Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The leukocyte integrin LFA-1 (CD11a/CD18) plays a key role in many adhesive interactions involving cells of the immune system. Recently, it has been shown that LFA-1 is not only involved in cell adhesion, but that stimulation of LFA-1 can also contribute to cell activation. We now demonstrate that triggering of LFA-1 on T lymphocytes by monoclonal antibodies (mAb) against the LFA-1 alpha chain, but not against the LFA-1 beta chain, promotes cell adhesion. Induction of homotypic adhesion was only observed in T cells that had been pre-activated with anti-CD3 and not in resting peripheral blood T lymphocytes. The induced homotypic adhesion is mediated by LFA-itself, because it was inhibited by anti-LFA-1 beta mAb. This notion is supported by the temperature and divalent cation dependence which is characteristic of LFA-1-mediated adhesion. mAb against ICAM-1 (CD54) did not block LFA-1 alpha-induced adhesion. The sensitivity of LFA-1 alpha-induced adhesion to H7, which prevents the activation of protein kinase C and protein kinase A, and to cytochalasin B, which inhibits microfilament formation, suggests that the activation of the LFA-1 pathway through the LFA-1 alpha chain involves cell activation and requires an intact cytoskeleton.
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PMID:Induction of homotypic T cell adhesion by triggering of leukocyte function-associated antigen-1 alpha (CD11a): differential effects on resting and activated T cells. 135 99

Regulation of the avidity of LFA-1 (CD11a/CD18, alpha L beta 2) for its ligand ICAM-1 (CD54) was studied in human B cells by evaluating the effects of a phorbol ester, anti-IgM antibodies, staurosporine, and okadaic acid. We monitored changes in LFA-1 avidity by quantifying binding of cells to an immobilized rICAM-1 fusion protein. In this assay, the protein kinase C-activating phorbol ester PDB and anti-IgM antibodies, as well as the protein kinase inhibitor, staurosporine, were able to induce LFA-1-dependent binding to ICAM-1. This demonstrates that the high avidity state of LFA-1 can be induced by a protein kinase C-dependent and by a protein kinase C-independent pathway. Furthermore, treatment of the cells with the protein phosphatase inhibitor, okadaic acid, inhibited binding to ICAM-1. Treatment with staurosporine before addition of okadaic acid not only induced enhanced binding of cells to ICAM-1, but also dramatically reduced the ability of okadaic acid to inhibit binding. These results suggest a critical role for a protein phosphatase in inducing the high avidity state of LFA-1 as well as a role for a protein kinase in inducing the low avidity state of LFA-1.
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PMID:Regulation of LFA-1 avidity in human B cells. Requirements for dephosphorylation events for high avidity ICAM-1 binding. 135 24

We have identified three anti-murine LFA-1 alpha monoclonal antibodies (M17/4.2, G-48, and FD441.8) which are capable of inducing homotypic aggregation of murine T cell lines (3A9 EL-4 cells). The LFA-1-induced aggregation is temperature-dependent, necessitates metabolic energy, and requires an intact cytoskeleton, but is independent of transcription and protein synthesis. The aggregation is inhibited in Ca2+ and Mg2+ free media and is also blocked with EDTA and EGTA. The aggregation does not involve protein kinase A or C or changes in intracellular calcium. The LFA-1 alpha-induced homotypic aggregation is inhibited with LFA-1 beta antibodies, but not with antibodies targeting ICAM-1, VCAM-1, VLA-4, or CD2. 3A9 cells do not express the LFA-1 ligand ICAM-1, whereas EL-4 cells express moderate amounts of ICAM-1. Thus, targeting LFA-1 alpha with mAb results in homotypic aggregation of T cell lines which is independent of ICAM-1/LFA-1 interactions, but may involve other LFA-1 ligands such as ICAM-2 or ICAM-3. Alternatively, LFA-1 may function as a signaling molecule, triggering other yet to be defined adhesion molecules to interact.
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PMID:Monoclonal antibodies targeting murine LFA-1 induce LFA-1/ICAM-1-independent homotypic lymphocyte aggregation. 135 33

Intercellular adhesion molecules (ICAM)-1 and -3 coexist on T lymphocytes and are counter-receptors for the integrin LFA-1. Signaling through ICAM-3 stimulates a number of T cell functions and involves phosphorylation of Fyn, Lck, CD45, and other proteins. In contrast, this type of specific signaling event has not been described for signaling through ICAM-1. Here, tyrosine phosphorylation of cellular proteins was examined after cross-linking of ICAM-1. Tyrosine phosphorylation of the 34-kDa cdc2 protein kinase was induced transiently after stimulation of the leukemic T cell line, Molt-3, or peripheral blood T cells. Stimulation through ICAM-1 had no effect on constitutive presence of cdc2 or phosphorylation of cdc2 on threonine. cdc2 kinase activity was constitutive in peripheral blood T cells, and transient inhibition of kinase activity after ICAM-1 stimulation correlated kinetically with phosphorylation of cdc2 on tyrosine.
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PMID:Cross-linking of ICAM-1 on T cells induces transient tyrosine phosphorylation and inactivation of cdc2 kinase. 749 27

