Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adhesion of human salivary gland (HSG) epithelial cells to fibronectin- or collagen I gel-coated substrates, mediated by beta1 integrins, has been shown to upregulate the expression of more than 30 genes within 3-6 h. Adhesion of HSG cells to fibronectin or collagen I for 6 h also enhanced total protein kinase C (PKC) activity by 1.8-2.3-fold. HSG cells expressed PKC-alpha, gamma, delta, epsilon, mu, and zeta. Adhesion of HSG cells to fibronectin or collagen I specifically activated PKC-gamma and PKC-delta. Cytoplasmic PKC-gamma and PKC-delta became membrane-associated, and immunoprecipitated PKC-gamma and PKC-delta kinase activities were enhanced 2.5-4.0-fold in HSG cells adherent to fibronectin or collagen I. In addition, adhesion of fibronectin-coated beads to HSG monolayers co-aggregated beta1 integrin and PKC-gamma and PKC-delta but not other PKC isoforms. Thus, integrin-dependent adhesion of HSG cells to fibronectin or collagen I activated PKC-gamma and PKC-delta. The role of this PKC upregulation on adhesion-responsive gene expression was then tested. HSG cells were treated with the specific PKC inhibitor bisindolylmaleimide I, cultured on non-precoated, fibronectin- or collagen I-coated substrates, and analyzed for changes in adhesion-responsive gene expression. Bisindolylmaleimide I strongly inhibited the expression of seven adhesion-responsive genes including calnexin, decorin, S-adenosylmethionine decarboxylase, steroid sulfatase, and 3 mitochondrial genes. However, the expression of two adhesion-responsive genes was not affected by bisindolylmaleimide I. Treatment with bisindolylmaleimide I did not affect cell spreading and did not significantly affect the actin cytoskeleton. These data suggest that adhesion of HSG cells to fibronectin or collagen I induces PKC activity and that this induction contributes to the upregulation of a variety of adhesion-responsive genes.
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PMID:Adhesion of epithelial cells to fibronectin or collagen I induces alterations in gene expression via a protein kinase C-dependent mechanism. 1157 7

In human neutrophils, IL-8 induces chemotaxis, the respiratory burst, and granule release, and enhances cellular adhesion, a beta(2) integrin-dependent event. IL-8 stimulates neutrophil adhesion to purified fibrinogen in a Mac-1-dependent manner. Mitogen-activated protein kinase (MAPK) activation was detected in human neutrophil lysates after treatment with IL-8 and PMA, but not the activating mAb CBR LFA 1/2. IL-8-stimulated neutrophil adhesion to fibrinogen was blocked 50% by the MAPK/extracellular signal-related kinase-activating enzyme inhibitor PD098059. Adhesion was blocked approximately 75% by inhibition of the phosphatidylinositol-3 kinase (PI3K) pathway with LY294002, supporting that activation of both MAPK and PI3K may play a role in IL-8-dependent inside-out signals that activate Mac-1. Activation of MAPK was inhibited in IL-8-stimulated cells in the presence of PI3K inhibitors LY294002 or wortmannin, supporting a model in which PI3K is upstream of MAPK. IL-8-stimulated neutrophil adhesion was inhibited 50% by bisindolylmaleimide-I, implicating protein kinase C (PKC) in the intracellular signaling from the IL-8R to Mac-1. A 74-kDa molecular mass species was detected by an activation-specific Ab to PKC when cells were stimulated with PMA or IL-8, but not a beta(2)-activating Ab. Inhibition of either MAPK or PKC resulted in partial inhibition of IL-8-stimulated polymorphonuclear neutrophil adhesion, and treatment with both inhibitors simultaneously completely abolished IL-8-stimulated adhesion to ligand. Inhibition of PI3K blocked MAPK activation, but not PKC activation, suggesting a branch point that precedes PI3K activation. These data suggest that both MAPK and PKC are activated in response to IL-8 stimulation, and that these may represent independent pathways for beta(2) integrin activation in neutrophils.
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PMID:Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1. 1197 Oct 3

