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PubMed2003

Discovery of small molecule leads in a biotechnology datastream.

A case study of the discovery of small molecule antagonists to the integrins GPIIbIIIa (alphaII(B)beta3), alphavbeta3, LFA-1 (alphaLbeta2), alpha4beta1 and alpha4beta7 is presented from the perspective of a biotechnology research organization. A strategy incorporating protein mutagenesis and structural studies to develop a structure-activity relationship (SAR) that described the 'epitope' of the integrin ligand was crucial to the identification of peptide analogs of these proteins, and subsequently, through parallel trends in SAR, to the identification of small molecule mimetics of these peptides, which are active analogs of the protein ligands themselves.

Biotechnology↗

PubMed2005

Integrin repertoire on myogenic cells changes during the course of primary myogenesis in the mouse.

Cells interact with the extracellular matrix through receptors, most commonly of the integrin family. We (Cachaco et al. [2003] Development 130:1659-1671) and others (Schwander et al. [2003] Dev. Cell 4:673-685) have demonstrated a role for beta1 integrins in mouse primary myogenesis. However, it is unclear what alpha subunits pair with beta1 during this process in vivo. Here, we determined alpha subunit expression patterns at embryonic day (E) 11.5-E14.5. Differentiated myotomal myocytes express all alpha subunits studied. As the muscle masses form both in trunk (E12.5) and limbs (E11.5-E12.5), laminin receptors alpha6beta1 and alpha7beta1 are undetectable, and an assembled laminin matrix is absent. Instead alpha1beta1, alpha4beta1, alpha5beta1, and an alpha v-containing integrin are expressed and unassembled laminin and fibronectin are abundant around myogenic cells. At E13.5-E14.5, alpha6beta1 and alpha7beta1 are expressed, and a laminin matrix forms around individual myotubes. Thus, myogenic cells change their integrin expression pattern during the course of primary myogenesis in the mouse, suggesting different roles for fibronectin- and laminin-containing matrices in this process.

Animals↗

PubMed1998

Intravenous and oral antiplatelet/antithrombotic efficacy and specificity of XR300, a novel nonpeptide platelet GPIIb/IIIa antagonist.

Currently used antiplatelet drugs including aspirin, ticlopidine, and others are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus our study was undertaken to define the antiplatelet efficacy, specificity, and the intravenous and oral antiplatelet/antithrombotic effects of a nonpeptide glycoprotein alphaIIb beta3 integrin (GPIIb/IIIa) antagonist XR300, an ethyl ester prodrug of XR299. XR300, on its conversion to the active form XR299, inhibited human platelet aggregation induced by 100 microM adenosine diphosphate (ADP) with a median inhibitory concentration (IC50) of 0.09 microM. Similarly, XR299 inhibited 125I-fibrinogen binding to human gel-purified platelets (IC50, 0.01 microM) regardless of the agonist used. In purified human GPIIb/IIIa, XR299 demonstrated a competitive high-affinity binding with an IC50 of 1.2 nM. XR299 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alphaIIb beta3) as compared with other integrins including alpha(v)beta3, alpha(v)beta5, and alpha4beta1, where IC50 values were >10 microM. XR300 administered to mongrel dogs either intravenously (0.5-1.0 mg/kg, i.v.) or orally at 1.0-2.0 mg/kg, demonstrated maximal antiplatelet effects with rapid onset and extended duration. XR300 demonstrated maximal antithrombotic efficacy in preventing the incidence of occlusive thrombosis or cyclic flow reduction (CFR) in the carotid or femoral artery thrombosis models induced either electrolytically or by mechanical injury along with stenosis. In conclusion, XR300 is a novel intravenous and oral antiplatelet/antithrombotic agent with high affinity and specificity for platelet GPIIb/IIIa receptors.

Administration, Oral↗

PubMed2004

In vitro exposure to paclitaxel modulates integrin expression by human T lymphocytes and inhibits T cell adhesion to breast carcinoma cells.