The fate of E-selectin expressed on TNF-activated monolayers of HUVEC was investigated by confocal laser scanning microscopy. Cytokine-activated endothelial cells internalized mAb to E-selectin in a very rapid, energy-dependent fashion. By contrast, mAb against ICAM-1 and VCAM-1 remained surface bound. The E-selectin mAb was recovered in intracellular compartments with a tubular morphology, some of which appeared to be interconnected. Cathepsin B, a ubiquitously expressed lysosomal protease, was found to co-localize in these structures. Functional specificity of E-selectin-internalization was observed upon addition of the fluorescent SLex-oligosaccharide to the activated HUVEC monolayers. Uptake into the same E-selectin-positive compartments was observed, whereas the control oligosaccharide Lex was not internalized at all. The process of internalization was found to be unaffected by most inhibitors of protein kinase C, cAMP-dependent PKA, or protein tyrosine kinase activity. Whereas cytochalasin B preincubation of HUVEC failed to inhibit the internalization process, colchicine and vinblastine, reagents that interfere with the metabolism of tubulin, prevented the formation of the elongated structures in which E-selectin would normally be internalized. Concomitantly, the expression of E-selectin at the cell surface was significantly increased.
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PMID:Cytokine-activated endothelial cells internalize E-selectin into a lysosomal compartment of vesiculotubular shape. A tubulin-driven process. 751 27

Cytokines induce the expression of E-selectin, VCAM-1, and ICAM-1 on human umbilical vein endothelial cells (HUVECs). We show that expression of these surface proteins is differently affected by cAMP. Increased cAMP levels decrease E-selectin and VCAM-1 but increase ICAM-1 expression. We demonstrate by mRNA half-life analysis and nuclear run-on assays that the cAMP repression of E-selectin occurs at the transcription level. This effect is abolished by protein kinase A inhibition, suggesting that repression is mediated by protein kinase A-driven phosphorylation. We found that a minimal E-selectin promoter sequence necessary to confer cytokine inducibility is also sufficient to mimic the cAMP effect in transfected HUVECs. Previously we characterized two regions (NF-kappa B and NF-ELAM1) of the minimal promoter that bind transcription factors necessary for E-selectin induction, Increased cAMP did not alter the binding of the complexes formed on either the NF-kappa B or NF-ELAM1 site. In contrast, in interleukin-1-treated HUVECs transactivity due to an NF-kappa B site is reduced by elevated cAMP. Increased cAMP in HUVECs appears to induce a protein kinase activity that reduces the cytokine signal for E-selectin and VCAM-1 expression. The reduction in signal may occur through an inhibitory phosphorylation of one or more of the factors responsible for regulating E-selectin expression.
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PMID:Inhibition of E-selectin gene transcription through a cAMP-dependent protein kinase pathway. 752 80

This article reports the results of the analysis of the activation signals delivered to T and B cells by means of the CD44 molecule and an agonistic mAb, i.e., CB05 mAb, which is able to induce cell activation and aggregation upon binding. The functional effects culminate in T-cell proliferation in the presence of autologous accessory cells. Such effects are barely detectable in thymocytes, while B cells prove refractory to the action of the agonistic mAb. All of these events have been followed by the expression of surface activation markers, by the transcription of selected cytokine genes (IFN-gamma, IL-4, and GM-CSF), and by the secretion of IL-2. Cell activation via CD44 has been evaluated as to its relationship with CD3 and CD2 activation pathways, proving synergistic with the latter. The CD44 signaling is protein kinase dependent. Furthermore, the role of surface molecules as cosignals in the CD44 pathway has been analyzed, showing that CD11a (and its ligand CD54), HLA class I, and CD25 are instrumental in the implementation of (a) efficient activation/proliferation signals and (b) a potent cytotoxic potential.
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PMID:Stimulation of T cells via CD44 requires leukocyte-function-associated antigen interactions and interleukin-2 production. 752 88

Asthma is a disease of airway inflammation and hyper-reactivity associated with lymphocytic infiltration in the bronchial submucosa. We recently demonstrated that human airway smooth muscle (ASM) cells express the cell adhesion molecules ICAM-1 and VCAM-1, which are up-regulated by cytokines such as TNF-alpha, and which mediate binding of activated T lymphocytes. In this study, we examined whether an increase in [cAMP]i, presumably via activation of cAMP-dependent protein kinase, modulates TNF-alpha-induced ICAM-1 and VCAM-1 on ASM. We found that treatment of ASM with either forskolin, which directly activates adenylyl cyclase, or with cholera toxin, which activates the heterotrimeric GTP-binding protein, Gs, inhibited TNF-alpha-induced cell adhesion molecule expression. In addition, treatment with either isoproterenol or prostaglandin E2, which activates receptors coupled to Gs and increases [cAMP]i, also inhibited TNF-alpha-induced expression of ICAM-1 and VCAM-1 on ASM. Furthermore, adhesion of activated T cells to TNF-alpha-stimulated ASM was inhibited by treating the ASM cells with either forskolin or PGE2. These data suggest that cAMP-dependent protein kinase activation decreases cytokine-induced expression of cell adhesion molecules on ASM cells, modulates T cell binding to airway myocytes and, thus, suggests novel therapeutic approaches to airway inflammation.
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PMID:Activation of cAMP-dependent pathways in human airway smooth muscle cells inhibits TNF-alpha-induced ICAM-1 and VCAM-1 expression and T lymphocyte adhesion. 753 67

