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At least 1,099 records · Page 61Linked to original sources
PubMed1979

Modulation of binding and bioactivity of insulin by anti-insulin antibody: relation to possible role of receptor self-aggregation in hormone action.

Incubation of physiological concentrations of 125I-labeled insulin with liver membranes in the presence of anti-insulin IgG results in a 7- to 15-fold increase in the specific binding of the hormone. The low-affinity/high-capacity binding sites are replaced by an apparently homogeneous class of high-affinity sites, and the nonlinear Scatchard plots are converted to linear plots without a change in the maximum number of binding sites. Similarly, the binding of insulin to receptors in 3T3 fibroblasts is increased substantially in the presence of anti-insulin antibody, and the biological activity of subactive concentrations of insulin is enhanced by antibody in these cells. However, the affinity of 125I-labeled epidermal growth factors (EGF) in fibroblasts is not affected by anti-EGF IgG. In adipocytes anti-insulin IgG in the same concentration range only inhibits the binding of insulin and suppresses insulin-mediated glucose oxidation. Monovalent Fab' fragments from anti-insulin IgG inhibit the binding of the hormone, indicating that the enhancement of binding in liver membranes and fibroblasts requires the bivalency of the antibody.

Animals↗
PubMed1976

Surface immunoglobulins and receptor sites for aggregated IgG on leukemic reticuloendotheliosis cells.

On blood lymph nodes and spleen cells of 4 patients with leukemic reticuloendotheliosis (LR) the binding of 125-J-labelled IgG aggregates as well as binding of 125J-labeled anti immunoglobulin sera was studied. Moreover the capacity to form spontaneous rosettes with sheep red blood cells to bind immune complement complexes as well as the proliferative response in the presence of PHA were investigated. On the surface of hairy cells a variety of immunoglobulins were demonstrable. IgG of both types was found to be the predominant surface bound immunoglobulin and evidence was obtained, that these antibodies were adsorbed from the serum via Fc-receptors. In all LR-cases the percentages of T-cell rosettes as well as the PHA responses were decreased when compared with the normal controls. The numbers of immune complement complex binding cells were in the range of the normal controls. Results are discussed with respect to the origin of hairy cells in LR.

Adult↗
PubMed1998

Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation.

Treatment options in acute stroke are limited by a dearth of safe and effective regimens for recanalization of an occluded cerebrovascular tributary, as well as by the fact that patients present only after the occlusive event is established. We hypothesized that even if the site of major arterial occlusion is recanalized after stroke, microvascular thrombosis continues to occur at distal sites, reducing postischemic flow and contributing to ongoing neuronal death. To test this hypothesis, and to show that microvascular thrombosis occurs as an ongoing, dynamic process after the onset of stroke, we tested the effects of a potent antiplatelet agent given both before and after the onset of middle cerebral arterial (MCA) occlusion in a murine model of stroke. After 45 min of MCA occlusion and 23 h of reperfusion, fibrin accumulates in the ipsilateral cerebral hemisphere, based upon immunoblotting, and localizes to microvascular lumena, based upon immunostaining. In concordance with these data, there is a nearly threefold increase in the ipsilateral accumulation of 111In-labeled platelets in mice subjected to stroke compared with mice not subjected to stroke. When a novel inhibitor of the glycoprotein IIb/IIIa receptor (SDZ GPI 562) was administered immediately before MCA occlusion, platelet accumulation was reduced 48%, and fibrin accumulation was reduced by 47% by immunoblot densitometry. GPI 562 exhibited a dose-dependent reduction of cerebral infarct volumes measured by triphenyltetrazolium chloride staining, as well as improvement in postischemic cerebral blood flow, measured by laser doppler. GPI 562 caused a dose-dependent increase in tail vein bleeding time, but intracerebral hemorrhage (ICH) was not significantly increased at therapeutic doses; however, there was an increase in ICH at the highest doses tested. When given immediately after withdrawal of the MCA occluding suture, GPI 562 was shown to reduce cerebral infarct volumes by 70%. These data support the hypothesis that in ischemic regions of brain, microvascular thrombi continue to accumulate even after recanalization of the MCA, contributing to postischemic hypoperfusion and ongoing neuronal damage.

Animals↗
PubMed1997

Exploiting the difference between intrinsic and extrinsic kinases: implications for regulation of signaling by immunoreceptors.

