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PubMed2003

Preliminary study on human protein adsorption and leukocyte adhesion to starch-based biomaterials.

In this study, the adsorption of human serum albumin (HSA), fibronectin (FN) and vitronectin (VN) onto the surface of novel biodegradable materials was evaluated by immunostaining. Specifically, polymeric blends of corn starch with cellulose acetate (SCA), ethylene vinyl alcohol copolymer (SEVA-C), and polycaprolactone (SPCL) were immersed in unitary and competitive systems; that is, binary and more complex protein solutions. For binary solutions, different HSA and FN protein distribution patterns were observed depending on the starch-based surface. Furthermore, the relative amount of proteins adsorbed onto starch-based surfaces was clearly affected by protein type: a preferential adsorption of VN and FN as compared to HSA was observed. On tests carried out with unitary, binary and more complex solutions, it was found that vitronectin adsorption ability was enhanced in competitive systems, which was associated with a lower amount of adsorbed albumin. In order to assess the effect of these human proteins on cell behavior, a mixed population of human lymphocytes and monocytes/macrophages was cultured over pre-coated SEVA-C surfaces. Through anti-CD3 and CD-14 monoclonal antibody labeling and cell counting, leukocyte adhesion onto pre-coated SEVA-C surfaces was analyzed. Based on the results, it was possible to detect albumin long-term effects and fibronectin short-term effects on cell adhesion proving that previously adsorbed proteins modulate leukocyte behavior.

Journal Article↗
PubMed2003

Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase.

Arachidonate 12-lipoxygenase (LOX) converts arachidonic acid to 12(S)-hydroxyeicosatetraenoic acid (HETE), a bioactive lipid implicated in tumor angiogenesis, growth, and metastasis. Alteration in 12-LOX expression or activity has been reported in various carcinomas including prostate carcinoma. However, little is known about the impact of the altered expression or activity of 12-LOX on tumor metastasis. In the present study, we examined whether or not an increase in 12-LOX expression in human prostate carcinoma cells can modulate their metastatic potential. We report that increased expression of 12-LOX in PC-3 cells caused a significant change in cell adhesiveness, spreading, motility, and invasiveness. Specifically 12-LOX transfected PC-3 cells were more adhesive toward vitronectin, type I and IV collagen, but not to fibronectin or laminin, than cells transfected with control vector. Increased spreading on vitronectin, fibronectin, collagen type I and IV also was observed in 12-LOX transfected PC-3 cells when compared to control PC-3 cells. The increased spreading of 12-LOX transfected PC-3 cells was blocked by treatment with 12-LOX inhibitors, baicalein and CDC. 12-LOX transfected PC-3 cells were more invasive through Matrigel than cells transfected with control vector. In vivo, tumor cell invasion to surrounding muscle or fat tissues was more frequent in nude mice bearing s.c. tumors from 12-LOX transfected PC-3 cells than in those from control vector transfected cells. When injected via the tail vein into SCID mice with implanted human bone fragments, there was an increase in tumor metastasis to human bone by 12-LOX transfected PC-3 cells in comparison to control vector transfected cells. Taken together, our data suggest that an increase in 12-LOX expression enhances the metastatic potential of human prostate cancer cells.

Adenocarcinoma↗
PubMed1999

Grafting an RGD motif onto an epidermal growth factor-like module: chemical synthesis and functional characterization of the chimeric molecule.