Paclitaxel (Taxol) is a drug that is commonly used in the treatment of metastatic breast cancer. In this study, we investigated the effect of prior exposure to submaximal cytotoxic concentrations (EC(25) and EC(50)) of paclitaxel on the subsequent ability of human Jurkat T lymphocytes to adhere to monolayers of MDA-MB-435 human breast carcinoma cells. Jurkat T cells that survived culture for 24 h in the presence of paclitaxel (0.1 or 3 micro g/ml) exhibited a diminished ability to adhere to MDA-MB-435 breast cancer cell monolayers. Flow cytometric analysis of paclitaxel-treated Jurkat T cells revealed reduced surface expression of alphaL, alpha4, alpha5, and beta7 integrins, but normal beta1 integrin expression. These data suggest that paclitaxel interferes with the expression of alphaLbeta2 (LFA-1), alpha4beta1 (VLA-4), alpha5beta1 (VLA-5), and alpha4beta7 (LPAM-1) adhesion molecules by surviving T cells. Blocking experiments with antibodies against alphaL, alpha4, alpha5, beta1, and beta7 integrins revealed that adhesion of Jurkat T cells to MDA-MB-435 breast cancer cell monolayers was dependent upon alphaL, alpha4, and beta7 but not alpha5 or beta1 integrins. We conclude that prior exposure to paclitaxel caused a reduction in Jurkat T cell adhesion to MDA-MB-435 breast carcinoma cells by preventing optimal alphaLbeta2 and alpha4beta7 interactions with their corresponding ligands on tumor cells. A similar effect by paclitaxel on T lymphocytes of breast cancer patients may compromise cell-mediated anti-tumor immune responses.

Antineoplastic Agents, Phytogenic↗

PubMed1999

Structural and functional characterization of EMF10, a heterodimeric disintegrin from Eristocophis macmahoni venom that selectively inhibits alpha 5 beta 1 integrin.

Alpha5beta1, a major fibronectin receptor, is a widely distributed integrin that is essential for cell growth and organ development. Here, we describe a novel heterodimeric disintegrin named EMF10, isolated from the Eristocophis macmahoni venom, that is an extremely potent and selective inhibitor of alpha5beta1. EMF10 inhibited adhesion of cells expressing alpha5beta1 to fibronectin (IC(50) = 1-4 nM) and caused expression of a ligand-induced binding site (LIBS) on the beta1 subunit of alpha5beta1 integrin. It partially inhibited adhesion of cells expressing alphaIIbbeta3, alphavbeta3, and alpha4beta1 to appropriate ligands only at concentration higher than 500 nM. Guinea pig megakaryocytes expressing alpha5beta1 adhered to immobilized EMF10 and showed extensive spreading and cytoskeletal mobilization. As determined by electrospray mass spectrometry, EMF10 is composed of two species with molecular masses of 14 575 and 14 949 Da, respectively. EMF10 is a heterodimer containing two subunits: EMF10A (Mr 7544 Da) and EMF10B (Mr 7405 and 7032 Da) linked covalently by S-S bonds. Subunit B showed heterogeneity and may be present as EMF10B1 (Mr 7032) and EMF10B2 (Mr 7405). In putative hairpin loops, EMF10A and EMF10B contained CKKGRGDNLNDYC and CWPAMGDWNDDYC motifs, respectively. The reduced and alkylated subunit B of EMF10 inhibited adhesion of K562 cells to fibronectin in a dose-dependent, saturable manner with IC(50) of 3 microM. The synthetic, cyclic CKKGRGDNLNDYC and CWPAMGDWNDDYC peptides expressed their inhibitory activity in the same system with IC(50) of 100 microM. We propose that alpha5beta1 recognition of EMF10 is associated with the MGDW motif located in a putative hairpin loop of the B subunit and that the expression of activity may also depend on the RGDN motif in the subunit A and on the C-termini of both subunits.

Amino Acid Sequence↗

PubMed1999

Matrix adhesion characteristics of corneal myofibroblasts.

PURPOSE: To investigate the adhesion characteristics of corneal myofibroblasts in a cell culture model. METHODS: Immunocytochemistry, immunoprecipitation, western blot analysis, and attachment assays were used to evaluate matrix adhesion characteristics of myofibroblasts. RESULTS: Myofibroblasts, defined by their expression of the smooth muscle isoform of alpha-actin, were evaluated and compared with fibroblasts. Myofibroblasts had larger vinculin-containing focal adhesions and expressed more of the classic fibronectin receptor (FNR) alpha5beta1 per cell. However, myofibroblasts had less surface expression of the higher molecular weight alpha4 subunit of another FNR, alpha4beta1, than did fibroblasts. Myofibroblasts adhered more avidly in an integrin-dependent manner to fibronectin than did fibroblasts. The attachment to fibronectin was actin-dependent for both phenotypes, but the myofibroblasts' adhesion was more resistant to disruption by cytochalasin than were fibroblasts'. In addition to the previously described expression of a 135-kDa classic cadherin, myofibroblasts also expressed a 115-kDa mesenchymal cadherin, cadherin-11. CONCLUSIONS: Differentiation of corneal fibroblasts into myofibroblasts is associated with characteristics that would indicate that the latter have a special role in wound closure. The increase in focal and cell adhesion molecules that accompanies smooth muscle-specific actin expression provides the basis for the myofibroblasts' enhanced cell-fibronectin and cell-cell adhesion.

