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PubMed1996

Expression and localization of alpha v integrins and their ligand vitronectin in normal ovarian epithelium and in ovarian carcinoma.

In an extension of a previous in vitro study [Carreiras et al., Int. J. Cancer 63, 530-536 (1995)] and in an effort to understand the adhesive interactions mediated by integrins within epithelial ovarian tumors, the presence of the alpha v and beta 3 subunits and that of vitronectin (Vn) in ovarian carcinomas at various stages of differentiation and in normal ovarian epithelium were comparatively investigated. The study was performed on material from 34 patients. By immunofluorescence, cryostat sections were analyzed for their expression of alpha v (34 cases), beta 3 (19 cases), and Vn (29 cases). alpha v was expressed in normal epithelium and in highly differentiated tumors as well as in a majority of moderately and poorly differentiated carcinomas with identical staining pattern. beta 3 subunit and Vn were also expressed in normal cases and highly differentiated carcinomas. However, they were lacking in most of the less differentiated tumors. The analysis of cases which were simultaneously tested for the presence of alpha v, beta 3, and Vn revealed that a large proportion of normal ovarian epithelium and highly differentiated tumors simultaneously expressed alpha v, beta 3, and Vn; in contrast, in all moderately and poorly differentiated carcinomas either beta 3 or Vn was absent. The potential role of the alpha v beta 3/Vn system in ovarian epithelium functions is discussed. It is also speculated that modifications of this system in ovarian carcinomas might contribute to tumor progression.

Antigens, CD↗
PubMed1999

Human ovarian adenocarcinoma cells synthesize vitronectin and use It to organize their adhesion.

Extracellular matrix components and integrin receptors are frequently altered in cancer, including ovarian adenocarcinoma. Vitronectin (Vn) is a matrix protein mainly synthesized by liver cells; it is present in normal ovarian surface epithelium and differentiated ovarian adenocarcinoma, but is frequently undetectable in undifferentiated carcinoma (F. Carreiras et al., 1996, Gynecol Oncol 62:260-267). Wondering about the cellular origin of Vn in ovarian carcinoma, we searched for evidence of Vn synthesis by these tumors. We demonstrated that three human ovarian adenocarcinoma cell lines were able to synthesize Vn, as revealed by the presence of Vn mRNA and the protein. The Vn matrix promotes adhesion of ovarian tumor cells through alphav integrins. Moreover, during in vitro growth, Vn is progressively organized into a particular pattern in combination with the recruitment of alphav into focal contacts. Our results suggest that Vn synthesis may participate in ovarian adenocarcinoma cell biology and raise the possibility that altered expression of Vn in some ovarian carcinomas could result from a defect in Vn synthesis.

Adenocarcinoma↗
PubMed2002

Vitronectin- and fibronectin-containing immune complexes in primary systemic vasculitis.

In primary systemic vasculitis anti endothelial cell autoantibodies (AECA) have been described frequently. They represent a heterogeneous group of autoantibodies whose target antigens are mostly unknown. We tried to find AECA-antigens by a co-operative binding assay with a panel of monoclonal antibodies (mAb) directed to human umbilical vein endothelial cells (HUVEC) and extracellular matrix proteins. The mAb were used to bind antigens from lysate of endothelial cells, and binding of human antibodies to these antigens was measured. mAb directed to Vitronectin (VN) and Fibronectin (FN) resulted in enhanced binding of antibodies in sera from patients with Churg Strauss Syndrome (CSS) and Wegener's Granulomatosis (WG) compared to normal sera. Neither free autoantibodies against VN or FN could be detected nor did the addition of endothelial cell lysate influence the binding activity from the patients' sera. This suggests that preformed VN and FN-containing immune complexes (IC) are present in the patient sera. The amount of IC was decreased by incubation with HUVEC, demonstrating that these IC can bind to endothelial cells. However, their involvement in the pathogenesis of the disease is not clearly defined. Our data suggest that there are preformed IC present in sera of patients with CSS and WG that contain VN and FN and bind to endothelial cells.

Antibodies, Monoclonal↗
PubMed1993

A conserved Streptococcus pyogenes extracellular cysteine protease cleaves human fibronectin and degrades vitronectin.