The ability of mitogens to rapidly induce tyrosine phosphorylation of cellular proteins has been taken as evidence of participation in subsequent signaling pathways. SSeCKS, a major protein kinase C (PKC) substrate with protein scaffolding and tumor suppressive properties, becomes tyrosine phosphorylated in NIH3T3 and rodent embryo fibroblasts after short-term treatment with epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or fetal calf serum in the presence of pervanadate, but not by treatment with insulin or insulin-like growth factor-1. The relative phosphotyrosine level on SSeCKS was higher in actively dividing cells than in confluent cultures. Tyrosine phosphorylation of SSeCKS was apparent in cells deficient in Src, Fyn, Yes, or Abl tyrosine kinases or in NIH3T3 cells expressing a temperature-sensitive v-Src allele, but not in FAK-deficient embryo fibroblasts. Purified FAK or Src enzyme failed to directly phosphorylate SSeCKS in vitro. EGF failed to induce SSeCKS tyrosine phosphorylation in FAK-/- fibroblasts, indicating that the EGF receptor is probably not the direct kinase of SSeCKS. Phosphorylation under these conditions was rescued by the transient reexpression of wt-FAK but not FAK mutated at Y397, a major autophosphorylation and SH2-based docking site. Adhesion of FAK+/+ cells to fibronectin failed to significantly induce SSeCKS tyrosine phosphorylation although FAK was activated, suggesting that SSeCKS phosphorylation is mediated through a growth factor receptor-FAK rather than an integrin-FAK pathway. Moreover, PDGF could induce SSeCKS tyrosine phosphorylation in the absence of FAK activation, suggesting a role for FAK SH2-based docking rather than kinase activity. Immunofluorescence analysis showed that in FAK-/- cells, SSeCKS costains along F-actin stress fibers, in contrast to FAK+/+ cells, where most SSeCKS stains at the cell edge and along a cortical cytoskeletal matrix. This correlated with increased coprecipitation of SSeCKS with biotin-phalloidin-bound F-actin from FAK-/- compared to FAK+/+ cell lysates. Similarly, bacterially expressed, unphosphorylated SSeCKS cosedimented with F-actin in ultracentrifugation assays. These data suggest that mitogen-induced, FAK-dependent tyrosine phosphorylation of SSeCKS modulates its binding to the actin-based cytoskeleton, suggesting a role for SSeCKS in mitogen-induced cytoskeletal reorganization.
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PMID:Mitogen-induced, FAK-dependent tyrosine phosphorylation of the SSeCKS scaffolding protein. 1208 96

We examined the effects of ruscogenin glycoside (Lm-3), isolated from Liriope muscari, on lymphocyte adhesion to extracellular matrix. Adhesion of Jurkat cells activated by anti-CD3 to type I collagen was inhibited by Lm-3 in a concentration- and time-dependent manner. Lm-3 also inhibited the cell attachment to fibronectin and laminin. However, the saponin did not influence anti-CD3-induced cell proliferation and Mn2+-induced adhesion. Protein kinase C activator, phorbol 12,13-dibutyrate, significantly enhanced, while its inhibitor, chlorpromazine, almost completely blocked, the adhesion of anti-CD3-activated Jurkat cells to collagen. Against phorbol 12,13-dibutyrate-activated Jurkat cells, Lm-3 treatment, either before or after activation, significantly inhibited the cell adhesion to collagen. Lm-3 also inhibited the adhesion activated by both anti-CD3 and phorbol 12,13-dibutyrate. Similar inhibition by Lm-3 of the phorbol 12,13-dibutyrate-induced adhesion to collagen was also observed in lymphocytes freshly isolated from mice with contact dermatitis. Furthermore, Lm-3 significantly decreased the leucocyte accumulation in an animal model of experimental pleurisy. These results suggest that the blockade of lymphocyte adhesion to extracellular matrix through interference with the protein kinase C pathway may be one of the mechanisms by which Lm-3 exerts anti-inflammatory activity.
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PMID:Ruscogenin glycoside (Lm-3) isolated from Liriope muscari inhibits lymphocyte adhesion to extracellular matrix. 1216 15

Cell adhesion to the extracellular matrix via integrins is a primary regulatory mechanism for numerous aspects of normal cellular function. However, disruption of this interaction can result in pathology. For example, one characteristic of transformed cells is loss of adhesion dependence for viability. Adhesion also is a necessary step in tumor metastasis. It has been shown previously, in HeLa cells, that cell attachment to a gelatin-coated substrate results in the release of arachidonic acid, which is metabolized by lipoxygenase. A subsequent cascade of lipid second messengers activates protein kinase C, which triggers actin polymerization leading to cell spreading. We now demonstrate by inhibitor studies and biochemical analysis, a parallel branch of arachidonic acid signaling that reorganizes the actin cytoskeleton into small bundles. This branch of the pathway is initiated by cyclooxygenase, which generates prostaglandins and causes the downstream activation of cyclic AMP-dependent protein kinase. This work elucidates a system of interacting signals in which arachidonic acid functions at a branch point in cytoskeletal signaling. The lipoxygenase branch provides polymerized actin; these actin filaments act as a substrate for the cylooxygenase branch to generate actin bundles.
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PMID:Arachidonic acid signaling to the cytoskeleton: the role of cyclooxygenase and cyclic AMP-dependent protein kinase in actin bundling. 1221 Nov 5