Animals↗

PubMed1998

Asp-698 and Asp-811 of the integrin alpha4-subunit are critical for the formation of a functional heterodimer.

The amino acid motif LDV is the principal binding site for alpha4 integrins in fibronectin, and homologous motifs are recognized in vascular cell adhesion molecule-1 and MAdCAM-1. Three conserved LDV motifs (LDV-1 to 3) occur in the ectodomain of the human and mouse alpha4-subunit, the functions of which are unknown. We demonstrate here that alpha4-transfected fibroblasts with mutation in LDV-1 (D489N) behaved like alpha4-wild type but that LDV-2 (D698N) and LDV-3 (D811N) mutants were impaired in binding and spreading on alpha4-specific substrates. On the RGD-containing fibronectin fragment FN-120 there was an inverse behavior; now the alpha4-wild type and the LDV-1 mutant could not adhere whereas the two other mutants could. The beta1 chain was critical for the differential integrin response. Biochemical analysis demonstrated that the LDV-2 and -3 mutations reduced the strength of the alpha4beta1 association, favored the formation of alpha5beta1, and prevented the expression of alpha4beta7 on the cell surface. Our results indicate that LDV-2 and LDV-3 are critical for the formation of a functional heterodimer. The presence of similar amino acid motifs in ligands and the alpha4-subunit suggest that metal coordination plays an important role in integrin-ligand binding as well as for heterodimer formation.

3T3 Cells↗

PubMed1997

Structural interlock between ligand-binding site and stalk-like region of beta1 integrin revealed by a monoclonal antibody recognizing conformation-dependent epitope.

Integrin activation and sebsequent ligand binding to it are regulated by intracellular mechanisms called inside-out signaling, which are not fully understood and are accompanied by dynamic structural changes of the integrin molecule itself. A monoclonal antibody recognizing a conformation-dependent epitope on human beta1 integrin was produced and characterized in detail. This antibody, AG89, reacted with human integrin beta1 chain regardless of the alpha subunit. AG89 can recognize resting state beta1 integrin on the cells, but the reactivity is increased approximately 2-fold upon integrin activation by activating anti-beta1 antibodies and approximately 3-fold by Mn2+. Furthermore, occupation of the ligand-binding pocket by a soluble ligand (RGD peptide for alpha(v)beta1 and CS-1 peptide for alpha4beta1) resulted in maximum binding of AG89, indicating that the epitope for AG89 is exposed during the conformational changes of beta1 integrin upon activation/ligation. Epitope mapping by using interspecies chimeric beta1 revealed that the epitope for AG89 lies within residues 426-587, which corresponds to the cysteine-rich repeat structure located in the middle of the beta1 chain. The fact that binding of AG89 itself could activate the resting beta1 integrin indicates that exposure of the AG89 epitope in the membrane-proximal stalk-like domain and "opening" of the ligand-binding pocket at the outermost domain are physically linked. We propose that the integrin "signaling" is mediated by this direct physical transduction of conformational information along the integrin molecule.

Antibodies, Monoclonal↗

PubMed1997

Genomic organization, chromosomal mapping, and analysis of the 5' promoter region of the human MAdCAM-1 gene.