When receptors must interact with an extrinsic kinase to initiate signaling, the kinase can play a regulatory role that is not available to intrinsic receptor kinases. Whether control is exercised at this level depends critically on the amount of kinase available to the receptors and on the potential for redistribution of the kinase during signaling. This study demonstrates that the high affinity receptor for IgE (Fc epsilonRI) on rat basophilic leukemia cells is regulated by its initiating kinase. We present a mathematical model that allows for the reversible recruitment of extrinsic kinases to phosphorylated immunoreceptor tyrosine-based activation motifs. By comparing model predictions to experimental time courses of phosphorylation, we infer that Lyn is limiting, that redistribution occurs after receptors are aggregated, and that the redistribution makes the relationship between tyrosine phosphorylation and receptor aggregation nonlinear.

Animals↗
PubMed1993

Tyrosine phosphorylation of pp125FAK by the aggregation of high affinity immunoglobulin E receptors requires cell adherence.

The aggregation of the high affinity IgE receptor (Fc epsilon RI) in adherent rat basophilic leukemia (RBL-2H3) cells induces the tyrosine phosphorylation of several proteins. We examined whether focal adhesion-associated tyrosine kinase, pp125FAK, is one of these proteins. Anti-pp125FAK monoclonal antibody immunoblotted and precipitated a 115-kDa tyrosine-phosphorylated protein. In the absence of Fc epsilon RI aggregation, pp125FAK was tyrosine-phosphorylated only in adherent cells. Aggregating Fc epsilon RI in adherent cells markedly enhanced tyrosine phosphorylation of pp125FAK. This increase was detectable within 1 min of Fc epsilon RI aggregation and was maximal by 15 min. In contrast, in nonadherent cells Fc epsilon RI aggregation did not induce tyrosine phosphorylation of pp125FAK. The enhanced influx of calcium by calcium ionophore or the activation of protein kinase C by phorbol myristate acetate induced tyrosine phosphorylation of pp125FAK only in adherent cells. Thus, Fc epsilon RI-induced tyrosine phosphorylation of pp125FAK could be mediated by the activation of protein kinase C and/or the induction of calcium influx. The data indicate that cell adherence is essential for Fc epsilon RI-induced tyrosine phosphorylation of pp125FAK.

Animals↗
PubMed2004

p28, a novel IgE receptor-associated protein, is a sensor of receptor occupation by its ligand in mast cells.

Mast cells express the high affinity receptor for IgE (FcepsilonRI). Aggregation of this receptor by IgE and antigen leads to a signaling cascade resulting in the secretion of histamine, in the synthesis of other pro-inflammatory mediators such as leukotrienes and prostaglandins, and in the production of various cytokines, all of which participate in the development of the allergic reaction. In the last years, growing evidence accumulated that binding of IgEs to FcepsilonRI in itself induces active signals leading to mast cell survival, increased expression of FcepsilonRI, transient induction of histidine decarboxylase synthesis, and increased cell adhesion. The mechanisms underlying monomeric IgE signaling in the absence of receptor aggregation are still poorly understood. Here, we show that a protein of 28 kDa (p28) is physically and constitutively associated with FcepsilonRI in mast cells. Coimmunoprecipitation studies from (125)I surface-labeled cells demonstrated that this association involves at least 50% of membrane-expressed FcepsilonRI. After the addition of monomeric IgE to the cells, the p28.FcepsilonRI complex dissociates almost completely in less than 2 min. This dissociation is temperature-sensitive and is not due to the recruitment of additional proteins to the complex. Stripping bound IgE from the cells by acidic treatment promotes a rapid reassociation between p28 and FcepsilonRI. Altogether, these data are consistent with a conformational regulation of the complex. Thus, p28 is a sensor for FcepsilonRI occupation by IgE on mast cells, and its dissociation from the receptor could represent an early step of monomeric IgE signaling.

Animals↗
PubMed1999

Cell surface aggregation of elastin receptor molecules caused by suramin amplified signals leading to proliferation of human glioma cells.

