the two-chain form. We have determined the presence of the Met381 and/or Thr381 alleles of the vitronectin gene in 42 individuals by oligonucleotide hybridization to genomic DNA. To determine whether this polymorphism is correlated with the susceptibility to cleavage of the Arg379-Ala380 peptide bond in vivo, we have prepared immunoblots of plasma from the same group of individuals. Nineteen individuals homozygous for the Thr381 allele had 17 +/- 9% (mean +/- S.D.) single chain vitronectin in their plasma samples. Nine individuals homozygous for the Met381 allele had 66 +/- 4% single chain vitronectin. Fourteen heterozygous individuals had 38 +/- 13% single chain vitronectin. The differences in mean values were statistically significant (p less than 0.001). These results suggest that the presence of threonine rather than methionine at position 381 of vitronectin increases the susceptibility of the protein to cleavage of the Arg379-Ala380 peptide bond in vivo.

Alleles↗
PubMed1990

[Vitronectin: mediator of cell adhesion in proliferative vitreoretinopathy?].

Vitronectin, also known as protein S, the "serum spreading factor", or epibolin, was detected as an essential mediator of adhesion and spreading in many cells in vitro. The relatively low molecular weight of 65 kDa and a high plasma level of 200 mg/l implicate vitronectin as a possibly important factor in the pathogenesis of proliferative vitreoretinopathy (PVR) which is characterized by a breakdown of blood-ocular barriers. In a study of 15 periretinal membranes, using double label immunofluorescence techniques, we found vitronectin to be a significant component of the specimens' extracellular matrix in 13 cases. Vitronectin is co-localized with fibronectin, a much larger glycoprotein suggested as being involved in the pathogenesis of PVR. Among the biological properties of fibronectin are a role in cellular migration, adhesion, and proliferation. Both proteins share a unique cell recognition amino acid sequence, which mediates the receptor-dependent interaction between the extracellular matrix macromolecules and proliferating cells. Plasma is suggested as the major source of vitronectin in PVR because vitronectin could be detected in vitreous aspirates from patients with PVR, using electrophoresis and immunoblotting, but not in physiological human vitreous.

Cell Adhesion↗
PubMed1991

The inhibition of tissue type plasminogen activator by plasminogen activator inhibitor-1. The effects of fibrinogen, heparin, vitronectin, and lipoprotein(a).

Plasminogen activator inhibitor-1 (PAI-1) regulates fibrinolysis by inhibiting tissue type plasminogen activator (t-PA). Fibrinogen, heparin, and vitronectin enhance the rate of inhibition of t-PA by PAI-1. Kinetic studies indicate that both fibrinogen and heparin increase the second-order inhibition constant by a maximum of approximately 4-fold, whereas vitronectin increases the rate constant by a maximum of approximately 6-fold. The dissociation constants of fibrinogen, heparin, and vitronectin for the inhibition reaction were 200 nM, 20 nM, and 600 pM, respectively. In addition, PAI-1 inhibition of t-PA may be regulated by the presence of lipoprotein(a) (Lp(a)). Previous studies demonstrated that Lp(a) competes with plasminogen for the active site of fibrinogen- and heparin-bound t-PA. Kinetic studies described here demonstrate that Lp(a) prevents the inhibition of t-PA by PAI-1 in the presence of fibrinogen and heparin, but has no effect on the reaction in the presence of vitronectin or in the absence of either fibrinogen or heparin. The data suggest that fibrinogen and heparin may enhance the rate of inhibition through an interaction with t-PA, and that vitronectin may enhance the inhibition through an interaction with PAI-1. In addition, these experiments indicate that Lp(a) may regulate fibrinolysis by competing with PAI-1 and plasminogen for fibrinogen- and heparin-bound t-PA. These data suggest that PAI-1 inhibition of t-PA in vivo is primarily mediated via interaction with fibrinogen, heparin, vitronectin, and Lp(a), and therefore, the functional levels of PAI-1 activity in the vasculature may be regulated by the presence of these components.

Fibrinogen↗
PubMed1986

Localization of vitronectin (S-protein of complement) in normal human skin.