MAdCAM-1, the endothelial addressin cell adhesion molecule-1, interacts preferentially with the leukocyte beta7 integrin LPAM-1 (alpha4beta7), but also with L-selectin, and with VLA-4 (alpha4beta1) on myeloid cells, and serves to direct leukocytes into mucosal and inflamed tissues. Overlapping cosmid and phage lambda genomic clones were isolated, revealing that the human MAdCAM-1 gene contains five exons where the signal peptide, two Ig domains, and mucin domain are each encoded by separate exons. The transmembrane domain, cytoplasmic domain, and 3' untranslated region are encoded together on exon 5. The mucin domain contains eight repeats in total that are subject to alternative splicing. Despite the absence of a human counterpart of the third IgA-homologous domain and lack of sequence conservation of the mucin domain, the genomic organizations of the human and mouse MAdCAM-1 genes are similar. An alternatively spliced MAdCAM-1 variant was identified that lacks exon 4 encoding the mucin domain, and may mediate leukocyte adhesion to LPAM-1 without adhesion to the alternate receptor, L-selectin. The MAdCAM-1 gene was located at p13.3 on chromosome 19, in close proximity to the ICAM-1 and ICAM-3 genes (p13.2-p13.3). PMA-inducible promotor activity was contained in a 700 base pair 5' flanking fragment conserved with the mouse MAdCAM-1 gene including tandem NF-kB sites, and an Sp1 site; and in addition multiple potential AP2, Adh1 (ETF), PEA3, and Sp1 sites. In summary, the data establish that the previously reported human MAdCAM-1 cDNA does indeed encode the human homologue of mouse MAdCAM-1, despite gross dissimilarities in the MAdCAM-1 C-terminal structures.

Amino Acid Sequence↗

PubMed2003

Alpha 4 integrin increases anoikis of human osteosarcoma cells.

Cell motility, growth, and proliferation are regulated by adhesion to the extracellular matrix. Detachment of adherent cells from extracellular matrix results in induction of apoptosis ("anoikis"). Transformed cells often show an anchorage-independent growth that enables them to acquire a motile, invasive phenotype. This phenotype has been associated with the altered expression and function of the integrin family of transmembrane proteins that mediate cell adhesion to the extracellular matrix. Although alpha4 integrin is normally expressed on leukocyte subpopulations, a number of metastatic melanomas and sarcomas express it as well. In this study, we demonstrated the expression of alpha4 integrins on the human osteosarcoma cell line SAOS and on metastatic osteosarcoma lesions from the lung and pericardium. We further demonstrated that alpha4 integrin is coupled to the beta1 subunit by biochemical analysis and by using a mAb directed against a combinatorial epitope unique to the alpha4beta1 molecule. SAOS cells undergo anoikis when adherence is denied. Anoikis involved the activation of caspase 3 and the release of cytochrome c from mitochondria. Treatment of non-adherent SAOS with an anti-alpha4 mAb increased anoikis while anti-beta1 integrin mAbs did not alter anoikis, thus indicating a novel function for the alpha4 subunit in the control of cell death. Since integrins can control cell migration, proliferation, and apoptosis these results demonstrate a potential role for alpha4 integrin during multiple aspects of osteosarcoma metastasis.

Anoikis↗

PubMed2006

Galectin-8 binds specific beta1 integrins and induces polarized spreading highlighted by asymmetric lamellipodia in Jurkat T cells.

Integrin-mediated encounters of T cells with extracellular cues lead these cells to adhere to a variety of substrates and acquire a spread phenotype needed for their tissue incursions. We studied the effects of galectin-8 (Gal-8), a beta-galactoside binding lectin, on Jurkat T cells. Immobilized Gal-8 bound alpha1beta1, alpha3beta1 and alpha5beta1 but not alpha2beta1 and alpha4beta1 and adhered these cells with similar kinetics to immobilized fibronectin (FN). Function-blocking experiments with monoclonal anti-integrin antibodies suggested that alpha5beta1 is the main mediator of cell adhesion to this lectin. Gal-8, but not FN, induced extensive cell spreading frequently leading to a polarized phenotype characterized by an asymmetric lamellipodial protrusion. These morphological changes involved actin cytoskeletal rearrangements controlled by PI3K, Rac-1 and ERK1/2 activity. Gal-8-induced Rac-1 activation and binding to alpha1 and alpha5 integrins have not been described in any other cellular system. Strikingly, Gal-8 was also a strong stimulus on Jurkat cells in suspension, triggering ERK1/2 activation that in most adherent cells is instead dependent on cell attachment. In addition, we found that patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disorder, produce Gal-8 autoantibodies that impede both its binding to integrins and cell adhesion. These are the first function-blocking autoantibodies reported for a member of the galectin family. These results indicate that Gal-8 constitutes a novel extracellular stimulus for T cells, able to bind specific beta1 integrins and to trigger signaling pathways conducive to cell spreading. Gal-8 could modulate a wide range of T cell-driven immune processes that eventually become altered in autoimmune disorders.

Androstadienes↗

PubMed2003

Rapid recruitment of inflammatory monocytes is independent of neutrophil migration.