Proper stimulation of cell cycle progression and DNA synthesis requires cooperating signals from integrin and growth factor receptors. We previously found that the proinflammatory peptide, macrophage migration inhibitory factor (MIF), functions as an autocrine mediator of growth factor-dependent ERK MAP kinase activation and cell cycle progression. We now report that MIF secretion is induced by cell adhesion to fibronectin in quiescent mouse fibroblasts. Adhesion-mediated release of MIF subsequently promotes integrin-dependent activation of MAP kinase, cyclin D1 expression, and DNA synthesis. Secretion of MIF requires protein kinase C activity, and recombinant MIF reconstitutes the activation of MAP kinases in the presence of protein kinase C inhibition. Finally, we show that cells deficient in MIF have significantly higher retinoblastoma tumor suppressor and lower E2F transcriptional activities. These results suggest that MIF is an important autocrine mediator of adhesion-dependent signaling events and may provide mechanistic insight into how MIF regulates proliferative and oncogenic processes.
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PMID:Adhesion-dependent signaling by macrophage migration inhibitory factor (MIF). 1229 13

Thrombin activates mast cells to release inflammatory mediators through a mechanism involving protease-activated receptor-1 (PAR-1). We hypothesized that PAR-1 activation would induce mast cell adhesion to fibronectin (FN). Fluorescent adhesion assay was performed in 96-well plates coated with FN (20 microg/ml). Murine bone marrow cultured mast cells (BMCMC) were used after 3-5 wk of culture (>98% mast cells by flow cytometry for c-Kit expression). Thrombin induced beta-hexosaminidase, IL-6, and matrix metalloproteinase-9 release from BMCMC. Thrombin and the PAR-1-activating peptide AparafluoroFRCyclohexylACitY-NH(2) (cit) induced BMCMC adhesion to FN in a dose-dependent fashion, while the PAR-1-inactive peptide FSLLRY-NH(2) had no effect. Thrombin and cit induced also BMCMC adhesion to laminin. Thrombin-mediated adhesion to FN was inhibited by anti-alpha(5) integrin Ab (51.1 +/- 6.7%; n = 5). The combination of anti-alpha(5) and anti-alpha(4) Abs induced higher inhibition (65.7 +/- 7.1%; n = 5). Unlike what is known for FcepsilonRI-mediated adhesion, PAR-1-mediated adhesion to FN did not increase mediator release. We then explored the signaling pathways involved in PAR-1-mediated mast cell adhesion. Thrombin and cit induced p44/42 and p38 phosphorylation. Pertussis toxin inhibited PAR-1-mediated BMCMC adhesion by 57.3 +/- 7.3% (n = 4), indicating that G(i) proteins are involved. Wortmannin and calphostin almost completely inhibited PAR-1-mediated mast cell adhesion, indicating that PI-3 kinase and protein kinase C are involved. Adhesion was partially inhibited by the mitogen-activated protein kinase kinase 1/2 inhibitor U0126 (24.5 +/- 3.3%; n = 3) and the p38 inhibitor SB203580 (25.1 +/- 10.4%; n = 3). The two inhibitors had additive effects. Therefore, thrombin mediates mast cell adhesion through the activation of G(i) proteins, phosphoinositol 3-kinase, protein kinase C, and mitogen-activated protein kinase pathways.
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PMID:Thrombin induces mast cell adhesion to fibronectin: evidence for involvement of protease-activated receptor-1. 1237 Mar 92