Vitronectin, now known to be identical to serum spreading factor and to S-protein of complement, is a multifunctional glycoprotein involved in the adhesion and spreading of cells and in the complement and coagulation pathways. The distribution of vitronectin in normal human skin was investigated with immunofluorescence using polyclonal antibodies, and with an avidin-biotin peroxidase complex technique, using polyclonal as well as monoclonal antibodies. Vitronectin immunreactivity was found to be localized on the elastic fibres in the dermis. Both the thin fibres in the papillary dermis and the thicker elastic fibres in the reticular dermis were stained. No crossreactivity was found between vitronectin and serum amyloid P component, known to bind to elastic fibres. The two proteins were immunohistochemically localized to the same structures in the skin. The distribution of vitronectin in the dermal tissue established in this study provides a basis for further studies of the function and behaviour of vitronectin in health and disease.

Fluorescent Antibody Technique↗
PubMed1989

Identification of vitronectin as a major plasma protein adsorbed on polymer surfaces of different copolymer composition.

The arrays of proteins adsorbed from plasma onto a series of polystyrene copolymeric latexes were analyzed by enzyme-linked immunosorbent assay (ELISA) of washed beads and immunoblotting of proteins desorbed from the beads and separated by polyacrylamide gel electrophoresis (PAGE). Beads were prepared by continuous emulsion polymerization in the absence of surfactant. Coomassie brilliant blue staining of gel electropherograms of desorbed proteins indicated that the presence of small amounts of comonomers (1 to 10 mole %) significantly influenced the composition of the adsorbed protein layer. Immunoblotting revealed that fibrinogen, fibronectin, and vitronectin were adsorbed by all surfaces investigated. C3 and Clq adsorption varied significantly with copolymer composition. The ELISAs revealed that although the concentrations of vitronectin and fibronectin in plasma are similar, the extent of vitronectin adsorption from 70% to 85% plasma was greater by two orders of magnitude than fibronectin adsorption. Vitronectin adsorbed on carboxylic acid-containing copolymers reacted more strongly with a conformationally sensitive antivitronectin monoclonal antibody (MoAb) than vitronectin adsorbed to polystyrene and was more susceptible to cleavage by plasma proteases(s). The results show that vitronectin is a major protein adsorbed from concentrated plasma and that small changes in the chemical composition of a copolymer profoundly affects the extent and nature of protein adsorption from complex mixtures such as plasma.

Acrylates↗
PubMed1988

Interaction of thrombin-stimulated platelets with vitronectin (S-protein of complement) substrate: inhibition by a monoclonal antibody to glycoprotein IIb-IIIa complex.

Platelets adhere to vitronectin substrate following activation with physiological concentrations of thrombin. Adhesion of activated platelets to vitronectin substrate is dependent upon the presence of divalent cations, the amount of vitronectin, and the duration of adhesion assay. The adhesion of platelets is inhibited by synthetic peptides containing the sequence of Arg-Gly-Asp. In addition, monoclonal antibodies to glycoprotein IIb-IIIa complex inhibit the adhesion of activated platelets to vitronectin substrate in a dose-dependent manner. These studies suggest that the glycoprotein IIb-IIIa complex on activated platelets may interact with vitronectin substrate through the Arg-Gly-Asp mechanism. Since vitronectin is present in the subendothelial matrix, it might be involved in platelet-vessel wall interactions.

Antibodies, Monoclonal↗
PubMed1991

Integrin expression in human melanoma cell lines: heterogeneity of vitronectin receptor composition and function.

Ten human melanoma cell lines were examined for integrin-receptor expression using a panel of antibodies directed against different integrin subunits. Considerable heterogeneity was detected for levels of expression of 7 integrins, including the alpha v beta 3 vitronectin receptor where a correlation between tumorigenic capacity in athymic nude mice and alpha v beta 3 levels was found. Detailed analysis of the vitronectin receptor on these lines revealed heterogeneity of composition. In one cell line, VUP, an alpha v beta 1 association was detected and, by antibody-inhibition studies, this receptor was shown to bind vitronectin as its ligand. In another line, DX3, evidence was obtained which indicated that apart from the alpha v beta 3 receptor the alpha v was able to associate with another beta subunit which was not beta 3. The existence of these alternative forms of the vitronectin receptor in this small sample of tumours of common origin might explain why the capacity to bind to fibrinogen and vitronectin substrates by these cells did not necessarily correlate with alpha v beta 3 levels.

Animals↗
PubMed1996

The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin.

