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PubMed1990

Interaction of epidermal growth factor receptors with the cytoskeleton is related to receptor clustering.

Recently it has been established that cytoskeleton-associated epidermal growth factor (EGF) receptors are predominantly of the high-affinity class and that EGF induces a recruitment of low-affinity receptors to the cytoskeleton. The nature of this EGF-induced receptor-cytoskeleton interaction, however, is still unknown. Therefore, we have studied the association of mutated EGF receptors with the cytoskeleton. Receptor deletion mutants lacking almost all intracellular amino acid residues displayed no interaction with the cytoskeleton, demonstrating that the cytoplasmic receptor domain is involved in this interaction. Further analysis revealed that receptor-cytoskeleton interaction is independent of receptor kinase activity and the C-terminal 126 amino acid residues, which include the auto-phosphorylation sites. Furthermore, it is shown that the high-affinity receptor subclass is not essential for association of low-affinity receptors to the cytoskeleton. EGF receptor-cytoskeleton interaction was increased, however, by treatment with sphingomyelinase, an enzyme known to induce membrane protein clustering, indicating that EGF receptor clustering may cause the association to the cytoskeleton.

Animals↗
PubMed1996

Cross-linking of the ninth consensus repeat domain of P-selectin (GMP-140, CD62P) with a monoclonal antibody enhanced leukocyte adhesive activity.

P-selectin (GMP-140, CD62P) is a member of the selectin family of cell adhesion molecules expressed on the cell surface of platelets and endothelial cells, which mediates leukocyte adhesion via carbohydrate ligands. We now report that a monoclonal antibody (mAb), recognizing the ninth consensus repeat domain of the human P-selectin molecule, enhanced the adhesion activity of neutrophils to platelets, whereas the monovalent Fab fragment of the mAb did not exert this effect. The enhancement by the mAb was thought to result from cross-linking of the P-selectin molecules. The results indicated that cross-linking adjacent to the transmembrane domain of P-selectin enhanced the cell adhesion activity.

Antibodies, Monoclonal↗
PubMed2000

Altered gene expression upon BCR cross-linking in Burkitt's lymphoma B cell line.

Burkitt's lymphoma cell line, BL2 was stimulated by surface BCR cross-linking and altered gene expression was analyzed by RDA methodology. Consistent with previous reports, we detected up-regulated MDC, IL6R and adhesion molecule LFA1. We also detected gene expression of SIRPalpha, anti-apoptotic A-20, signal regulatory SLP76 and BCAR3, DNA binding proteins EGR2 and DEC1 in addition to some new genes.

Antibodies↗
PubMed1996

Homotypic interactions mediated through LFA-1/ICAM-3 decrease the proliferative response of activated T cells.

T cell activation occurs when the T cell receptor (TCR) is engaged by an antigen-MHC complex on the surface of an antigen-presenting cell (APC). Additional signals provided by accessory molecules serve to modulate this response. Independent of TCR engagement, treatment of T lymphocytes with a combination of phorbol ester and CD28 ligation will result in a proliferative response. This also induces homotypic adhesion mediated by LFA-l/ICAM interactions. We demonstrate that the prevention of homotypic interactions between T cells resulted in a two- to fivefold increase in the proliferative response. This occurred whether the homotypic interactions were prevented by blockade of LFA-1, by the use of plate immobilized antibodies against other cell surface molecules, or by culture at low cell density. We further demonstrate that the increased proliferation was a result of interference with a negative signal delivered to the T cell as a result of ICAM-3-mediated events. These data demonstrate LFA-1/ICAM-3 interactions between T cells in turn regulate an LFA-1-independent pathway that results in homotypic adhesion and a downregulation of the proliferative response of activated T cells.

Adjuvants, Immunologic↗
PubMed1999

Diverse effects of neutrophil integrin occupation on respiratory burst activation.

