Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

mAb against human glycosyl-phosphatidylinositol-linked leucocyte surface Ag CD59 and CD55 immunoprecipitated from detergent lysates of HPB ALL cell line in addition to the respective Ag a common 80-kDa glycoprotein component and (glyco)lipids. The 80-kDa glycoprotein is different from otherwise similar CD44 Ag. The CD59 immunoprecipitate contained also a small amount of the CD55 glycoprotein and the CD55 immunoprecipitate minute amount of the CD59 Ag. These results are interpreted in terms of existence of noncovalent complexes resistant to dissociation by mild detergents and consisting of the 80-kDa glycoprotein, CD59 and CD55 glycoproteins, relatively tightly bound (glyco)lipids and possibly other so far unidentified components. These complexes contain probably also other glycosyl-phosphatidylinositol-linked Ag, as an anti-CD48 mAb immunoprecipitated also an apparently very similar complex. The complexes immunoprecipitated by mAb against the CD55, CD59, and CD48 Ag also contain a protein kinase activity. This type of complexes could not be demonstrated in several other cell types such as RBC, PBMC, and HeLa cells. However, a qualitatively very similar set of components was immunoprecipitated from the murine thymoma EL-4 cell line by an anti-Thy-1 mAb.
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PMID:Association of the CD59 and CD55 cell surface glycoproteins with other membrane molecules. 171 64

A brief incubation of lymphocytes with either PMA, stimulating protein kinase C, or with dibutyryl-cAMP, leading to protein kinase A activation, led to increased lymphocyte penetration through intact endothelial monolayers in vitro. The PMA-induced penetration could be dose-dependently down-regulated with a protein kinase C inhibitor, H7. Similarly HA 1004, being mainly a protein kinase A inhibitor, decreased the dibutyryl-cAMP induced penetration. Treatment of lymphocytes with PMA and cAMP did not alter the expression of CD44 homing receptors on lymphocytes. Stimulation of lymphocytes with dibutyryl-cGMP or calcium ionophore had no effect on lymphocyte penetration. These results suggest that activation of both protein kinases A and C is important in the lymphocyte binding to endothelium.
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PMID:Activation of protein kinases A and C increase lymphocyte penetration through endothelial monolayers. 216 4

Hyaluronan-binding function of the CD44 molecule has not been so far detected in myeloid cells. To study pure populations of primitive myeloid cells, we investigated the hyaluronan-binding function of the CD44 molecule from three myeloid cell lines: KG1a, KG1, and HL60. Both KG1a and KG1 cells express the CD34 antigen characteristic of the hematopoietic stem cells and HL60 cells do not; accordingly, KG1a and KG1 cells are generally considered as the most primitive and HL60 cells as the most mature of these cell lines. Measurement of cell adhesion to hyaluronan-coated surfaces (using 51Cr-labeled cells) and of aggregate formation in hyaluronan-containing solutions, showed that 45% of KG1 cells and 22% to 24% of KG1a spontaneously bind to hyaluronan, whereas HL60 cells do not either spontaneously or after treatment with a phorbol ester. Hyaluronan binding by KG1a and KG1 cells is mediated by CD44, because it is specifically abolished by monoclonal antibodies (MoAbs) to this molecule. The binding might require phosphorylation by protein kinase C and perhaps also by protein kinase A, because it is prevented by staurosporine, which inhibits these enzymes. 12-O-tetradecanoylphorbol-13-acetate (TPA) which activates protein kinase C, rises to 80% the proportion of KG1 and KG1a cells that bind hyaluronan; this activation is dependent on protein synthesis, for it is abrogated by cyclophosphamide, a protein synthesis inhibitor. Binding of TPA-treated cells to hyaluronan is only partly inhibited by MoAb to CD44: this suggests that TPA may induce synthesis of a hyaluronan-binding protein distinct from CD44. Considering the abundance of hyaluronan in human bone marrow, these results suggest that CD44 may be involved in mediating precursor-stroma interaction.
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PMID:CD44 mediates hyaluronan binding by human myeloid KG1A and KG1 cells. 750 30