Laminins are alphabetagamma heterotrimeric extracellular proteins that regulate cellular functions by adhesion to integrin and nonintegrin receptors. Laminins containing alpha4 and alpha5 chains are expressed in bone marrow, but their interactions with hematopoietic progenitors are unknown. We studied human bone marrow cell adhesion to laminin-10/11 (alpha5beta1gamma1/alpha5beta2gamma1), laminin-8 (alpha4beta1gamma1), laminin-1 (alpha1beta1gamma1), and fibronectin. About 35% to 40% of CD34(+) and CD34(+)CD38(-) stem and progenitor cells adhered to laminin-10/11, and 45% to 50% adhered to fibronectin, whereas they adhered less to laminin-8 and laminin-1. Adhesion of CD34(+)CD38(-) cells to laminin-10/11 was maximal without integrin activation, whereas adhesion to other proteins was dependent on protein kinase C activation by 12-tetradecanoyl phorbol-13-acetate (TPA). Fluorescence-activated cell-sorting (FACS) analysis showed expression of integrin alpha6 chain on most CD34(+) and CD34(+)CD38(-) cells. Integrin alpha6 and beta1 chains were involved in binding of both cell fractions to laminin-10/11 and laminin-8. Laminin-10/11 was highly adhesive to lineage-committed myelomonocytic and erythroid progenitor cells and most lymphoid and myeloid cell lines studied, whereas laminin-8 was less adhesive. In functional assays, both laminin-8 and laminin-10/11 facilitated stromal-derived factor-1alpha (SDF-1alpha)-stimulated transmigration of CD34(+) cells, by an integrin alpha6 receptor-mediated mechanism. In conclusion, we demonstrate laminin isoform-specific adhesive interactions with human bone marrow stem, progenitor, and more differentiated cells. The cell-adhesive laminins affected migration of hematopoietic progenitors, suggesting a physiologic role for laminins during hematopoiesis.
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PMID:Laminin isoform-specific promotion of adhesion and migration of human bone marrow progenitor cells. 1239 39

We have previously shown that platelets express 2 receptor tyrosine kinases, EphA4 and EphB1, and the Eph kinase ligand, ephrinB1, and proposed that transcellular Eph/ephrin interactions made possible by the onset of platelet aggregation promote the further growth and stability of the hemostatic plug. The present study examines how this might occur. The results show that clustering of either ephrinB1 or EphA4 causes platelets to adhere to immobilized fibrinogen via alpha(IIb)beta(3). Adhesion occurs more slowly than with adenosine diphosphate (ADP) and requires phosphatidylinositol 3 (PI3)-kinase and protein kinase C activity but not ephrinB1 phosphorylation. By itself, Eph and ephrin signaling is insufficient to cause aggregation or the binding of soluble fibrinogen, but it can potentiate aggregation initiated by a Ca(++) ionophore or by agonists for thrombin and thromboxane receptors. It also enhances Rap1 activation without requiring ADP secretion, ephrinB1 phosphorylation, or the activation of PI3-kinase and Src. From this we conclude that (1) Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca(++); (2) this is accomplished in part by activating Rap1; and (3) these effects require oligomerization of ephrinB1 but not phosphotyrosine-based interactions with the ephrinB1 cytoplasmic domain.
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PMID:Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1. 1457 67

A role of oxidative stress in atherosclerosis lies on experimental results carried out in vitro and in animal models. In humans, the supplementation with the antioxidant vitamin E has given in some cases supportive results and in others no effects. From in vitro studies, a large amount of data has shown that alpha-tocopherol (the major component of vitamin E) regulates key events in the cellular pathogenesis of atherosclerosis. We first described the inhibition of protein kinase C (PKC) activity by alpha-tocopherol to be at the basis of the vascular smooth muscle cell growth inhibition by this compound. Subsequently, PKC was recognized to be the target of alpha-tocopherol in different cell types, including monocytes, macrophages, neutrophils, fibroblasts and mesangial cells. Inhibiting the activity of protein kinase C by alpha-tocopherol results in different events in different cell types: inhibition of platelet aggregation, of nitric oxide production in endothelial cells, of superoxide production in neutrophils and macrophages as well as impairment of smooth muscle cell proliferation. Adhesion molecule expression and inflammatory cell cytokine production are also influenced by alpha-tocopherol. Scavenger receptors, particularly important in the formation of atherosclerotic foam cells, are also modulated by alpha-tocopherol. The oxidized LDL scavenger receptors SR-A and CD36 are down regulated at the transcriptional level by alpha-tocopherol. The relevance of CD36 expression in the onset of atherosclerosis has been indicated by the protection against atherosclerosis by CD36 knockout mice. In conclusion, the effect of alpha-tocopherol against atherosclerosis is not due only to the prevention of LDL oxidation but also to the down regulation of the scavenger receptor CD36 and to the inhibition of PKC activity.
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PMID:The role of alpha-tocopherol in preventing disease. 1505 95


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