Integrin occupation can alter the function of neutrophils (PMN), but the mechanism(s) involved is still unclear. This study demonstrated that the occupation of PMN integrins (especially those of the beta(3) subfamily) strongly enhances TNF stimulation of the respiratory burst but down-regulates that induced by PMA, fMLP, Con A, and serum treated zymosan. Treatment of PMN with genistein, staurosporine, and wortmannin, inhibitors of tyrosine kinases, protein kinase C, and phosphotidylinostol 3-kinase (PI 3-kinase) respectively, completely blocked the TNF-stimulated respiratory burst in PMN. Genistein and wortmannin enhanced the PMA-stimulated respiratory burst but only in cells adherent to RGD peptide. These findings suggest that PMN integrins (beta(3) subfamily) can generate signals that regulate the PMN agonist responses, probably through the activities of tyrosine kinases and PI 3-kinase.

Antibodies↗
PubMed2000

Ligation of ICAM-1 molecules inhibits target cell-induced granule exocytosis of IL-12-activated natural killer cells.

The importance of cell adhesion molecules such as ICAM-1 is emphasized in cell-to-cell interactions that are critical in the generation of effective immune reactions. In this study, the involvement of ICAM-1 in natural killer (NK) cell activities was characterized in IL-12-activated human NK cells. To address the question of whether ligation of ICAM-1 molecules can modulate NK cell cytolytic activities, a 4-h (51)Cr-release assay was performed after pretreatment of NK cells with R6.5 mAb (anti-human ICAM-1 mAb). Ligation of membrane ICAM-1 molecules significantly inhibited IL-12-enhanced NK cytotoxicity against K562, and the pretreatment of neutralizing soluble ICAM-1 with R6.5 mAb blocked this inhibitory effect. The involvement of Ca(2+)-dependent granular exocytosis was evaluated. BLT esterase assay demonstrated that the ligation of ICAM-1 molecules inhibited granular exocytosis of NK cells. Additionally, the ICAM-1-mediated inhibition of Ca(2+) flux in NK cells was detected using Fluo-3AM, while the pretreatment of NK cells with R6.5 mAb did not affect conjugate formation between NK and K562 cells. Collectively, these results suggest that the signals transduced from ICAM-1 molecules might be sufficient to induce inhibitory effects on NK cells.

Antibodies, Monoclonal↗
PubMed2000

Induction of interleukin-12/p40 by superantigens in macrophages is mediated by activation of nuclear factor-kappaB.

Multimerization of the MHC class II molecule by superantigens results in activation of cellular signal transduction pathways in macrophage and B cells. Here we show that superantigen staphylococcal enterotoxin B (SEB) induces IL-12/p40 secretion in macrophages. SEB-induced expression of the IL-12/p40 gene involves activation and nuclear translocation of nuclear factor kappaB (NF-kappaB). The NF-kappaB heterodimer bound to the NF-kappaB consensus sequence of the IL-12/p40 gene promoter is p50/C-Rel. Inhibition of PKC and PKA activation results in suppression of activation and translocation of NF-kappaB. We conclude that signals for IL-12/p40 gene transcription from MHC class II molecules follow activation of PKC and PKA, which in turn leads to the activation and translocation of NF-kappaB to the nucleus. Our study suggests that superantigens are capable of influencing the nature of the immune response by regulating cytokine production. Induction of IL-12 production by superantigens may therefore play a role in the regulation of Th 1-mediated immune response and autoimmune disease.

Animals↗
PubMed1997

Soluble integrin ligands and growth factors independently rescue neuroblastoma cells from apoptosis under nonadherent conditions.