A novel protein was engineered by inserting the GRGDS motif of fibronectin within the 14-residue loop of the EGF-like module from human complement protease C1r. The resulting chimeric EGF-RGD module (52 residues, three disulfide bridges) was assembled by automated solid-phase synthesis using the t-Boc strategy. Using reduced/oxidized glutathione, the EGF-RGD module was folded as efficiently as the natural C1r-EGF module, resulting in formation of the appropriate disulfide bridge pattern as shown by mass spectrometry and N-terminal sequence analyses of thermolytic fragments. Circular dichroism and NMR measurements provided further indication that introduction of the GRGDS motif had no significant effect on the folding. Using Chinese Hamster Ovary (CHO) cells bearing the integrin receptors specific for fibronectin and vitronectin, EGF-RGD was shown to induce cell adhesion via the introduced GRGDS motif. Cell binding was inhibited specifically and efficiently by the synthetic peptide GRGDSP and by fibronectin, and to a much lesser extent by vitronectin, whereas the monoclonal antibody PB1 directed to the alpha5 subunit of alpha5beta1 integrin had no effect. The ability of EGF-RGD to trigger significant cell spreading and intracellular signaling was also demonstrated using immunofluorescence and confocal microscopy.

Amino Acid Sequence↗
PubMed1998

N-methylformamide induces changes on adhesive properties and lung-colonizing potential of M14 melanoma cells.

We have studied whether N-methylformamide can affect the expression pattern of adhesion molecules and the attachment behaviour of M14 human melanoma cells. The role of N-methylformamide on experimental and spontaneous pulmonary metastases from M14 cells in nude mice was also investigated. We demonstrate that N-methylformamide in vitro pretreatment of M14 cells, although inducing a significant increase in the expression of alpha2beta1, alpha6beta1 and alpha(v)beta3 integrin receptors, slightly modifies alpha5beta1 heterodimer and beta1 subunit expression. After this modulation, enhancement of cell adhesion to laminin, collagen I, vitronectin and fibrinogen, which is blocked by specific anti-integrin antibodies, also occurs. No changes in binding to fibronectin are observed. In vitro N-methylformamide pretreatment also results in an increased number of experimental nodules and in a decrease in spontaneous metastases. Moreover, in vivo treatment with N-methylformamide significantly reduces the number of spontaneous metastases. Collectively, these data show that N-methylformamide modulates the expression of some adhesion receptors, cell adhesion to laminin, collagen I, vitronectin and fibrinogen as well as the metastatic behaviour of M14 cells. Our data also suggest that the effect of N-methylformamide might be evaluated in combination with antineoplastic agents for the treatment of human melanoma.

Animals↗
PubMed1995

Human melanoma integrins contribute to arrest and stabilization potential while flowing over extracellular matrix.

To form distant metastases, tumour cells must stabilize adhesive interactions that prevent detachment at secondary sites. Primary receptor-ligand interactions alone may not maintain prolonged adhesive contacts without secondary events that lead to adhesion stabilization. Computerized imaging methods enable us to examine various substrates for: (i) the wall shear adhesion threshold (WSAT), a measure of the dynamic adhesive potential of tumour cells; (ii) the number of tumour cells that adhered; and (iii) the adhesion stabilization lag time (ASLT) or length of time required for tumour cells to stabilize adhesive contacts capable of withstanding high wall shear force (up to 100 dynes/cm2). The relative WSAT ratios found were: wheat germ agglutinin (WGA) > laminin > fibronectin > vitronectin > collagen I > collagen IV > von Willebrand factor (vWF) (the greater the shear rate the higher the adhesive potential). The relative stabilization ratios found were as follows: laminin < fibronectin < vitronectin < collagen IV < collagen I < vWF < WGA (shorter times correlate with greater stabilization potential). Stabilization data using fibronectin as a substrate correlated the best with metastatic potential. Using three melanoma lines of different metastatic potential semiquantitative reverse transcriptase-polymerase chain reaction (PCR) showed a two- to four-fold increase in alpha1, alpha3, alpha4, alpha5, alpha6, and ICAM-1 in the highly metastatic 70W cells compared to the MeWo and non-metastatic 3S5 melanoma cells. There were no differences in alphav, beta1 and beta3 levels among the three melanoma lines, and PCR products for alphaIIb, alpha2, CD36, or ICAM-2 were not detected. The 70W cells also had higher levels of alphax and beta2 (CD11/CD18 and p150 leukocyte antigen) than either the MeWo or 3S5 cells. The data indicate that melanoma cells exhibit differences in the adhesion properties under fluid shear and differences in the expression of adhesion components that correlate with their metastatic potential.