Leukocyte recruitment is a key step in the inflammatory reaction. Several changes in the cell morphology take place during lymphocyte activation and migration: spheric-shaped resting T cells become polarized during activation, developing a well defined cytoplasmic projection designated as cellular uropod. We found that the chemotactic and proinflammatory chemokines RANTES, MCP-1, and, to a lower extent, MIP-1 alpha, MIP-1 beta, and IL-8, were able to induce uropod formation and ICAM-3 redistribution in T lymphoblasts adhered to ICAM-1 or VCAM-1. A similar chemokine-mediated effect was observed during T cells binding to the fibronectin fragments of 38- and 80-kD, that contain the binding sites for the integrins VLA-4 and VLA-5, respectively. The uropod structure concentrated the ICAM-3 adhesion molecule (a ligand for LFA-1), and emerged to the outer milieu from the area of contact between lymphocyte and protein ligands. In addition, we found that other adhesion molecules such as ICAM-1, CD43, and CD44, also redistributed to the lymphocyte uropod upon RANTES stimulation, whereas a wide number of other cell surface receptors did not redistribute. Chemokines displayed a selective effect among different T cell subsets; MIP-1 beta had more potent action on CD8+ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-1 alpha targeted selectively CD4+ T cells. We have also examined the involvement of cAMP signaling pathway in uropod formation. Interestingly, several cAMP agonists were able to induce uropod formation and ICAM-3 redistribution, whereas H-89, a specific inhibitor of the cAMP-dependent protein kinase, abrogated the chemokine-mediated uropod formation, thus pointing out a role for cAMP-dependent signaling in the development of this cytoplasmic projection. Since the lymphocyte uropod induced by chemokines was completely abrogated by Bordetella pertussis toxin, the formation of this membrane projection appears to be dependent on G proteins signaling pathways. In addition, the involvement of myosin-based cytoskeleton in uropod formation and ICAM-3 redistribution in response to chemokines was suggested by the prevention of this phenomenon with the myosin-disrupting agent butanedione monoxime. Interestingly, this agent also inhibited the ICAM-3-mediated cell aggregation, but not the cell adhesion to substrata. Altogether, these results demonstrate that uropod formation and adhesion receptor redistribution is a novel function mediated by chemokines; this phenomenon may represent a mechanism that significantly contributes to the recruitment of circulating leukocytes to inflammatory foci.
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PMID:Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. 759 74

The myeloid differentiation protein CD14 that is expressed on the surface of mature monocytes contributes to the adherence of monocytes to cytokine-stimulated monolayers of human macrovascular endothelial cells (EC). It has also been observed that the initial adherence of monocytes to cultured cytokine-stimulated EC eventually results in an ICAM-1- and LFA-1 (CD11a/CD18)-dependent adherence, which coincides with stretching and lateral migration of the monocytes over the surface of EC. Recently, it was reported that CD14 mediates monocyte activation and can induce a change in the avidity of CD11a/CD18 for its ligand ICAM-1. The aim of the present study was to investigate whether activation of monocytes by CD14 elicits a CD11/CD18-dependent adhesion of monocytes to ICAM-1 on rIL-1 alpha-stimulated EC. Incubation of monocytes with murine anti-CD14 mAb alone did not mobilize intracellular calcium but the subsequent addition of F(ab')2 anti-mouse Ig, which caused cross-linking of CD14 on the surface of monocytes, induced a transient rise in cytosolic free calcium concentration and enhanced the percentage monocytes that adhered to monolayers of macrovascular venous EC stimulated with rIL-1 alpha for 24 h, but not to nonstimulated EC. The elevated adhesion was decreased with monocytes were preincubated with staurosporine, an inhibitor of intracellular protein kinase activity and was markedly inhibited by mAb against the common beta 2-subunit (CD18) of the CD11/CD18 molecules on monocytes and by mAb against ICAM-1 on 24-h rIL-1 alpha-stimulated venous EC. These studies provide evidence for the hypothesis that the binding of monocytes via CD14 to rIL-1 alpha-stimulated EC generates an intracellular response in monocytes and triggers an adhesion mechanism that allows CD11/CD18 molecules on monocytes to bind to ICAM-1 on EC.
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PMID:Cross-linking of CD14 molecules on monocytes results in a CD11/CD18- and ICAM-1-dependent adherence to cytokine-stimulated human endothelial cells. 767 28


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