We have investigated the role of extracellular matrix (ECM) and growth factors in the survival of nonadherent human neuroblastoma cells (line SK-N-BE). Cells cultured in serum-free medium under nonadherent conditions died with apoptotic-like features (chromatin condensation and nuclear fragmentation). SK-N-BE cells underwent neuronal differentiation in response to retinoic acid (RA). While RA itself did not induce apoptosis, differentiation increased the susceptibility of SK-N-BE cells to detachment-induced apoptosis. The appearance of the apoptotic-like phenotype required the maintenance in suspension of SK-N-BE cells for at least 16 h (12.43 +/- 1.40% of cells undergoing apoptosis) and the percentage increased up to 46.84 +/- 3.15% after 24 h. Suspension-induced apoptosis did not depend on increased intracellular Ca2+ levels nor on de novo protein synthesis and was not associated with extensive DNA degradation. Stimulation by soluble collagen I rescued suspended cells from apoptosis, even in the absence of cell adhesion and spreading. The survival promoting effect of ECM was mediated by the integrin receptors, since (1) the protective effect of soluble collagen I was blocked by anti-integrin antibodies to beta 1 and alpha 1 subunits and (2) the antibody-induced clustering of alpha 1, alpha 3, alpha v, beta 1, and beta 3 integrins rescued SK-N-BE cells cultured in suspension from apoptosis. As expected, adhesion on immobilized ECM proteins, collagen I, or laminin (0.1 to 10 micrograms/ml) also rescued SK-N-BE cells from apoptosis in a dose-dependent manner. The de novo protein synthesis was required to promote the survival effect of ECM, since cycloheximide completely abolished the protective effect of collagen I and protection from apoptosis by ECM or by anti-beta 1 antibody was associated with the increased expression of bcl-2. In addition to integrin stimulation, serum, insulin, and nerve growth factor inhibited suspension-induced apoptosis of SK-N-BE cells. The survival effect of serum and growth factors did not require the synthesis of new proteins, unlike the ECM effect. These data show that matrix proteins can promote cell survival in neuronal cells via integrin receptors. This effect does not require cell adhesion and the subsequent changes in cell shape as it can be mediated by soluble integrin ligands in suspended cells and involves a signaling pathway different from that triggered by growth factors.

Apoptosis↗
PubMed1999

MHC-I-induced apoptosis in human B-lymphoma cells is dependent on protein tyrosine and serine/threonine kinases.

In addition to providing the framework for peptide presentation, major histocompatibility complex class I (MHC-I) molecules can act as signal transducing molecules in lymphoid cells. Here we show that the mobilization of intracellular calcium, which follows crosslinking of MHC-I molecules on human B lymphoma cells, is dependent on protein tyrosine kinases and the phosphatidylinositol 3 (PI-3) kinase. Functional studies showed that MHC-I crosslinking induced almost complete inhibition of the spontaneous proliferation of the B lymphoma cells as early as 6 h post-crosslinking and apoptosis 24 h post-crosslinking. Preincubation with either protein tyrosine kinase or protein serine/threonine kinase inhibitors reduced the MHC-I-induced apoptosis to background levels, whereas inhibition of PI-3 kinase had no effect. These data demonstrate a pivotal role for protein tyrosine and serine/threonine kinases in MHC-I-mediated apoptosis in human B-cells and suggest the presence of several MHC-I signaling pathways leading to diverse effects in these cells.

Androstadienes↗
PubMed2001

LMP1 structure and signal transduction.

The oncogenic Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has structural features and functions reminiscent of a constitutively active TNF family receptor. LMP1 aggregates at the plasma membrane and initiates the activation of signalling pathways, such as NF- kappa B, the mitogen-activated protein kinases JNK and p38, the small GTPase Cdc42 and the JAK/STAT cascade. The constitutive engagement of these signals and the characteristic molecular interactions that regulate them provide the basis for the molecular explanation of the transforming properties of this key EBV protein.

Amino Acid Sequence↗
PubMed1985

Internalization of insulin: structures involved and significance.

The binding of insulin to its receptor is followed by aggregation of hormone-receptor complexes and their internalization into the cell. Internalized hormone is concentrated in Golgi-enriched not lysosomal endocytotic structures which, in rat liver, contain lipoprotein particles and can be resolved by centrifugation techniques into three different entities. Recent work has shown that the bulk of endocytotic structures can be resolved from biochemically defined (i.e., galactosyltransferase-containing) Golgi elements. The endosomal apparatus or endosomes appear to function as a sorting center wherein internalized hormone-receptor complexes are concentrated and dissociated prior to directing hormone to lysosomes and receptor back to the cell surface for reutilization. Endosomes are heterogeneous and different functions might be subserved by different endosomal structures. Since an insulin stimulable receptor kinase activity can be identified in endosomes certain aspects of insulin action might be initiated herein.