Streptococcus pyogenes secretes an extracellular cysteine protease that cleaves human interleukin 1 beta precursor to form biologically active IL-1 beta, a major cytokine mediating inflammation and shock. To further investigate the potential role of the cysteine protease in host-parasite interactions, the enzyme was purified to apparent homogeneity and tested for ability to degrade several human extracellular matrix proteins. Purified protease cleaved fibronectin, apparently at specific sites, and rapidly degraded vitronectin. In contrast, the protease did not have substantial activity against laminin. The cysteine protease also cleaved fibronectin from human umbilical vein endothelial cells grown in vitro. Allelic variation in the cysteine protease structural gene was studied in 67 strains expressing 39 M protein serotypes and five provisional M serologic types, and representing 50 phylogenetically distinct clones identified by multilocus enzyme electrophoresis. The gene is well conserved and allelic variation is due solely to accumulation of point mutations. Based on predicted amino acid sequences, one mature cysteine protease variant would be made by clones expressing serotypes M2, M3, M4, M5, M6, M9, M10, M11, M12, M14, M18, M22, M23, M25, M27, M41, M49, M56, M59, two provisional M types, and two clones non-typeable for M protein. Moreover, 33 of the 39 speB alleles identified encode one of three mature protease variants that differ from one another at only one or two amino acids clustered in a ten-amino acid region. All 39 alleles, and virtually all strains, encode a product that reacts with polyclonal antisera specific for purified cysteine protease. No compelling evidence was found for a primitive differentiation of the speB gene into two distinct classes, as has been proposed for M protein, opacity factor phenotype, and vir regulon architecture. The results demonstrate that the cysteine protease is well conserved in natural populations of S. pyogenes, provide additional evidence that this enzyme is involved in host-parasite interactions, and suggest that the protease plays a role in bacterial dissemination, colonization, and invasion, and inhibition of wound healing.

Alleles↗
PubMed1994

Entry of coxsackievirus A9 into host cells: specific interactions with alpha v beta 3 integrin, the vitronectin receptor.

Attachment and entry of coxsackievirus A9 (CAV-9) to GMK cells were previously shown to be dependent on an arginine-glycine-aspartic acid (RGD) motif in the capsid protein VP1, suggesting integrins as candidate receptors for the virus. We have pursued the matter further and show that antibodies specific for the alpha v and/or beta 3 integrin subunits protect GMK cells from CAV-9 infection. Affinity purification of radioiodinated cell surface proteins using CAV-9 or virus-specific peptide (RRRGDL) columns confirmed that the alpha v beta 3 heterodimer, known as the vitronectin receptor, is recognized by the virus in GMK cells. Other proteins, of lower molecular weight (less than 40 kDa), were also bound to and specifically eluted from the columns, but their possible role in attachment and entry of CAV-9 remains to be elucidated by further studies. Of several other related viruses studied, only echovirus 22, which also has an RGD motif in the VP1 capsid protein, was found to compete for cell surface binding with CAV-9.

Animals↗
PubMed1996

Evidence that extrahepatic cells express vitronectin mRNA at rates approaching those of hepatocytes.

Although the liver is the major source of the adhesive glycoprotein vitronectin (Vn) in vivo, we recently demonstrated low levels of extrahepatic Vn transcription. In this report, in situ hybridization was employed to identify the Vn-producing cells at these extrahepatic sites. In the central nervous system (CNS), high levels of Vn transcripts were prominent in arachnoid cells and in cells frequently present in the vicinity of brain capillaries. Significant amounts of Vn mRNA were also detected in selected peripheral organs. In the myocardium, the signal was localized to cells in the endomysium and subepicardial fat. Additionally, the pulmonary alveolar walls contained Vn-positive cells. The parenchyma of the kidney and spleen were negative. Moreover, larger blood vessels and adjacent cells in the CNS and peripheral organs were devoid of the Vn transcript. Unexpectedly, the rate of Vn gene expression in subsets of cells present in the CNS was similar to that of hepatocytes. These results suggest that the low level of Vn gene expression detected by quantitative PCR may reflect relatively high levels of synthesis by a small subset of cells, and raise the possibility that tissue Vn may, in part, be derived from local biosynthesis rather than from plasma.

Animals↗
PubMed1996

The vitronectin receptor (alpha V beta 3) as an example for the role of integrins in T lymphocyte stimulation.

