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Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human polymorphonuclear leukocytes (PMN) respond to LPS with strongly increased integrin-mediated adhesion. While the first step of this process has been identified as the interaction of LPS with CD14 on the cell surface, subsequent steps remain to be elucidated. The experiments presented here suggest that monomeric LPS is internalized in vesicles, and uptake may be required for signaling. Fluorescently labeled LPS presented as monomeric complexes with soluble CD14 appeared in the plasma membrane of PMN by 5 min and was concentrated in cytoplasmic vesicles by 20 min. Adhesion in response to LPS/soluble CD14 occurred only after a 15- to 20-min lag period, consistent with endocytosis occurring before signal generation. In contrast, there was no time lag for adhesion in response to the formyl peptide formyl-norleucyl-leucyl-phenylalanine (fNLLP). Adhesion in response to LPS, but not fNLLP, was completely blocked by lowering the temperature to 19 degrees C, a procedure that prevents vesicle fusion. These studies indicated that an event with the time and temperature dependence of endocytosis precedes signaling by LPS. Cytochalasin D, an inhibitor of phagocytosis, and wortmannin, an inhibitor of phosphatidylinositol 3-kinase that blocks vesicle fusion and phagocytosis, both completely blocked adhesion in response to LPS but not in response to fNLLP. These results support the idea that LPS internalization and early endosomal fusion may be required for signal transduction. Parallel studies showed that the adhesion response to TNF had time, temperature, and inhibitor sensitivities nearly identical with those of LPS, suggesting that responses to TNF may also include an obligate vesicle fusion step.
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PMID:Potential role of membrane internalization and vesicle fusion in adhesion of neutrophils in response to lipopolysaccharide and TNF. 895 11

Adhesion molecules play an essential role in the host immune response by mediating the adhesive interactions that are essential for immune cell trafficking and activation. Integrins are one family of adhesion receptors that leukocytes utilize to interact with other cells and with components of the extracellular matrix. Since leukocytes rapidly alternate between adhesive and nonadhesive states, the functional activity of integrins expressed on leukocytes is carefully and precisely regulated. Resting T lymphocytes express integrin receptors, but they mediate minimal cell adhesion. However, activation of the T cell results within minutes in increased integrin functional activity that occurs without a change in the level of integrin expression on the cell surface. Increased integrin-mediated adhesion appears to be a general response of T cells to activation, since a diverse array of activation stimuli are capable of inducing this rapid increase in integrin functional activity. We have used DNA-mediated gene transfer and site-directed mutagenesis to elucidate the intracellular signaling pathways that regulate integrin-mediated cell adhesion. Our studies have revealed two important general themes. First, the lipid kinase phosphatidylinositol 3-kinase (PI 3-K) plays a role in integrin regulation mediated by many regulators of integrin function. Second, there are cell-specific differences in the signaling pathways that regulate integrin function. These studies illustrate the complex nature of the signaling pathways that regulate lymphocyte adhesion.
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PMID:Intracellular signaling pathways and the regulation of cell adhesion. 918 46

The monomeric G-protein Ras is now considered to function as an initial regulator of multiple signaling pathways in both normal and transformed cell types. Adhesion and chemoattractant receptors are known to trigger activation of Ras in human neutrophils, but the signaling mechanism that activates Ras has only been partially elucidated. The present results show that in neutrophils, a time- and dose-dependent f-Met-Leu-Phe (FMLP)-induced activation of Ras is mediated by Gi2-proteins, because such activation is inhibited by pertussis toxin and because direct stimulation of heterotrimeric G-proteins with AlF4- is sufficient to activate Ras. Pretreatment of neutrophils with tyrosine kinase inhibitors, i.e. genistein or erbstatin that completely block FMLP-stimulated protein tyrosine phosphorylations, did not affect the FMLP-induced activation of Ras. Moreover, FMLP did not induce any detectable translocation of Grb2 and Sos to the plasma membrane of neutrophils. Other signaling molecules, such as protein kinase C, phosphatidylinositol 3-kinase and Ca2+, do not appear to be involved in the FMLP-induced Ras activation. Instead, stimulation of neutrophils with FMLP or C5a, the latter of which also activates Gi2-proteins, resulted in transient inhibition of the activity of Ras GTPase-activating proteins (GAP) with kinetics that correlated well with the kinetics of Ras activation. Moreover, decreased Ras-GAP activity was found in p120-GAP but not in neurofibromin immunoprecipitates of FMLP-stimulated cells. These results suggest that tyrosine kinase-dependent Ras exchange factors do not contribute to the FMLP-induced activation of Ras but that such activation is mediated via inhibition of p120-GAP in neutrophils.
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PMID:Chemotactic peptide-induced activation of Ras in human neutrophils is associated with inhibition of p120-GAP activity. 928 61