Base Sequence↗
PubMed1995

Activation of the terminal complement cascade in renal infarction.

Ischemic injury is an important cause of functional derangement in the kidney. The complement (C) system has previously been shown to be an important mediator of ischemic tissue injury in myocardial infarction. In the present study we therefore investigated the possible role of C in renal ischemic lesions. The deposition and distribution of various C components (C1q, C3c, C3d, C4, C5, C6, C9) and regulators [vitronectin, clusterin and protectin (CD59)] in human renal infarction lesions were studied by indirect immunofluorescence microscopy. Deposition of components of the terminal C complex (TCC), as well as vitronectin and clusterin, were observed throughout the infarcted areas. The strongest deposits were seen on the membranes of tubular epithelial cells and in the tubular lumina of the infarction areas, especially in the border zone between normal and infarcted tissue. Using markers for different segments of tubuli (Tamm-Horsfall glycoprotein and brush border antigens) it was possible to localize deposits of TCC predominantly to the proximal tubuli. In the glomeruli of the infarcted areas deposits of TCC were seen as a crescent-like pattern at and immediately beneath the Bowman's capsule. The expression of cell membrane-associated protectin was diminished in tubular epithelial cells of the infarction lesions. A clue for the possible mechanism of C activation in renal infarction was obtained from in vitro experiments, in which the contact of normal human serum with urine was observed to lead to the generation of TCC.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement Activation↗
PubMed1998

Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis.

1. Elevated plasminogen activator inhibitor 1 (PAI-1) is a risk factor for thrombosis, and inhibitors of the interaction between PAI-1 and tissue plasminogen activator (t-PA) have antithrombotic and prothrombolytic activity in animals. We describe the antithrombotic effects in the rat of a monoclonal antibody (MA33H1) which converts PAI-1 to a non-inhibitory substrate. 2. The activity of MA33H1 against rat PAI-1 was confirmed using two-chain t-PA and a chromogenic substrate. MA33H1 was evaluated in rat venous (thromboplastin + stasis in the abdominal vena cava) and arterial (electric current applied to a carotid artery) thrombosis models. The effects on tail-transection bleeding time were studied. 3. MA33H1 at 100 ng ml(-1) inhibited both human (44.1%) and rat PAI-1 (49.7%). This effect was concentration-dependent. Its effect on human PAI-1 was not significantly inhibited by 1 microg ml(-1) fibrin or a approximately 7 fold molar excess of vitronectin (1 nM). Inhibition of rat PAI-1 was unchanged by fibrin, but vitronectin reduced inhibition from 0.5 nM. 4. In the venous thrombosis model, MA33H1 significantly reduced thrombus weights by 38 and 58.6% at 50 and 100 microg kg(-1) min(-1) i.v. respectively. This effect was inhibited by tranexamic acid. In the arterial model, MA33H1 significantly increased the delay to occlusive thrombus formation by 58 and 142% at 50 and 100 microg kg(-1) min(-1) i.v., and did not affect bleeding time at 300 microg kg(-1) min(-1) i.v. 5. Thus, a monoclonal antibody which transforms PAI-1 to a t-PA substrate prevents thrombus formation in the rat with no effect on bleeding time at a higher dose.

Animals↗
PubMed2000

Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization, cell adhesion and cell migration revealed by overexpression of a dominant negative mutant.