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

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

IFN-alpha influences the recirculation and growth of normal and malignant B lymphocytes, although the mechanisms involved are not currently known. Lymphocyte recirculation is fundamentally dependent on cell-to-cell interactions that are mediated by cell surface adhesion molecules. In this report, we examined the relationship between the effect of IFN-alpha on cell-to-cell adhesion processes and induction of the Leu-13 cell surface protein in established human Daudi B lymphoid cell lines that are either sensitive or resistant to the antiproliferative activity of IFN-alpha. IFN-alpha directly triggered homotypic adhesion of IFN-sensitive Daudi B cells in a time- and dose-dependent manner. In contrast, IFN-alpha had no effect on the cell-to-cell adhesion of IFN-resistant Daudi B cells. The capacity of IFN-alpha to trigger homotypic aggregation correlated directly with the level of induction of the cell surface protein Leu-13 and could be potentiated by anti-Leu-13 mAb. Other cytokines also known to influence the proliferation, differentiation, or recirculation of B lymphocytes such as IFN-gamma, IL-2, IL-4, IL-6, TNF-alpha, and low molecular weight B cell growth factor did not induce either Leu-13 expression or homotypic aggregation of Daudi B cells. The adhesion pathway triggered by the IFN-inducible protein Leu-13 required metabolic energy and an intact cytoskeleton but was not dependent on: 1) new protein synthesis; 2) protein kinase C, protein kinase A, or tyrosine kinase activities; or 3) the function of known adhesion molecules including LFA-1, ICAM-1, CD44, or VLA-4. Taken together, these studies demonstrate a fundamental role for IFN-alpha and the IFN-inducible protein Leu-13 in regulating a novel homotypic adhesion pathway in B lymphocytes, and provide insight into the possible mechanisms by which IFN-alpha regulates biologic processes including recirculation.
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PMID:IFN-alpha induces homotypic adhesion and Leu-13 expression in human B lymphoid cells. 842 37

We investigated the role of surface adhesion molecules in regulating vascular permeability, in vitro and in vivo. Cultured rat endothelial cells (RECs) express Thy-1, intercellular adhesion molecule-1 (ICAM-1), and CD44. Permeability of albumin across the REC monolayer increased through the interaction of Thy-1 and anti-Thy-1 monoclonal antibodies (mAbs), but no increase was seen through ICAM-1 and anti-ICAM-1, CD44 and anti-CD44, and RT1A and anti-RT1A mAbs. The potential of anti-Thy-1 mAb for permeability increase depended on antibody concentration, it peaked at 12h, and was neither mediated by injury nor by growth modulation to the REC monolayer. Effect of anti-Thy-1 mAb was inhibited significantly by the calmodulin antagonist W-7 or the protein kinase inhibitors H-7 and HA-1004, and was completely blocked by the combined addition of W-7 and H-7. It seems likely that both calmodulin and protein kinases are involved in related intracellular signal pathways. Thy-1 expression on RECs was up-regulated with IL-1 beta treatment and was down-regulated with mixed lymphocyte reaction (MLR) supernatant treatment. Although Thy-1 expression on rat vascular endothelium in vivo was not detected, the expression of Thy-1 was induced on dermal endothelial cells at the site of inflammation induced by Freund's complete adjuvant (FCA). Vascular permeability in the inflamed dermis significantly increased when anti-Thy-1 but not anti-ICAM-1, anti-CD44, or anti-RT1A mAbs were given intravenously. The collective evidence suggests that inducible Thy-1 on the endothelium is one important regulatory event in vascular permeability at sites of inflammation.
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PMID:[Expression and role of Thy-1 on endothelial cells at sites of inflammation--a novel function of Thy-1; vascular permeability regulation]. 854 76