Integrins are a family of cell surface receptors which mediate the adhesion of cells to each other or to extracellular matrix (ECM) proteins. The interaction of integrins with their ligands or counter-receptors was initially considered to be a one-way process in that cells actively regulate the interaction of integrins with their ligands ('inside-out signal'). In contrast, it was not obvious that cells would receive a signal from the outside via the integrin heterodimers following ligand binding ('outside-in signal'). Recent evidence increasingly supports the active role of integrins in cell activation and proliferation. Many reports describe the effects of integrin-mediated signaling in lymphoid cells. Our studies of gamma/delta T cells, expressing the beta 3 integrin vitronectin receptor (VNR), reflect some of the consequences this active interaction between lymphocytes and the ECM could have for T cell activation and differentiation. The VNR has been described as a T cell costimulatory molecule. We recently reported that the VNR has the potential to stimulate cytokine secretion in T cell hybridomas without involvement of T cell receptor-mediated signals. Further studies demonstrated tyrosine phosphorylation of proteins following VNR cross-linking and the interaction of the VNR with protein kinases. Intensive research focuses on the signal transduction mechanisms of integrins and their interaction with other costimulatory or activation molecules. This knowledge is important to better understand the role of adhesion molecules, the ECM, and the cellular microenvironment for lymphocyte activation and differentiation.

Animals↗
PubMed1997

Localization of vitronectin in the normal and atherosclerotic human vessel wall.

Vitronectin (Vn) regulates proteolytic enzyme systems, as well as cell migration and tissue remodelling. These processes have been implicated in the pathogenesis of atherosclerosis. In this study, the distribution of Vn antigen in apparently normal and atherosclerotic human blood vessels was evaluated. Normal and diseased vessels showed Vn immunostaining in the lamina elastica interna and externa, and in strand-like structures in the adventitia. In most of these instances, the Vn antigen appeared to be located in the proximity of elastin. In pulmonary arteries, Vn staining was additionally detected in the media. The intima was devoid of Vn antigen in all vessels studied. In general, there was increased deposition of Vn antigen in the atherosclerotic arteries. In particular, strong Vn staining was apparent in amorphous material adjacent to cholesterol clefts and in acellular fibrous tissue, in plaques present in the carotic artery and aorta. Collagen layers and fresh fibrin depositions were devoid of Vn antigen. In spite of the abundance of Vn immunostaining throughout the normal and diseased vessel wall, the Vn transcript was not detectably by in situ hybridization. These results indicate that Vn is a constituent of the normal vessel wall and raise the possibility that increased local deposition of Vn may be related to the development of atherosclerotic vascular disease.

Arteriosclerosis↗
PubMed2003

Multimeric vitronectin in ascites is involved in fibroblast spreading of EPS in patients on CAPD therapy.

BACKGROUND: Although encapsulating peritoneal sclerosis (EPS) is a serious complication of continuous ambulatory peritoneal dialysis (CAPD) therapy, the mechanism of the fibroneogenesis in EPS remains unknown. Because fibroblast adhesion and spreading to the extracellular matrix is the first step in peritoneal fibrosis, we investigated fibroblast spreading factor in ascites obtained from patients with EPS (EPS ascites). METHODS: To analyze fibroblast spreading activity, various concentrations of EPS ascites obtained from two EPS patients were coated on culture plates, and then the number of human fibroblasts (TIG-3) that had spread was counted. Each fraction of gel-filtered EPS ascites was also analyzed by this activity. Next, we examined the effect of the addition of Arg-Gly-Asp (RGD) peptides, several antibodies against adhesion molecules, and heparin on the fibroblast spreading activity in the EPS ascites. RESULTS: The fibroblast spreading activity of EPS ascites was about four times greater than that in ascites from a patient with nephrotic syndrome. Two major peaks (peak I and II) of spread cells were obtained when ascites were gel-filtered. The fibroblast spreading activities of the two peaks were abolished by the addition of RGD peptides and polyclonal antibody against vitronectin (VN). Immunoblotting analysis revealed that the two peaks contained VN and that peak I contained multimeric VN. Heparin, at 10 microg/ml, augmented the fibroblast spreading activity of peak I to about three times greater than the control. CONCLUSIONS: The results indicate that multimeric VN in EPS ascites plays a potential role in peritoneal fibrogenesis in EPS and that heparin may participate in peritoneal fibrosis in EPS.

Animals↗
PubMed1991

Homology of placental protein 11 and pea seed albumin 2 with vitronectin.