SHP-2, a SRC homology 2 domain-containing protein tyrosine phosphatase, mediates activation of Ras and mitogen-activated protein kinase by various mitogens and cell adhesion. Inhibition of endogenous SHP-2 by overexpression of a catalytically inactive (dominant negative) mutant in Chinese hamster ovary cells or Rat-1 fibroblasts has now been shown to induce a marked change in cell morphology (from elongated to less polarized) that is accompanied by substantial increases in the numbers of actin stress fibers and focal adhesion contacts. Overexpression of the SHP-2 mutant also increased the strength of cell-substratum adhesion and resulted in hyperphosphorylation of SHPS-1, a substrate of SHP-2 that contributes to cell adhesion-induced signaling. Inhibition of SHP-2 also markedly increased the rate of cell attachment to and cell spreading on extracellular matrix proteins such as fibronectin and vitronectin, effects that were accompanied by enhancement of adhesion-induced tyrosine phosphorylation of paxillin and p130Cas. In addition, cell migration mediated by fibronectin or vitronectin, but not that induced by insulin, was impaired by overexpression of the SHP-2 mutant. These results suggest that SHP-2 plays an important role in the control of cell shape by contributing to cytoskeletal organization, and that it is an important regulator of integrin-mediated cell adhesion, spreading, and migration as well as of tyrosine phosphorylation of focal adhesion contact-associated proteins.

Animals↗
PubMed2001

TGF-beta1 up-regulates paxillin protein expression in malignant astrocytoma cells: requirement for a fibronectin substrate.

Cytokines can influence the interactions between members of the integrin cell adhesion receptor family and the extracellular matrix thereby potentially affecting cell function and promoting cell adhesion, growth and migration of malignant astrocytoma tumor cells. As malignant astrocytoma cells synthesize TGF-beta1 in vivo, we analysed the effects of TGF-beta1 on signaling events associated with integrin receptor ligation, focusing on the effects on paxillin, a phosphorylated adaptor protein, that acts as a scaffold for signaling molecules recruited to focal adhesions. TGF-beta1-stimulation of primary astrocytes and serum-starved U-251MG malignant astrocytoma cells attached to fibronectin induced a substantial increase in the levels of paxillin protein (fivefold increase at 2.0 ng/ml) in a dose- and time-dependent manner compared to the levels observed on plating onto fibronectin in the absence of stimulation. In the astrocytoma cells, this resulted in an increase in the pool of tyrosine-phosphorylated paxillin, although it did not appear to alter the extent of phosphorylation of the paxillin molecules. In contrast, in primary astrocytes the protein levels were upregulated in the absence of a parallel increase in phosphorylation. The TGF-beta1-stimulated increase in paxillin levels required ligation of the fibronectin receptor, as it was not induced when the cells were plated onto vitronectin, collagen or laminin. The increase in the pool of paxillin on TGF-beta1 stimulation of the fibronectin-plated astrocytoma cells was associated with an increase in translation, but was not associated with an increase in the steady-state levels of paxillin mRNA. Stimulation with TGF-beta1 on a fibronectin substrate increased subsequent attachment and spreading of U-251MG cells onto fibronectin and, to a lesser extent, vitronectin, but not collagen. Our results indicate that physiologic levels of TGF-beta1 stimulate the expression of paxillin protein at the level of translation through a process that requires engagement of the fibronectin receptor, and promotes attachment and spreading of malignant astrocytoma cells on fibronectin.

Animals↗
PubMed2003

Ras oncogene directs expression of a differentially sialylated, functionally altered beta1 integrin.

Intense investigation has centered on understanding the regulation of integrin cell adhesion receptors. In the present study, we propose that variant N-glycosylation represents an important mechanism for regulation of beta1, but not beta3 or beta5 integrins. We find that expression of oncogenic ras in HD3 colonocytes causes increased alpha2-6 sialylation of beta1 integrins, whereas expression of dominant-negative ras induces decreased alpha2-6 sialylation, relative to cells with wild-type ras. In contrast, neither beta3 nor beta5 integrins are alpha2-6 sialylated, regardless of the state of ras activation. Results from RT-PCR analyses suggest that differential integrin sialylation is due to a ras-dependent alteration in the expression of ST6Gal I, the enzyme that adds alpha2-6-linked sialic acids. Cells that express differentially sialylated beta1 integrins exhibit altered adhesion to collagen I (a beta1 ligand), but not to vitronectin (a beta3 or beta5 ligand). Similarly, the enzymatic removal of cell surface sialic acids from control cells alters binding to collagen, but not to vitronectin. Finally, using a cell-free receptor/ligand-binding assay, we show that purified, desialylated alpha1beta1 integrins have diminished collagen-binding capability, providing strong evidence that sialic acids play a causal role in regulating beta1 integrin function.