Early neutrophil entry into an inflammatory site is thought to mediate a chemokine switch, inducing subsequent monocyte recruitment through the regulation of monocyte chemoattractant protein-1 (MCP-1) release. As the murine monocyte is poorly characterized and difficult to identify, there has been little examination of either its early recruitment in inflammatory models or of the factors that influence its early migration. The phenotyping of rapidly recruited inflammatory leukocytes with 7/4 and Gr-1 monoclonal antibodies (mAbs) identifies 2 distinct populations, which we characterize as murine monocytes and neutrophils. Monocytes migrate in the first 2 hours of inflammation making use of alpha4beta1 but not of Mac-1 or lymphocyte function-associated antigen-1 (LFA-1) integrins. Early migration is dependent on MCP-1, but neither MCP-1 release nor monocyte recruitment is affected by the reduced neutrophil migration seen in LFA-1-/- mice. Endogenous peritoneal macrophages and mesothelial cells lining the peritoneum contain MCP-1, which is released following thioglycollate stimulation. The murine monocyte therefore responds rapidly to chemokines produced in situ by tissue cells at the site of inflammation with no requirement for prior influx of neutrophils.

Animals↗

PubMed2000

EC3, a heterodimeric disintegrin from Echis carinatus, inhibits human and murine alpha4 integrin and attenuates lymphocyte infiltration of Langerhans islets in pancreas and salivary glands in nonobese diabetic mice.

The venom of Echis carinatus suchoreki contains a monomeric disintegrin echistatin (Mr 5,500 Da) that strongly inhibits alphaIIbbeta3, alphavbeta3, and alpha5beta1 integrins and a heterodimeric disintegrin called EC3 (M(r) 14,762 Da). At nanomolar concentration, EC3 inhibits adhesion of human cell lines expressing alpha4beta1 and alpha4beta7 to immobilized VCAM-1; it has a lower inhibitory effect on alpha5beta1-mediated cell adhesion. In this study, we demonstrated that EC3, in contrast to echistatin, inhibited binding of monoclonal anti-alpha4 and anti-alpha5 antibodies to cells expressing alpha4beta7. In a dose-dependent manner and to the same extent, EC3 inhibited adhesion of Jurkat cells and murine splenic lymphocytes to immobilized VCAM-1, whereas echistatin was not active. EC3 injected intraperitoneally into nonobese diabetic (NOD mice) suppressed development of insulitis and sialoadenitis, whereas echistatin had no significant effect. We propose that the effect of EC3 is mediated, at least, in part, by blocking alpha4beta1 and alpha4beta7 on murine lymphocytes.

Amino Acid Sequence↗

PubMed1997

Regulation of human T lymphocyte coactivation with an alpha4 integrin antagonist peptide.

The cyclic hexapeptide CWLDVC (TBC 772) is an antagonist of alpha4 integrins and a potent inhibitor of lymphocyte interactions with fibronectin, vascular cell adhesion molecule-1, and muscosal vascular addressin cell adhesion molecule-1 (MAdCAM-1). As such, peptide TBC 772 effectively inhibits the activation of freshly isolated human T lymphocytes stimulated with purified vascular cell adhesion molecule-1 coimmobilized with anti-CD3 mAb. The influence of peptide binding on distinct sites of the alpha4beta1 complex was determined by flow cytometry and cellular adhesion assays employing a panel of mAbs. Binding of the alpha4-specific mAb L25 and the beta1-specific mAb 33B6 was not altered by the peptide; however, binding of mAb 19H8, which is specific for a combinatorial epitope of alpha4beta1, was dramatically inhibited. Treatment of lymphocytes with the peptide caused an increase in a ligand-induced epitope on beta1 integrin defined by mAb 15/7. In T cell activation studies using coimmobilized anti-CD3 mAb and the anti-integrin mAbs, the peptide had broader inhibitory activity, suppressing costimulation induced by all the integrin mAbs. The peptide was not generally toxic and was integrin selective in its suppressive activity, as coactivation by ligation of CD3 in conjunction with CD28 or CD26 was not affected. These results suggest that the antagonist peptide CWLDVC can effectively neutralize integrin coactivation systems by a mechanism independent of competitive binding.

Antibodies, Monoclonal↗

PubMed2006

Ligand density and integrin repertoire regulate cellular response to LPA.