We have recently shown that glioma cell lines, as well as cells of human malignant gliomas in situ, synthesize tropoelastin. In addition, glioma cells degrade tropoelastin using metalloproteinase(s), and the resulting peptides, incapable of assembling in the extracellular fibers, interact with the 67-kDa cell surface elastin binding protein (EBP), to transduce signals leading to up-regulation of cell proliferation. In this report, we show that exposure to the polysulfonated bis-naphthylurea suramin causes accumulation of physiologically active EBP molecules on the cell surface of a panel of glioma cell lines (U87, MG, U251 MG, U343 MG-A, U373 MG, SF 126, SF188, SF539), which results in an increase of cellular attachment to elastin-coated dishes and in an efficient binding of radiolabeled tropoelastin. Moreover, 100-200 microM suramin stimulates [3H]-thymidine incorporation by those tropoelastin-producing glioma cell lines, but not by A 2058 melanoma cells, which do not produce elastin. Treatment of all glioma cell lines with 100 microM suramin consistently increased expression of cyclin A and its cyclin-dependent kinase, cdk 2, to levels reached following the exposure to exogenous elastin-degradation products (kappa-elastin). Our data suggest that a suramin-stimulated accumulation of EBP molecules on the cell surface of glioma cells amplifies the elastin-derived signals, leading to their progression through the cell cycle.

Cell Division↗
PubMed1995

Interactions between gametes leading to fertilization: the sperm's eye view.

Sexual reproduction requires that the gamete carrying the male-derived haploid chromatin join with the gamete carrying the female-derived haploid chromatin during fertilization to produce the diploid zygote. To accomplish this feat, the sperm must not only meet the egg, it must recognize the egg and be recognized in turn by the egg, and in the end must enter and be engulfed by the egg. In this selective overview of gamete interactions that lead to fertilization, encounters of three kinds, followed by the finale of gamete fusion, are considered from the sperm's viewpoint, with particular emphasis on the mammalian species with the mouse as the principal model. The first encounter is with the zona pellucida of the egg, to whose surface the sperm must bind. Mouse sperm appear to have four binding sites for zona ligands. Three interact with sugar moieties of the oligosaccharide chains of the mouse zona glycoprotein ZP3; the fourth binds a peptide backbone arginine. Capacitation is not required for this encounter, but is obligate for the second encounter--induction of the acrosome reaction in the bound sperm. The acrosome reaction is an exocytotic process that makes available the enzymatic machinery needed for sperm penetration the zona which is the end point of a sequence of reactions directed by intracellular signalling systems. In mouse sperm, these systems are presumed to be activated by ligands on ZP3 binding to ligand-specific sperm receptors with consequent aggregation of receptors. No receptor has been identified with certainty, nor have candidates for putative ZP3 ligands been identified. Completion of the acrosome reaction allows the sperm to penetrate the zona and, bind to the egg plasma membrane, thereby completing the third encounter. In the mouse, a 94-kDa protein appears essential for this binding. In the guinea-pig, a sperm plasma membrane protein (formerly PH-30, now fertilin), is a strong candidate for the mediator of the fusion process by which the egg engulfs the sperm. Decondensation of the sperm chromatin reverses the remarkable packing of DNA organized by sperm protamines. Mitochondrial DNA is also engulfed by the egg; the question of whether this DNA makes a small finite, or null, contribution to cytosolic inheritance is still in debate. The puzzles attending these encounters are presented as reminders of the intricacy and fascination, as well as of the vital necessity, of gamete interaction.

Animals↗
PubMed1983

Aggregates of acetylcholine receptors are associated with plaques of a basal lamina heparan sulfate proteoglycan on the surface of skeletal muscle fibers.

Hybridoma techniques have been used to generate monoclonal antibodies to an antigen concentrated in the basal lamina at the Xenopus laevis neuromuscular junction. The antibodies selectively precipitate a high molecular weight heparan sulfate proteoglycan from conditioned medium of muscle cultures grown in the presence of [35S]methionine or [35S]sulfate. Electron microscope autoradiography of adult X. laevis muscle fibers exposed to 125I-labeled antibody confirms that the antigen is localized within the basal lamina of skeletal muscle fibers and is concentrated at least fivefold within the specialized basal lamina at the neuromuscular junction. Fluorescence immunocytochemical experiments suggest that a similar proteoglycan is also present in other basement membranes, including those associated with blood vessels, myelinated axons, nerve sheath, and notochord. During development in culture, the surface of embryonic muscle cells displays a conspicuously non-uniform distribution of this basal lamina proteoglycan, consisting of large areas with a low antigen site-density and a variety of discrete plaques and fibrils. Clusters of acetylcholine receptors that form on muscle cells cultured without nerve are invariably associated with adjacent, congruent plaques containing basal lamina proteoglycan. This is also true for clusters of junctional receptors formed during synaptogenesis in vitro. This correlation indicates that the spatial organization of receptor and proteoglycan is coordinately regulated, and suggests that interactions between these two species may contribute to the localization of acetylcholine receptors at the neuromuscular junction.