Base Sequence↗
PubMed2004

Overexpression of FAK promotes Ras activity through the formation of a FAK/p120RasGAP complex in malignant astrocytoma cells.

Focal adhesion kinase (FAK) signaling may be mediated through the modulation of Ras activity. We have shown previously that grade III malignant astrocytoma biopsy samples exhibit elevated levels of FAK, and that overexpression of FAK in U-251MG malignant astrocytoma cells promotes the phosphorylation of Shc, a potential upstream mediator of Ras activity. Here, we report that overexpression of FAK promotes Ras activity in U-251MG malignant astrocytoma cells cultured in aggregate suspension or as monolayers adherent to vitronectin. The overexpression of FAK also promoted the association of FAK with p120RasGAP, which is a negative regulator of Ras activity, in the U-251MG cells cultured in aggregate suspension, with this association being abrogated upon plating of the cells onto vitronectin. An association of FAK with p120RasGAP also was observed in malignant astrocytoma biopsy samples, but not in normal brain samples. As overexpression of FAK in U-251MG cells in aggregate suspension culture reduced the amount of p120RasGAP complexed with active Ras, we hypothesize that the association of FAK with p120 RasGAP may facilitate Ras activity. The overexpression of a mutated FAK in which the Y397 had been mutated to F did not result in the formation of the FAK/p120RasGAP complex and did not promote Ras activity, indicating that the Y397 residue of FAK plays a role in the formation of this complex and in the activation of Ras. Moreover, the overexpression of mutated FAK (397F) was found to inhibit anchorage-independent growth. These data provide the basis for a previously undescribed mechanism in which the elevated expression of FAK can promote Ras activity through its competitive recruitment of p120RasGAP, thereby diminishing the association of p120RasGAP with active Ras.

Animals↗
PubMed2000

Mechanisms of pertussis toxin-induced myelomonocytic cell adhesion: role of CD14 and urokinase receptor.

Pertussis toxin (PTX) has been shown previously to promote myelomonocytic cell adhesion in serum. The aim of the present study was to identify, using transforming growth factor-beta1 and 1, 25-(OH)2 vitamin D3 (TGF-beta1/D3)-primed U937 cells, the PTX-binding site(s) and the adhesion molecule(s) responsible for PTX-induced myelomonocytic cell adhesion. Monoclonal antibodies (mAbs) directed against CD14, CD11b, CD18 or urokinase receptor (uPAR) significantly inhibited PTX-induced primed U937 cell adhesion in serum in a concentration-dependent manner. However, only anti-CD14 and anti-CD18 mAbs were able to prevent the myeloid cells from binding to PTX-coated plates and significantly inhibited a PTX-induced rise of [Ca2+]i in primed U937 cells. A receptor-isolation study showed that biotinylated PTX recognized a 48 000-molecular weight protein in primed U937 cell lysates, which could be specifically blocked by excess unlabelled PTX or by anti-CD14 mAb. On the other hand, mAb directed against uPAR significantly blocked PTX-induced myeloid cell adhesion to serum and to immobilized vitronectin, a major extracellular matrix protein in serum. Taken together, our data suggest that PTX may bind to cell-surface CD14 to induce myelomonocytic cell adhesion to vitronectin in serum via uPAR activation, which may represent a pathogenetic mechanism for the respiratory tract infection induced by Bordetella pertussis.

Bone Marrow Cells↗
PubMed2001

Decrease of breast cancer cell invasiveness by sodium phenylacetate (NaPa) is associated with an increased expression of adhesive molecules.