Animals↗
PubMed1977

The development of membrane specializations in the receptor-bipolar-horizontal cell synapse of the chick embryo retina. A freeze-fracture study.

Retinae of chick embryos and chicks one to six weeks after hatching were examined in ultrathin sections and in freeze-etch specimens. The development of the synaptic contacts between receptor cells and bipolar cells starts at the end of the second week of incubation with the enclosure of the dendritic prolongations, invaginating receptor terminals accompanied by the appearance of electron dense material at the synaptic contact sites. Subsequently receptor terminals become filled with synaptic vesicles which surround the synaptic lamellae that appear on the 16th day of incubation. The application of the freeze-fracture technique demonstrates that the differentiation of the synaptic membranes continues into the first week post hatching. E-fracture faces of the presynaptic membranes are characterized by crater-like structures, called synaptopores. Their number is rather small during incubation and increases after hatching. In the P-fracture faces of the dendrites, which are enclosed by the receptor terminals, small particle aggregations appear on the 16th day of incubation. These small particle clusters increase by the apposition of further particles which become arranged in lines and bring out a lattice-like aspect. This arrangement of particles in the inner part of the cell membrane is the morphological expression of the maturation process. The significance of these aggregations as a postsynaptic receptor for neurotransmitters in excitatory cells is discussed.

Animals↗
PubMed1992

Patching and capping of LFA-1 molecules on human lymphocytes.

The distribution and dynamics of LFA-1 molecules over the surface of human lymphocytes were analysed using immunogold label-fracture and fracture-flip methods. Patching and capping were induced by incubation at 37 degrees C with antibodies directed against the alpha and beta chains respectively of the heterodimeric LFA-1 molecule, and were followed by immunofluorescence. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) to link LFA-1 molecules to the cytoskeleton increased the percentage of capped cells, implying a faster and more efficient process of capping. At all times of clustering or upon phorbol ester treatment, the concentration of LFA-1 in patches and then in caps was not accompanied by a parallel concentration of membrane particles on the freeze-fractured plasma membranes. Our results support the role of the cytoskeleton in regulating the capping phenomenon and in controlling the structural organization of the plasma membranes.

Antibodies↗
PubMed1988

Different effects of furosemide on alpha-adrenoceptors and on platelet aggregation in man.

The effect of a long-term administration of furosemide (2 x 30 mg/day for 3 weeks) on platelet alpha 2-adrenoceptor density and the fraction of high-affinity binding sites, as well as on platelet aggregation induced by adrenaline and ADP, was studied ex vivo in 8 normotensive volunteers. For comparison the in vitro effect of furosemide on platelet aggregation was also evaluated. Furosemide decreased alpha 2-adrenoceptor-density (P less than 0.01) and the fraction of high-affinity binding sites (P less than 0.05). Adrenaline-induced platelet aggregation was not altered ex vivo and in vitro. Furosemide inhibited ADP-induced platelet aggregation ex vivo (P less than 0.05) and in parallel in vitro (P less than 0.01) in a dose-dependent manner. The reduction of the density of alpha 2-adrenoceptors in the high affinity state may be of functional importance for the hemodynamic effects of furosemide. The inhibitory effect of furosemide on ADP-induced platelet aggregation ex vivo and in vitro, which is not related to the effects on adrenoceptors, seems to involve direct effects of furosemide on platelet function. It remains to be seen whether the latter effect is of clinical importance.

Adult↗
PubMed1984

Agents interfering with the platelet-vessel wall interaction.

Drugs that inhibit platelet activation may prevent thrombosis and atherosclerosis. The mechanism by which coumarins, heparin, calmodulin inhibitors, calcium entry blockers, drugs that interfere with cyclic AMP function and arachidonate metabolism, and several other compounds might achieve this protection, is discussed. Only a few of these drugs (acetylsalicylic acid, dipyridamole, sulfinpyrazone) have been tested for clinical efficacy in man. So far the results of these studies have revealed modest protection from infarction and other cardiovascular diseases.

Arachidonic Acid↗