During wound healing, migrating cells increase expression of both the vitronectin receptor (VNR) integrins and plasminogen activators. Here we report that vitronectin significantly enhances the migration of smooth muscle cells (SMCs), and that the specific VNR alpha V beta 3 is required for cell motility. We also show that the alpha V beta 3 attachment site on vitronectin overlaps with the binding site for plasminogen activator inhibitor (PAI)-1, and that the active conformation of PAI-1 blocks SMC migration. This effect requires high-affinity binding to vitronectin, and is not dependent on the ability of PAI-1 to inhibit plasminogen activators. Formation of a complex between PAI-1 and plasminogen activators results in loss of PAI-1 affinity for vitronectin and restores cell migration. These data demonstrate a direct link between plasminogen activators and integrin-mediated cell migration, and show that PAI-1 can control cell-matrix interactions by regulating the accessibility of specific cell-attachment sites. This indicates that the localization of plasminogen activators at sites of focal contact does not initiate a proteolytic cascade leading to generalized matrix destruction, but instead is required to expose cryptic cell-attachment sites necessary for SMC migration.

Animals↗
PubMed1995

The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin.

The integrin family of adhesion receptors consists of at least 21 heterodimeric transmembrane proteins that differ in their tissue distribution and ligand specificity. The recently identified alpha 8 integrin subunit associates with beta 1 and is predominantly expressed in smooth muscle and other contractile cells in adult tissues, and in mesenchymal and neural cells during development. We now show that alpha 8 beta 1 specifically localizes to focal contacts in cells plated on the extracellular matrix proteins fibronectin or vitronectin. In addition we show that human embryonic kidney cells (293), transfected with alpha 8 cDNA, express alpha 8 beta 1 on their surface and use this receptor for adhesion to fibronectin and vitronectin. Furthermore, alpha 8 beta 1 binds to both fibronectin- and vitronectin-Sepharose and can be specifically eluted from either matrix protein by the arginine-glycine-aspartic acid (RGD)-containing peptide, GRGDSP. Because fibronectin and vitronectin adhesion appeared to be mediated by RGD, we examined additional RGD-containing proteins, including tenascin, fibrinogen, thrombospondin, osteopontin, and denatured collagen type I. We found that only tenascin was able to mediate adhesion of alpha 8-transfected 293 cells. By using recombinant fragments of tenascin in adhesion assays, we were able to localize the alpha 8 beta 1 binding domain of tenascin to the RGD-containing third fibronectin type III repeat. These data strongly suggest that tenascin, fibronectin, and vitronectin are ligands for alpha 8 beta 1 and that this integrin binds to the RGD site in each of these ligands through mechanisms that are distinct and separate from alpha 5- and alpha v-containing integrins.

Adult↗
PubMed1996

Integrin alpha v beta 5-dependent serine phosphorylation of paxillin in cultured human macrophages adherent to vitronectin.

The macrophage colony-stimulating factor (M-CSF) is able to induce the expression of the alpha v beta 5 integrin receptor on the surface of cultured human macrophages (De Nichilo, M. O., and Burns, G. F. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2517-2521). In the present study, we establish that the adhesion of M-CSF-treated macrophages to vitronectin is mediated by the integrin alpha v beta 5, and show by indirect immunofluorescence analysis that alpha v beta 5 and the cytoskeletal protein paxillin localize to focal contacts upon adhesion to vitronectin. Immunoprecipitation and Western blot analysis revealed that M-CSF-treated macrophages do not express focal adhesion kinase (FAK), thereby providing direct evidence for integrin-dependent localization of paxillin to focal contacts in the absence of FAK expression. Investigation of paxillin phosphorylation by two-dimensional phosphoamino acid analysis indicates that paxillin is 99% phosphorylated on serine residue(s) in response to vitronectin adhesion, and only 1% phosphorylated on tyrosine. Stimulation of protein kinase C (PKC) activity with the phorbol ester phorbol 12-myristate 13-acetate enhances paxillin phosphorylation, while two selective inhibitors of PKC, GF109203X and chelerythrine chloride, effectively block the phosphorylation of paxillin induced in response to vitronectin adhesion. Taken together, these data demonstrate that in M-CSF-treated macrophages adherent to vitronectin, paxillin localizes to focal contacts in the absence of FAK expression and is predominantly phosphorylated on serine residue(s) in a PKC-dependent manner.

Cell Adhesion↗
PubMed1994

Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin.