Vitronectin (complement S-protein), a plasma and tissue glycoprotein of 75 kDa, shares the amino-terminal somatomedin B domain with the membrane glycoprotein PC1 of plasma cells and several hemopexin-type repeats with hemopexin and the non-catalytic carboxy-terminal domain of collagenases. It serves as a ligand for certain integrin receptors, binds to distinct members of the serpin family and inhibits the pore-forming cytolytic reaction of the terminal complement pathway. Computer-assisted data base searches revealed the presence of a single somatomedin B domain in the recently cloned placental protein 11, and four hemopexin-type repeats in the cytosolic plant protein PA2, the major albumin of pea seeds, whose function is unknown. Our finding shows that hemopexin-type repeats are present in extracellular as well as in cytosolic proteins and most likely originated before the divergence of the animal and plant kindoms.

2S Albumins, Plant↗
PubMed1991

Vitronectin in the substratum of endothelial cells is cross-linked and phosphorylated.

Vitronectin (VN), previously shown to be a substrate for purified transglutaminases, was demonstrated in this study to be cross-linked when incubated with HUVEC and EAhy926 cells. The cross-linking was calcium-dependent and required that VN be plated at the substratum of the cells. These cells also phosphorylated VN, but in contrast to a previous study demonstrating a cAMP-dependent protein kinase in platelets, the phosphorylation of VN by was decreased with the addition of 1mM cAMP. The cross-linking of VN by endothelial cells demonstrates that the adhesion of these cells to VN is a dynamic process in which the substratum may be enzymatically altered. Furthermore, the modifications of VN by cross-linking and phosphorylation could modulate the functions of VN and influence events such as endothelial cell proliferation and angiogenesis.

Adenosine Triphosphate↗
PubMed1991

Arg-Gly-Asp constrained within cyclic pentapeptides. Strong and selective inhibitors of cell adhesion to vitronectin and laminin fragment P1.

Cyclic Arg-Gly-Asp-Phe-Val peptides with either D-Phe or D-Val residues were 20- to more than 100-fold better inhibitors of cell adhesion to vitronectin and/or laminin fragment P1 when compared to a linear variant or Gly-Arg-Gly-Asp-Ser. No or only little increase in inhibitory capacity was observed for fibronectin adhesion and for the binding of platelet receptor alpha IIb beta 3 to fibrinogen. NMR studies of the two most active cyclic peptides showed for both an all-trans conformation with a beta II' and gamma turn. Subtle conformational differences, however, exist between both peptides and may contribute to selectivity of inhibition.

Amino Acid Sequence↗
PubMed1994

Inhibition of rat mast cell protease 1 by vitronectin.

Rat mast cell protease 1 (RMCP-1) is a chymotrypsin-like serine protease specifically expressed by connective tissue-type mast cells. The enzyme is stored in the secretory granules in a macromolecular complex with heparin proteoglycan. In the present investigation it was shown that RMCP-1 is inhibited by vitronectin (VN), an RGD-containing adhesive glycoprotein with heparin-binding properties. RMCP-1 that had been separated from heparin proteoglycan was less susceptible to inhibition than RMCP-1 present in complex with heparin proteoglycan. Pre-incubation of VN with purified heparin partially blocked the RMCP-1 inhibiting activity of VN. Plasma VN had negligible RMCP-1-inhibiting activity. However, heat treatment of plasma VN, which is known to expose the heparin-binding domain, induced RMCP-1-inhibiting activity. Affinity chromatography on immobilized VN showed that RMCP-1 bound with high affinity to VN. The binding of RMCP-1 to VN was not heparin-dependent since free RMCP-1 bound with equal affinity to the immobilized VN as RMCP-1 present in complex with heparin. The inhibition of RMCP-1 by VN was shown to be reversible.

Animals↗
PubMed1995

Evidence that conformational changes upon the transition of the native to the modified form of vitronectin are not limited to the heparin binding domain.

Vitronectin (Vn) exists in vivo in at least two different conformational states, the native and the modified form, and these forms have different ligand binding properties. To characterize the molecular events associated with this conformational flexibility, modified Vn was analyzed by competitive ELISA using a panel of conformationally sensitive antibodies with known epitopes. These studies provided evidence for major molecular rearrangements upon the transition from the native to the modified form that are not limited to the C-terminal heparin binding domain, but also occur in the N-terminal part of the molecule.