Aberrant glycosylation expressed in glycosphingolipids and glycoproteins in tumor cells has been implicated as an essential mechanism in defining stage, direction, and fate of tumor progression. This general concept is supported by results from three lines of study: (a) Numerous clinicopathological studies have shown a clear correlation between aberrant glycosylation status of primary tumor and invasive/metastatic potential of human cancer as reflected by 5- or 10-year survival rates of patients. (b) Carbohydrates expressed in tumor cells are either adhesion molecules per se or modulate adhesion receptor function. Some are directly involved in cell adhesion. They are recognized by selectins or other carbohydrate-binding proteins or by complementary carbohydrates (through carbohydrate-carbohydrate interaction). N- or O-glycosylation of functionally important membrane components may alter tumor cell adhesion or motility in a direction that either promotes or inhibits invasion and metastasis. Examples of such receptors are E-cadherin, integrins, immunoglobulin family receptors (e.g., CD44), and lysosome-associated membrane protein. (c) Gangliosides and sphingolipids modulate transmembrane signaling essential for tumor cell growth, invasion, and metastasis. The transducer molecules susceptible to gangliosides and sphingolipids include integrin receptors, tyrosine kinase-linked growth factor receptors, protein kinase C, and G-protein-linked receptor affecting protein kinase A. Some glycosphingolipids (e.g., Gb3Cer, Le(y), ceramide, and sphingosine induce tumor cell differentiation and subsequent apoptosis. Shedded gangliosides may block immunogenicity of tumor cells, providing conditions favorable for "escape" from immunological suppression of tumor growth by the host. Various reagents that block carbohydrate-mediated tumor cell adhesion or block glycosylation processing have been shown to inhibit tumor cell metastasis. This provides the basis for further development of "anti-adhesion therapy." Ganglioside analogues and sphingolipid analogues that inhibit protein kinase C and receptor-associated tyrosine kinase have been applied for inhibition of metastasis. A crucial mechanism for inhibition of metastasis by these reagents may involve blocking of transmembrane signaling for expression of P- and E-selectin. This provides the basis for development of "ortho-signaling therapy."
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PMID:Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. 896 75

A general characteristic of lupus-prone mice (and humans) is the expedited accumulation of large numbers of presumably self-reactive activated/memory phenotype T cells. The mechanism by which these cells escape apoptosis has not been defined. We used activated/memory phenotype CD4+ cells from male BXSB mice with early-life severe lupus-like disease to investigate cell cycle status and apoptosis susceptibility, and to determine the role of corresponding genes in survival of these cells. In vitro acridine orange staining indicated that most of the rapidly accumulating memory phenotype CD4+ T cells of 4-month-old male BXSB mice are G1 arrested. Long-term bromodeoxyuridine in vivo labeling also showed that with advanced age, there was a shift of the CD4+ CD44(hi) male cells from predominantly cycling to predominantly noncycling. Moreover, the CD4+ CD44(hi) cells of older males were refractory to anti-CD3-induced proliferation and apoptosis. Using a multiprobe RNase protection assay encompassing riboprobe panels for cell cycle and apoptosis-related genes, we found that these cells exhibited high expression of certain members of the Ink4 (p18Ink4C) and Cip/Kip (p21Cip1) families of cyclin kinase inhibitors as well as of the apoptosis-inhibiting Bcl-xL gene. Western blot analysis confirmed increased levels of Bcl-xL and p21Cip1, and also identified increases in another cyclin kinase inhibitor, p27Kip1. We propose that in autoimmunity, self-reactive CD4+ cells are subjected to successive rounds of activation/division that eventually lead to a build-up in cyclin-dependent kinase inhibitors. Once high levels of such inhibitors are reached, they cause refractoriness to further activation, impaired cell cycle entry and resistance to apoptosis, a situation akin to replicative senescence.
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PMID:G1 arrest and high expression of cyclin kinase and apoptosis inhibitors in accumulated activated/memory phenotype CD4+ cells of older lupus mice. 929 25

The cortical cytoskeleton of eucaryotic cells provides structural support to the plasma membrane and also contributes to dynamic processes such as endocytosis, exocytosis, and transmembrane signaling pathways. The ERM (ezrin-radixin-moesin) family of proteins, of which ezrin is the best studied member, play structural and regulatory roles in the assembly and stabilization of specialized plasma membrane domains. Ezrin and related molecules are concentrated in surface projections such as microvilli and membrane ruffles where they link the microfilaments to the membrane. The present knowledge about ezrin is discussed from an historical perspective. Both biochemical and cell biological studies have revealed that ezrin can exist in a dormant conformation that requires activation to expose otherwise masked association sites. Current results indicate that activated ezrin monomers or head-to-tail oligomers associate directly with F-actin through a domain in its C terminus, and with the membrane through its N-terminal domain. The association of ezrin with transmembrane proteins can be direct, as in the case of CD44, or indirect through EBP50. Other binding partners, including the regulatory subunit of protein kinase A and rho-GDI, suggest that ezrin is an integral component of these signaling pathways. Although the membrane-cytoskeletal linking function is clear, further studies are necessary to reveal how the activation of ezrin and its association with different binding partners is regulated.
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PMID:Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures. 936 71


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