Sodium phenylacetate (NaPa), a non-toxic phenylalanine metabolite, has been shown to induce in vivo and in vitro cytostatic and antiproliferative effects on various cell types. In this work, we analysed the effect of NaPa on the invasiveness of breast cancer cell (MDA-MB-231, MCF-7 and MCF-7 ras). Using the highly invasive breast cancer cell line MDA-MB-231, we demonstrated that an 18-hour incubation with NaPa strongly inhibits the cell invasiveness through Matrigel (86% inhibition at 20 mM of NaPa). As cell invasiveness is greatly influenced by the expression of urokinase (u-PA) and its cell surface receptor (u-PAR) as well as the secretion of matrix metalloproteinases (MMP), we tested the effect of NaPa on these parameters. An 18-hour incubation with NaPa did not modify u-PA expression, either on MDA-MB-231 or on MCF-7 and MCF-7 ras cell lines, and induced a small u-PA decrease after 3 days of treatment of MDA-MB-321 with NaPa. In contrast, an 18 h incubation of MDA-MB-231 increased the expression of u-PAR and the secretion of MMP-9. As u-PAR is a ligand for vitronectin, a composant of the extracellular matrix, these data could explain the increased adhesion of MDA-MB-231 to vitronectin, while cell adhesivity of MCF-7 and MCF-7 ras was unmodified by NaPa treatment. NaPa induced also an increased expression of both Lymphocyte Function-Associated-1 (LFA-1) and Intercellular Adhesion Molecule-1 (ICAM-1), which was obvious from 18 hour incubation with NaPa for the MDA-MB-231 cells, but was delayed (3 days) for MCF-7 and MCF-7 ras. Only neutralizing antibodies against LFA-1 reversed the decreased invasiveness of NaPa-treated cells. Therefore we can conclude that the strong inhibition of MDA-MB-231 invasiveness is not due to a decrease in proteases involved in cell migration (u-PA and MMP) but could be related both to the modification of cell structure and an increased expression of adhesion molecules such as u-PAR and LFA-1.

Antineoplastic Agents↗
PubMed2002

Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a molecular understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome analysis. Liquid chromatography tandem MS analyses of drusen preparations from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochemical studies have thus far localized approximately 16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins observed in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also observed, including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidation of docosahexaenoate-containing lipids. By Western analysis they were found to be more abundant in AMD than in normal Bruch's membrane and were found associated with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a critical role in drusen formation.

Aged↗
PubMed1987

The very late antigen family of heterodimers is part of a superfamily of molecules involved in adhesion and embryogenesis.

The very late antigen (VLA) protein family contains at least five related heterodimers, including a fibronectin receptor structure, and probably other cell substrate adhesion receptors. These cell-surface VLA proteins were immunopurified from human placenta (VLA-1, VLA-3, and VLA-5), platelets (VLA-2), and Molt-4 cells (VLA-4) using a series of monoclonal antibody-Sepharose immunoaffinity columns. After further purification by gel electrophoresis, the N-terminal amino acid sequence for each of the five VLA alpha subunits was determined. In the first 14 positions, the five VLA alpha subunits showed an average of 42% homology to each other, rising to 59% including conservative amino acid substitutions. In addition, the alpha subunits from the LFA-1, Mac-1 (CR-3), and p150,95 family of heterodimers, the vitronectin receptor-platelet GPIIb/IIIa family, and a position-specific (PS) antigen important in Drosophila embryogenesis each showed average homologies of 31-40% to individual VLA alpha sequences and 46-52% homology to VLA alpha subunits including conservative substitutions. Taken together, these results suggest that the VLA proteins, the LFA-1, Mac-1, and p150,95 family, the GPIIb/IIIa, vitronectin receptor family, and the Drosophila PS antigens have evolved as four subgroups in a highly conserved supergene family of receptors involved in fundamentally important functions, such as cell adhesion, migration, and embryogenesis.