FG human pancreatic carcinoma cells adhere to vitronectin using integrin alpha v beta 5 yet are unable to migrate on this ligand whereas they readily migrate on collagen in an alpha 2 beta 1-dependent manner. We report here that epidermal growth factor receptor (EGFR) activation leads to de novo alpha v beta 5-dependent FG cell migration on vitronectin. The EGFR specific tyrosine kinase inhibitor tyrphostin 25 selectively prevents EGFR autophosphorylation thereby preventing the EGF-induced FG cell migration response on vitronectin without affecting constitutive migration on collagen. Protein kinase C (PKC) activation also leads to alpha v beta 5-directed motility on vitronectin; however, this is not blocked by tyrosine kinase inhibitors. In this case, PKC activation appears to be associated with and downstream of EGFR signaling since calphostin C, an inhibitor of PKC, blocks FG cell migration on vitronectin induced by either PKC or EGF. These findings represent the first report implicating a receptor tyrosine kinase in a specific integrin mediated cell motility event independent of adhesion.

Cell Adhesion↗
PubMed1991

Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells.

Glioblastoma multiforme, the most malignant astroglial-derived tumor, grows as an adherent mass and locally invades normal brain. An examination of adult cerebral glioblastoma biopsy material for the expression of adhesive proteins that might potentiate adhesion and invasion demonstrated tumor cell-associated vitronectin (5/5). In contrast, vitronectin was not detected associated with glial cells in low grade astroglial tumors (0/4), reactive astrogliosis (0/4), or in normal adult cortex and cerebral white matter (0/5). Also, a wide variety of other adhesive ligands were absent from the glioblastoma tumor parenchyma. The alpha v beta 3 integrin was the only vitronectin receptor identified in glioblastoma tumors in situ, and was also not expressed on low grade astroglial-derived tumors, reactive astrogliosis, or on glia or neurons in normal adult cortex and cerebral white matter. In a cell attachment assay, cultured glioblastoma cells attached to the parenchyma of glioblastoma tumor cryostat sections at the sites of vitronectin expression, but failed to attach to normal brain. This adhesion was inhibited by antibodies directed against vitronectin, the alpha v beta 3 integrin, and with an Arg-Gly-Asp-containing peptide. These data provide evidence for a cell adhesion mechanism in glioblastoma tumors that might potentiate glioblastoma cell invasion of normal brain.

Animals↗
PubMed1996

Reactive glial cells express a vitronectin-like protein in the hippocampus of epileptic rats.

Injection of kainic acid into the amygdala induces in addition to a local cell loss a seizure related distal damage of the hippocampal complex, in particular in the CA3 field and hilus. This neuronal lesion is associated with hypertrophy and proliferation of astroglial cells which start around 3 days after kainate and peaks within 20 days of kainate. We now report that reactive astrocytes are labelled with antibodies against vitronectin in the CA3 field and hilus. In the present study we also exclude that the presence of vitronectin into the brain is due to an extravasation from serum throughout a blood brain barrier leakage. The present results constitute the first demonstration for a glial expression of vitronectin in vivo. Vitronectin is an extracellular matrix glycoprotein involved in axonal growth. The glial expression of vitronectin may therefore contribute to the synaptic remodeling of mossy fibers induced in the hippocampus by such treatment.

Amygdala↗
PubMed2005

Direct measurement of interactions between adsorbed vitronectin layers: the influence of ionic strength and pH.

Vitronectin (Vn) is an adhesive protein in the plasma serum and plays an important role in cell attachment, spreading, and proliferation. The interactions between protein bovine vitronectin layers adsorbed onto a silica probe and a mica surface have been investigated with the use of atomic force microscopy (AFM). Adsorption of vitronectin was confirmed by XPS surface analysis. The force-separation curves and pull-off forces were measured as a function of ionic strength and solution pH. The pull-off force (adhesion force) decreased as the salt concentration increased, which suggests that some binding domains of this protein may associate with the ionic species and reduce its binding ability. Discrete jumps, or discontinuities, in the separation force curve were observed to extend to a maximum of 300 nm, evidence that the protein molecules bridge between the surfaces. As a function of pH, the adhesion force on separation of the protein-coated surfaces showed a maximum at pH 5 (i.e.p. of vitronectin), decreasing in magnitude at lower and higher pH values. At pH 5, the approaching curves illustrated a jump-in force; whereas for pH values away from 5, the approaching force curves were repulsive. Correlation of the interaction forces with Vn conformational changes in different pH environments, directly visualized with the use of AFM imaging, was developed. In its i.e.p. region, the Vn molecular conformation appeared to be dense and compact. Significantly, at wounds/injured sites the pH is low (approximately 5) which this study discovered to facilitate adsorption and formation of vitronectin aggregates, known to trigger their subsequent biological functions.

Adhesiveness↗