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)

Tumor cell interaction with endothelial cells is a crucial step leading to organ-selective metastasis. Adhesion of murine B16 amelanotic melanoma cells (B16a) to murine microvascular endothelial cells (CD3) was enhanced, in a dose- and time-dependent manner, by pretreating CD3 cells with 12(S)-hydroperoxyeicosatetraenoic acid [i.e., 12(S)-HETE], a 12-lipoxygenase metabolite of arachidonic acid. The metabolic precursor of 12(S)-HETE, 12-HPETE (12-hydroperoxyeicosatetraenoic acid) also enhanced B16a cell adhesion to CD3 monolayers, whereas other lipoxygenase products, i.e., 5(S), 11(S), and 15(S)-HETEs were ineffective. 12(S)-HETE-enhanced tumor cell adhesion was blocked by treating endothelial cells with antibodies against the alpha v beta 3 complex or against individual subunits but not with antibodies against alpha 5 beta 1. In contrast, neither of these two integrins appeared to be involved in tumor cell adhesion to unstimulated endothelium. Flow cytometric analysis, immunofluorescent labeling, and image analysis indicated that 12(S)-HETE induced a time- and dose-dependent increase in the surface expression of alpha v beta 3 but not alpha 5 beta 1 on CD3 cells. The increased surface expression of alpha v beta 3 on endothelial cells did not result from an increased transcription or translation of alpha v beta 3 message as confirmed by quantitative reverse transcription-polymerase chain reaction, Northern blotting, and quantitative Western blotting. Instead, subcellular fractionation studies revealed an increased translocation of alpha v beta 3 integrins from the cytosolic pool to the membrane fractions. Pretreatment of endothelial cells with several cytoskeleton-disrupting agents (i.e., cycloheximide or acrylamide to disrupt intermediate filament vimentin, cytochalasin D to disrupt microfilaments, colchicine or Nocodazole to disrupt microtubules) abolished the 12(S)-HETE-enhanced alpha v beta 3 surface expression as well as tumor cell adhesion to endothelial cells. Also, pretreatment of CD3 cells with protein kinase C inhibitor calphostin C, but not with protein kinase A inhibitor H8, blocked 12(S)-HETE-enhanced alpha v beta 3 surface expression and tumor cell adhesion. Collectively, these results suggest that eicosanoid 12(S)-HETE modulates tumor cell interaction with endothelium via protein kinase C- and cytoskeleton-dependent up-regulation of the surface expression of alpha v beta 3 integrin.
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PMID:Activation of microvascular endothelium by eicosanoid 12(S)-hydroxyeicosatetraenoic acid leads to enhanced tumor cell adhesion via up-regulation of surface expression of alpha v beta 3 integrin: a posttranscriptional, protein kinase C- and cytoskeleton-dependent process. 831 70

Granulocyte-macrophage colony-stimulating factor (GM-CSF) that is produced by metastatic Lewis lung carcinoma (LLC-LN7) cells functions as an autocrine stimulator of tumor-cell motility through protein kinase A (PKA) signal transduction. This GM-CSF-mediated enhancement of LLC-LN7 cell motility coincides with a reduction in the level of polymerized F-actin. In contrast, non-metastatic LLC-C8 tumor cells, which have a diminished level of PKA signaling, do not produce GM-CSF and do not respond to exogenous GM-CSF, since they remain non-motile and retain a high content of filamentous actin. The capacity of PKA to regulate the cytoskeletal organization of tumor cells was further studied with the use of LLC variants that had been stably transfected to over-express the C alpha subunit of PKA (CEV cells) or to express a mutant cAMP-resistant PKA RI alpha subunit resulting in a defective PKA (REV cells). When compared with wild-type metastatic LLC-LN7 cells, in which the F-actin staining was too diffuse to be clearly visualized microscopically, the PKA-defective REV-LN7 transfectants had an increased level of F-actin. In comparison with the wild-type non-metastatic LLC-C8 cells, which had a high content of F-actin, the CEV-C8 transfectants that over-expressed PKA activity had a reduced level of F-actin. The reduced polymerization of actin in these CEV-C8 transfectants was accompanied by reduced levels of the intermediate filament protein vimentin and a shift in the distribution both of F-actin and of vimentin to the periphery of the cells. These results show reduced cytoskeletal organization in metastatic LLC-LN7 cells as compared with that of non-metastatic LLC-C8 cells, and indicate that elevation of PKA activity, either by autologous GM-CSF or by genetic manipulation, diminishes cytoskeletal organization.
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PMID:Activation of the protein kinase a signal transduction pathway by granulocyte-macrophage colony-stimulating factor or by genetic manipulation reduces cytoskeletal organization in Lewis lung carcinoma variants. 831 33