Engagement of integrin receptors by the extracellular matrix (ECM) protein fibronectin (FN) activates intracellular signaling, cytoskeletal reorganization and cellular tension. The soluble factor lysophosphatidic acid (LPA) acts through Rho GTPase and its effector Rho kinase (ROCK) to enhance alpha5beta1 integrin-mediated cell spreading on the Arg-Gly-Asp (RGD) cell-binding domain of FN. A second cell-binding site for alpha4 integrins resides in the CS1 segment of the alternatively spliced V region of FN. We show here that LPA treatment of alpha4beta1-expressing CHOalpha4 cells on FN induced a significant decrease in spread cell area. LPA also decreased apoptosis induced by serum-deprivation in CHOalpha4 and human A375 melanoma cells in an alpha4beta1-dependent manner. Improvement in cell viability and changes in cell morphology were dependent on ROCK and on the number of substrate binding sites for alpha4beta1. LPA signaling combined with alpha4beta1-mediated adhesion appears to sustain cell viability in situations where FN matrix is limiting. Such cooperation may impact dynamic cellular events such as wound healing, fibrosis, and metastasis.

Animals↗

PubMed2002

Selective alpha4beta7 integrin antagonists and their potential as antiinflammatory agents.

The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin alpha4beta7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of alpha4beta7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that alpha4beta7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective alpha4beta7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded alpha4beta7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for alpha4beta7 by more than 500-fold to afford a potent and selective alpha4beta1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for alpha4beta7 compared to other integrins.

Alanine↗

PubMed2002

The role of the specificity-determining loop of the integrin beta subunit I-like domain in autonomous expression, association with the alpha subunit, and ligand binding.

Integrin beta subunits contain a highly conserved I-like domain that is known to be important for ligand binding. Unlike integrin I domains, the I-like domain requires integrin alpha and beta subunit association for optimal folding. Pactolus is a novel gene product that is highly homologous to integrin beta subunits but lacks associating alpha subunits [Chen, Y., Garrison, S., Weis, J. J., and Weis, J. H. (1998) J. Biol. Chem. 273, 8711-8718] and a approximately 30 amino acid segment corresponding to the specificity-determining loop (SDL) in the I-like domain. We find that the SDL is responsible for the defects in integrin beta subunit expression and folding in the absence of alpha subunits. When transfected in the absence of alpha subunits into cells, extracellular domains of mutant beta subunits lacking SDL, but not wild-type beta subunits, were well secreted and contained immunoreactive I-like domains. The purified recombinant soluble beta1 subunit with the SDL deletion showed an elongated shape in electron microscopy, consistent with its structure in alphabeta complexes. The SDL segment is not required for formation of alpha5beta1, alpha4beta1, alphaVbeta3, and alpha6beta4 heterodimers, but is essential for fomation of alpha6beta1, alphaVbeta1, and alphaLbeta2 heterodimers, suggesting that usage of subunit interface residues is variable among integrins. The beta1 SDL is required for ligand binding and for the formation of the epitope for the alpha5 monoclonal antibody 16 that maps to loop segments connecting blades 2 and 3 of beta-propeller domain of alpha5, but is not essential for nearby beta-propeller epitopes.

Amino Acid Sequence↗

PubMed2006

Platelet binding to monocytes increases the adhesive properties of monocytes by up-regulating the expression and functionality of beta1 and beta2 integrins.

Human monocytes adhere to activated platelets, resulting in the formation of platelet-monocyte complexes (PMC). Complex formation depends on the interaction between platelet-displayed P-selectin and the specific ligand for P-selectin on leukocytes, P-selectin glycoprotein ligand-1 (PSGL-1). We have recently shown that monocytes within PMC have increased adhesive capacity to the activated endothelium. To better understand the effect of platelet binding on the capacity of monocytes to adhere to activated endothelium, the P-selectin-PSGL-1 interaction-induced changes in integrin functionality were studied. The binding of platelets to monocytes via P-selectin-PSGL-1 interactions was shown to increase expression and activity of alpha4beta1 and alphaMbeta2integrin, with a concomitant decrease in L-selectin expression. Furthermore, the binding of platelets to monocytes resulted in increased monocyte adhesion to intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and fibronectin. Platelet binding was also responsible for an increase in monocyte transendothelial migration. Similar effects were observed after engagement of PSGL-1 with specific antibodies or with P-selectin immunoglobulin protein. Our data suggest that platelets, by binding via P-selectin to PSGL-1 on monocytes, induce up-regulation and activation of beta1 and beta2integrins and increased adhesion of monocytes to activated endothelium. Hence, monocytes within PMC are in a higher state of activation and may have, therefore, an increased atherogenic capacity.

Antibodies↗