Animals↗
PubMed1991

Gene targeting of the aggregation stage cAMP receptor cAR1 in Dictyostelium.

cAR1, a G-protein-linked surface cAMP receptor, plays a central role in the development of Dictyostelium. To investigate its role, we sought to target the cAR1 gene by homogolous recombination. Transformation of these amoebas with appropriately designed vectors results in integration into the cAR1 locus with high frequency. cAR1 "null" mutants, resulting from double crossover events, fail to bind or sense cAMP and arrest in early development. The null mutants can be rescued by constitutive expression of a wild-type cAR1 cDNA. Carboxy-terminal deletion mutants, derived from single crossover events, express a truncated form of cAR1 that binds and senses cAMP. These cells proceed through the developmental program, albeit with a delay. Constitutive expression of a similar truncated form of cAR1 also rescues the null mutant. These observations prove that cAR1-mediated signal transduction controls the development of Dictyostelium and allow structural/functional studies of a G-protein-linked receptor in its natural context.

Base Sequence↗
PubMed2000

Glycoprotein IIb/IIIa receptor inhibitor attenuates platelet aggregation induced by thromboxane A2 during in vitro nonpulsatile ventricular assist circulation.

A recent development in antithrombotic research allows the inhibition of platelet aggregation via protection of the glycoprotein IIb/IIIa receptor on the platelet membrane. We hypothesized that a GP IIb/IIIa receptor inhibitor would inhibit thromboxane-induced platelet aggregation during circulation in our in vitro ventricular assist device (VAD) circuit and preserve long-term platelet function. Twenty-one in vitro nonpulsatile centrifugal VAD circuits were simulated for 4 days using 450 ml of fresh human whole blood with or without glycoprotein IIb/IIIa receptor inhibitor (tirofiban). Platelet aggregation and degranulation were measured in whole blood induced by ristocetin, collagen, ADP, and thromboxane A2 (TXA2). The tirofiban-treated group preserved the platelet count and tended to exert these beneficial effects by inhibiting pathologic platelet aggregation induced by TXA2, collagen, and ADP as well as degranulation. Tirofiban may be useful in preserving platelet number and function during clinical VAD use.

Adenosine Diphosphate↗
PubMed1987

Dissociation of neutrophil aggregation, adhesiveness, and Fc receptor activity.

Neutrophils that bear receptors for the Fc portion of immunoglobulin G have been demonstrated to be more active in assays of adherence, aggregation, and chemotaxis compared to Fc receptor-negative cells. We examined the relationship of neutrophil Fc receptor activity and cell-cell adherence or aggregation induced by phorbol myristate acetate. In contrast to 1-isoproterenol, isobutyl-methyl-xanthine, and dibutyryl cAMP, each of which inhibited Fc receptor activity and neutrophil aggregation, theophylline significantly impaired aggregation without affecting Fc receptor activity. The selective beta-2 agonist, metaproterenol, and 8-Bromo cAMP failed to inhibit Fc receptor activity or neutrophil aggregation. Three known inducers of neutrophil intracellular cyclic AMP, PGE1, PGE2, and cholera toxin, also did not inhibit Fc receptor activity. Inhibition of Fc receptor activity by 95% in the presence of purified Fc fragments did not affect neutrophil aggregation. Similarly suppression of Fc receptor activity by purified Fc fragments did not inhibit neutrophil adhesion to nylon fiber columns. These data demonstrate that the Fc receptor does not mediate phorbol myristate acetate-induced cell-cell adhesion and is not necessary for optimal neutrophil adhesion to nylon fibers. Our results are consistent with the possibility that the reversible inhibitory activity of beta-adrenergic agonists on rosette formation may be a steric effect rather than a metabolic effect. These data tend to dissociate Fc receptor activity, neutrophil aggregation, and adhesion and support the hypothesis that the Fc receptor may be a marker of neutrophil heterogeneity rather than a component necessary for optimal neutrophil aggregation or adhesion.

1-Methyl-3-isobutylxanthine↗