Amino Acid Sequence↗
PubMed1990

Cloning of an integrin beta subunit exhibiting high homology with integrin beta 3 subunit.

cDNAs for another beta subunit of the integrin family were isolated with the aid of polymerase chain reaction and sequenced. The combined cDNA sequence is 3110 base pairs (bp) in size and has one long open reading frame of 2388 bp. The deduced amino acid sequence is similar to those of other integrin beta subunits but does not correspond to beta 1, beta 2, beta 3, or beta 4 subunits. This beta subunit is divided by a membrane-spanning domain into a large extracellular domain at the N-terminal side and a small intracellular domain at the C-terminal side. The extracellular domain has a cysteine-rich region that contains four repeats of 8-cysteine motifs. All 56 cysteine residues found in the extracellular domains of other mature beta subunits are present in this beta subunit. The beta subunit reported here has particularly high homology with the beta 3 subunit. The mRNA for the molecule is approximately 3.5 kbp in size and is expressed in various cell types. Other researchers have recently reported additional beta subunits that associate with the vitronectin receptor alpha subunit. The deduced amino acid sequence of this molecule contains the N-terminal partial amino acid sequence of one of these beta subunits, beta x. The beta subunit described herein seems to be identical to the beta x subunit and to function as the beta subunit of a vitronectin receptor.

Amino Acid Sequence↗
PubMed1998

beta3 Integrins mediate the cellular entry of hantaviruses that cause respiratory failure.

Newly emerged hantaviruses replicate primarily in the pulmonary endothelium, cause acute platelet loss, and result in hantavirus pulmonary syndrome (HPS). We now report that specific integrins expressed on platelets and endothelial cells permit the cellular entry of HPS-associated hantaviruses. Infection with HPS-associated hantaviruses, NY-1 and Sin Nombre virus (SNV), is inhibited by antibodies to beta3 integrins and by the beta3-integrin ligand, vitronectin. In contrast, infection with the nonpathogenic (no associated human disease) Prospect Hill virus was inhibited by fibronectin and beta1-specific antibodies but not by beta3-specific antibodies or vitronectin. Transfection with recombinant alphaIIb beta3 or alphav beta3 integrins rendered cells permissive to NY-1 and SNV but not Prospect Hill virus infection, indicating that alphaIIb beta3 and alphav beta3 integrins mediate the entry of NY-1 and SNV hantaviruses. Furthermore, entry is divalent cation independent, not blocked by arginine-glycine-aspartic acid peptides and still mediated by, ligand-binding defective, alphaIIb beta3-integrin mutants. Hence, NY-1 and SNV entry is independent of beta3 integrin binding to physiologic ligands. These findings implicate integrins as cellular receptors for hantaviruses and indicate that hantavirus pathogenicity correlates with integrin usage.

Animals↗
PubMed2003

Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury.

Complex DNA viruses have tapped into cellular serpin responses that act as key regulatory steps in coagulation and inflammatory cascades. Serp-1 is one such viral serpin that effectively protects virus-infected tissues from host inflammatory responses. When given as purified protein, Serp-1 markedly inhibits vascular monocyte invasion and plaque growth in animal models. We have investigated mechanisms of viral serpin inhibition of vascular inflammatory responses. In vascular injury models, Serp-1 altered early cellular plasminogen activator (tissue plasminogen activator), inhibitor (PAI-1), and receptor (urokinase-type plasminogen activator) expression (p < 0.01). Serp-1, but not a reactive center loop mutant, up-regulated PAI-1 serpin expression in human endothelial cells. Treatment of endothelial cells with antibody to urokinase-type plasminogen activator and vitronectin blocked Serp-1-induced changes. Significantly, Serp-1 blocked intimal hyperplasia (p < 0.0001) after aortic allograft transplant (p < 0.0001) in PAI-1-deficient mice. Serp-1 also blocked plaque growth after aortic isograft transplant and after wire-induced injury (p < 0.05) in PAI-1-deficient mice indicating that increase in PAI-1 expression is not required for Serp-1 to block vasculopathy development. Serp-1 did not inhibit plaque growth in uPAR-deficient mice after aortic allograft transplant. We conclude that the poxviral serpin, Serp-1, attenuates vascular inflammatory responses to injury through a pathway mediated by native uPA receptors and vitronectin.

Angioplasty↗