Adhesion of epithelial cells to matrix is known to inhibit apoptosis. However, the role of cell-cell adhesion in mediating cell survival remains uncertain. Primary cultures of mouse proximal tubular (MPT) cells were used to examine the role of cell-cell adhesion in promoting survival. When MPT cells were deprived of both cell-matrix and cell-cell adhesion, they died by apoptosis. However, when incubated in agarose-coated culture dishes (to prevent cell-matrix adhesion) and at high cell density (to allow cell-cell interactions), MPT cells adhered to one another and remained viable. Expression of E-cadherin among suspended, aggregating cells increased with time. A His-Ala-Val (HAV)-containing peptide that inhibits homophilic E-cadherin binding prevented cell-cell aggregation and promoted apoptosis of MPT cells in suspension. By contrast, inhibition of potential beta(1)-integrin-mediated interactions between cells in suspension did not prevent either aggregation or survival of suspended cells. Aggregation of cells in suspension activated phosphatidylinositol 3-kinase (PI3K), an event that was markedly reduced by the presence of the HAV peptide. LY-294002, an inhibitor of PI3K, also inhibited survival of suspended cells. In summary, we provide novel evidence that MPT cells, when deprived of normal cell-matrix interactions, can adhere to one another in a cadherin-dependent fashion and remain viable. Survival of aggregated cells depends on activation of PI3K.
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PMID:Mouse proximal tubular cell-cell adhesion inhibits apoptosis by a cadherin-dependent mechanism. 1080 87

Neutrophils (PMN) are critical host defense cells that have a role in the pathophysiology of a variety of inflammatory diseases, particularly those diseases associated with antigen-antibody immune complexes (IC) deposited in tissues. Activation of PMN by IC is most efficient if the IC are presented immobilized on a surface. Adhesion to the immobilized IC is important for subsequent activation of PMN effector functions, such as generation of reactive oxygen metabolites. Adhesion of human PMN to immobilized IC requires the expression and activation of adhesion receptors called integrins. Of the integrins expressed on PMN, the beta 2 family has been found to be of particular importance for PMN function. The mechanism of beta 2 integrin activation during adhesion to IC has been studied in human PMN, but not in equine PMN. We show here that adhesion of equine PMN to immobilized IC requires beta 2 integrins. Like adhesion, IC-induced respiratory burst activity is dependent on beta 2 integrins. Furthermore, the signaling pathway triggering beta 2 integrin-dependent adhesion of equine PMN to IC and subsequent generation of respiratory burst activity is inhibited by the specific phosphatidylinositol 3-kinase (PI3K) antagonists wortmannin and LY294002 with IC(50) (concentration at which 50% inhibition is achieved) similar to the published values for inhibition of PI3K enzymatic activity. In contrast, PMA-induced activation of beta 2 integrin-dependent adhesion and respiratory burst activity are wortmannin and LY294002 insensitive. These data demonstrate that like in human PMN, IC-induced activation of beta 2 integrins and beta 2 integrin-dependent functions in equine PMN is dependent on PI3K activity.
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PMID:Signaling mechanism for equine neutrophil activation by immune complexes. 1155 96