Binding Sites↗
PubMed1995

Degradation of vitronectin by matrix metalloproteinases-1, -2, -3, -7 and -9.

The susceptibility of vitronectin (Vn) purified from human plasma to digestion by matrix metalloproteinases (MMPs) was examined. MMP-2, -3, -7 and -9 except for MMP-1 degraded Vn into multiple fragments. MMP-7 showed the highest activity to the substrate among these MMPs, digesting 8-, 30- and 44-fold more preferentially than MMP-2, -3, and -9, respectively. These data suggest that MMP-2, -3, -7 and -9 may be responsible for the pathological degradation and/or normal turnover of Vn.

Blood Proteins↗
PubMed1988

Detecting distant homologies of mosaic proteins. Analysis of the sequences of thrombomodulin, thrombospondin complement components C9, C8 alpha and C8 beta, vitronectin and plasma cell membrane glycoprotein PC-1.

Recognition of homologies may give hints about the structure and function of proteins; therefore, we are developing strategies to aid sequence comparisons. Detecting homology of mosaic proteins is especially difficult since the modules constituting these proteins are usually distantly related and their homology is not readily recognized by conventional computer programs. In the present work we show that the rules of the evolution of mosaic proteins can guide the identification of modules of mosaic proteins and can delineate the group of sequences in which the presence of homologous sequences may be expected. By this approach we can concentrate the search for homology to a limited group of sequences; thus ensuring a more intense and more fruitful search. The power of this approach is illustrated by the fact that it could detect homologies not identified by earlier methods of sequence comparison. In this paper we show that thrombomodulin contains a domain homologous with animal lectins, that complement components C9, C8 alpha and C8 beta have modules homologous with one of the repeat units of thrombospondin and that the somatomedin B module of vitronectin is homologous with the internal repeats of plasma cell membrane glycoprotein PC-1.

Amino Acid Sequence↗
PubMed1991

Adhesion and growth of cultured human endothelial cells on perfluorosulphonate: role of vitronectin and fibronectin in cell attachment.

The suitability of neutralized perfluorosulphonic acid (Nafion) as a surface for the attachment and growth of human cells was investigated in tissue culture. Nafion was equivalent to tissue culture polystyrene (TCP), and markedly better than polytetrafluoroethylene (Teflon), for the attachment and growth of human umbilical artery endothelial (HUAE) cells. The attachment and growth of HUAE cells on Fn-coated Nafion was equivalent to that on Fn-coated TCP. The contribution to the attachment and spreading of HUAE cells that is due to adsorption of serum fibronectin (Fn) or vitronectin (Vn) on to the Nafion or TCP was directly tested by selective removal of Fn or Vn from the serum before addition to the culture medium. HUAE cells seeded on to Nafion or TCP in medium depleted of Vn failed to attach and spread on to these surfaces, as measured after 4 or 24 h of culture. HUAE cells seeded in medium depleted of Fn, but containing Vn, attached and spread on to Nafion, albeit to a decreased extent as compared to that in intact serum when measured after 4 h of culture, and there was no effect of depletion of Fn when measured after 24 h of culture. HUAE cells seeded on to TCP in medium depleted of Fn became attached and spread during 4 h of culture. Our results show that Nafion is a suitable polymeric surface for the attachment and growth of human cells, including endothelial cells. For HUAE cells, adsorption on to the surface of an adhesive glycoprotein, such as Vn or Fn, is an essential step for attachment and spreading of the cells onto the Nafion surface.

Biocompatible Materials↗
PubMed1993

Adhesion of staphylococci to chemically modified and native polymers, and the influence of preadsorbed fibronectin, vitronectin and fibrinogen.

A commercially available poly(ether urethane), polyethylene, and modifications of these polymers have been compared with respect to adsorption of fibronectin, fibrinogen and vitronectin. The adhesion of staphylococcal strains (characterized for ability to bind immobilized proteins, cell surface hydrophobicity and charge) was studied by bioluminescence with and without preadsorption of proteins to the surfaces. The least amount of proteins and the fewest bacteria adhered to the amphiphilic surfaces. When polymers were preincubated with plasma or albumin, lower numbers of bacteria adhered, except to Pellethane grafted with PEG 20,000, to which coagulase-negative staphylococci adhered to a higher extent.

Adsorption↗