Classical cadherins mediate cell recognition and cohesion in many tissues of the body. It is increasingly apparent that dynamic cadherin contacts play key roles during morphogenesis and that a range of cell signals are activated as cells form contacts with one another. It has been difficult, however, to determine whether these signals represent direct downstream consequences of cadherin ligation or are juxtacrine signals that are activated when cadherin adhesion brings cell surfaces together but are not direct downstream targets of cadherin signaling. In this study, we used a functional cadherin ligand (hE/Fc) to directly test whether E-cadherin ligation regulates phosphatidylinositol 3-kinase (PI 3-kinase) and Rac signaling. We report that homophilic cadherin ligation recruits Rac to nascent adhesive contacts and specifically stimulates Rac signaling. Adhesion to hE/Fc also recruits PI 3-kinase to the cadherin complex, leading to the production of phosphatidylinositol 3,4,5-trisphosphate in nascent cadherin contacts. Rac activation involved an early phase, which was PI 3-kinase-independent, and a later amplification phase, which was inhibited by wortmannin. PI 3-kinase and Rac activity were necessary for productive adhesive contacts to form following initial homophilic ligation. We conclude that E-cadherin is a cellular receptor that is activated upon homophilic ligation to signal through PI 3-kinase and Rac. We propose that a key function of these cadherin-activated signals is to control adhesive contacts, probably via regulation of the actin cytoskeleton, which ultimately serves to mediate adhesive cell-cell recognition.
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PMID:E-cadherin homophilic ligation directly signals through Rac and phosphatidylinositol 3-kinase to regulate adhesive contacts. 1174 1

Mast cells are inflammatory and immunoregulatory cells resident in tissues. They develop from bone marrow-derived progenitor cells that enter the tissue through the blood circulation. The specific localization and migration of mast cells in tissues is dependent on their interaction with extracellular matrix (ECM) proteins. Adhesion of human mast cells isolated from intestinal mucosa and cultured in the presence of stem cell factor (SCF) to ECM proteins is analyzed. It was observed that SCF is a unique cytokine enhancing mast cell adhesion to all tested ECM proteins (fibronectin, laminin, collagen I, III, IV, VI, XIV) up to 5-fold, particularly to fibronectin (54% +/- 12% of mast cells) and to denatured collagens (40% +/- 12% on cyanogen bromide-cleaved peptides of collagen I). Most noteworthy, preculture of mast cells with interleukin-4 (IL-4), in addition to SCF, reduced their potency to adhere to ECM proteins to one third compared to mast cells cultured with SCF alone. Mast cell adhesion was preferentially mediated by beta1 integrins, and most cells expressed the ECM-binding integrins alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, and alphaVbeta3. SCF-induced mast cell adhesion was totally blocked by wortmannin and apigenin, indicating an involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase, and it was related to an up-regulation of the HUTS-21 beta1 epitope, which is associated with an activated conformation of beta1. In conclusion, these data indicate that SCF induces the adhesion of cultured mast cells to ECM proteins, whereas IL-4 may promote detachment from the ECM.
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PMID:Regulatory effects of stem cell factor and interleukin-4 on adhesion of human mast cells to extracellular matrix proteins. 1180

Neutrophil recruitment during acute inflammation is triggered by G-protein-linked chemotactic receptors that in turn activate beta(2) integrin (CD18), deemed a critical step in facilitating cell capture and arrest under the shear force of blood flow. A conformational switch in the I domain allosteric site (IDAS) and in CD18 regulates LFA-1 affinity for endothelial ligands including intercellular adhesion molecule 1 (ICAM-1). We examined the dynamics of CD18 activation in terms of the efficiency of neutrophil capture of ICAM-1, and we correlated this with the membrane topography of 327C, an antibody that recognizes the active conformation of CD18 I-like domain. Adhesion increased in direct proportion to chemotactic stimulus rising 7-fold over a log range of interleukin-8 (IL-8). A threshold dose of approximately 75 pm IL-8, corresponding to ligation of only approximately 10-100 receptors, was sufficient to activate approximately 20,000 CD18 and a rapid boost in the capture efficiency on ICAM-1. This was accompanied by a rapid redistribution of active LFA-1, but not Mac-1, into membrane patches, a necessary component for optimum adhesion efficiency. Shear-resistant arrest on a monolayer of ICAM-1 was reversed within minutes of chemotactic stimulation correlating with a shift from high to low affinity CD18 and dispersal of patches of active CD18. Mobility of active CD18 into high avidity patches was dependent on phosphatidylinositol 3-kinase activity and not F-actin polymerization. The data reveal that the number of chemotactic receptors bound and the topography and lifetime of high affinity LFA-1 tightly regulate the efficiency of neutrophil capture on ICAM-1.
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PMID:Dynamic regulation of LFA-1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow. 1192 76

Transmembrane proteins of the tetraspanin superfamily are assembled in multimeric complexes on the cell surface. Spatial orientation of tetraspanins within these complexes may affect signaling functions of the associated transmembrane receptors (e.g. integrins, receptor-type tyrosine kinases). The structural determinants that control assembly of the tetraspanin complexes are unknown. We have found that various tetraspanins and the alpha(3) integrin subunit are palmitoylated. The stability and molecular composition of the palmitoylated alpha(3)beta(1)-tetraspanin complexes are not affected by adhesion. To assess the significance of palmitoylation in the function of the alpha(3)beta(1)-tetraspanin complexes we mapped the sites of palmitoylation for CD151. Mutation of six cysteines, Cys(11), Cys(15), Cys(79), Cys(80), Cys(242), and Cys(243) was necessary to completely abolish palmitoylation of CD151. The association of the palmitoylation-deficient mutant of CD151 (CD151Cys8) with CD81 and CD63 was markedly decreased, but the interaction of the alpha(3)beta(1)-CD151Cys8 complex with phosphatidylinositol 4-kinase was not affected. Ectopic expression of CD151Cys8 in Rat-1 cells impaired the interactions of the endogenous CD63 and CD81 with the alpha(3)beta(1) integrin. Although the expression of the palmitoylation-deficient CD151 does not change cell spreading on the extracellular matrix, the number of focal adhesions increased. Adhesion-induced phosphorylation of PKB/c-Akt is markedly increased in cells expressing a palmitoylation-deficient mutant, thereby providing direct evidence for the role of the tetraspanin microdomains in regulation of the integrin-dependent phosphatidylinositol 3-kinase signaling pathway. In contrast, activation of FAK and ERK1/2 were not affected by the expression of CD151Cys8. Our results demonstrate that palmitoylation of tetraspanins is critical not only for the organization of the integrin-tetraspanin microdomains but also has a specific role in modulation of adhesion-dependent signaling.
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PMID:Expression of the palmitoylation-deficient CD151 weakens the association of alpha 3 beta 1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signaling. 1211 Jun 79

GeneCalling, a genome-wide method of mRNA profiling, reveals that endothelial cells adhering to fibronectin through the alpha 5 beta 1 integrin, but not to laminin through the alpha 2 beta 1 integrin, undergo a complex program of gene expression. Several of the genes identified are regulated by the NF-kappa B transcription factor, and many are implicated in the regulation of inflammation and angiogenesis. Adhesion of endothelial cells to fibronectin activates NF-kappa B through a signaling pathway requiring Ras, phosphatidylinositol 3-kinase, and Rho family proteins, whereas adhesion to laminin has a limited effect. Retroviral transfer of the superrepressor of NF-kappa B, I kappa B-2A, blocks basic fibroblast growth factor-induced angiogenesis in vivo. These results suggest that engagement of the alpha 5 beta 1 integrin promotes an NF-kappa B-dependent program of gene expression that coordinately regulates angiogenesis and inflammation.
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PMID:Alpha 5 beta 1 integrin activates an NF-kappa B-dependent program of gene expression important for angiogenesis and inflammation. 1213 1


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