Our previous studies have shown that vimentin can serve as a substrate for the v-Mos protein kinase in vitro. Furthermore, the amount of vimentin molecules in Moloney murine sarcoma virus (Mo-MuSV) transformed cells is decreased relative to uninfected cells and a lower molecular weight form is observed in these v-mos transformed cells (Singh & Arlinghaus, Virology 173: 144-156, 1989). Vimentin filaments are hyperphosphorylated and disassemble when cells enter mitosis. Here, we show that vimentin was coprecipitated with p85gag-mos from mitotic cell extracts by two different anti-Mos antibodies that do not crossreact with vimentin. However, we were unable to detect vimentin/v-Mos complexes interphase extracts, possibly due to lack of soluble vimentin. p37env-mos was also found to associate with purified bovine lens vimentin in vitro. The significance of these findings with regard to v-mos-induced cellular transformation is discussed.
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PMID:Association of v-Mos with soluble vimentin in vitro and in transformed cells. 833 43

The effects of guanosine 3',5'-cyclic monophosphate (cGMP) on the secretory response of activated human neutrophils were investigated using LY-83583, an inhibitor of soluble guanylate cyclase, and L-arginine, the precursor of nitric oxide formation. A 30% release of myeloperoxidase (MPO) and lactoferrin (LF) from the primary and specific granules, respectively, was detected by enzyme-linked immunosorbent assay in adhered neutrophils stimulated with 0.1 microM N-formyl-methionyl-leucyl-phenylalanine (FMLP) or 20 microM A-23187. LY-83583 (100 microM) inhibited the release of both LF and MPO after stimulation with FMLP or A-23187. Conversely, preincubation of neutrophils with 0.5 mM L-arginine augmented the release of LF and MPO in FMLP- and A-23187-stimulated cells. Concurrent with the increase in the degranulation response was an elevation of cGMP levels in L-arginine-treated cells, while stimulated cGMP levels were reduced in LY-83583-treated cells. Furthermore, cGMP-dependent protein kinase (G-kinase) activity was reduced in LY-83583-treated cells, as determined by the delay in G-kinase translocation to intermediate filaments and the inhibition of vimentin phosphorylation. Degranulation, elevation of cGMP levels, and targeting of G-kinase were also dependent on the concentration of A-23187 or FMLP. These data suggest that activators of neutrophil degranulation mediate this response through a cGMP-dependent protein kinase mechanism.
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PMID:Regulation of human neutrophil degranulation by LY-83583 and L-arginine: role of cGMP-dependent protein kinase. 833 31

Synthetic peptide representing the site Ser-41 in vimentin, Leu-Gly-Ser41-Ala42-Leu-Arg44-Arg-Arg-NH2, and its analogs in which Ala-42 was replaced by various amino acids were tested as substrates for cdc2 kinase. Among them, the analog containing sarcosine as well as proline was an excellent substrate. The result suggests that the N-substituted structure of proline immediately following the site is important for cdc2 kinase phosphorylation. Replacement of Ala-42 by polar amino acids, especially lysine, had negative effects on peptide phosphorylation. The peptides in this study were also assayed with another type of proline-directed protein kinase, tau protein kinase II. The substrate specificity differed essentially from that of cdc2 kinase.
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PMID:Phosphorylation of synthetic vimentin peptides by cdc2 kinase. 837 19

Previously we identified p34cdc2 as one of two protein kinases mediating the hyperphosphorylation and disassembly of vimentin in mitotic BHK-21 cells. In this paper, we identify the second kinase as a 37 kDa protein. This p37 protein kinase phosphorylates vimentin on two adjacent residues (thr-457 and ser-458) which are located in the C-terminal non-alpha-helical domain. Contrary to the p34cdc2 mediated N-terminal phosphorylation (at ser-55) which can disassemble vimentin intermediate filaments (IF) in vitro, p37 protein kinase phosphorylates vimentin-IF without obviously affecting its structure in vitro. We have further examined the in vivo role(s) of vimentin phosphorylation in the disassembly of the IF network in mitotic BHK cells by transient transfection assays. In untransfected BHK cells, the interphase vimentin IF networks are disassembled into non-filamentous aggregates when cells enter mitosis. Transfection of cells with vimentin cDNA lacking the p34cdc2 phosphorylation site (ser55:ala) effectively prevents mitotic cells from disassembling their IF. In contrast, apparently normal disassembly takes place in cells transfected with cDNA containing mutated p37 kinase phosphorylation sites (thr457:ala/ser458:ala). Transfection of cells with vimentin cDNAs lacking both the N- and C-terminal phosphorylation sites yields a phenotype indistinguishable from that obtained with the single N-terminal mutant. Taken together, our results demonstrate that the site-specific phosphorylation of the N-terminal domain, but not the C-terminal domain of vimentin plays an important role in determining the state of IF polymerization and supramolecular organization in mitotic cells.
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PMID:The relative roles of specific N- and C-terminal phosphorylation sites in the disassembly of intermediate filament in mitotic BHK-21 cells. 871 73

Transgenic mice expressing the oncogenic protein-serine/threonine kinase Mos at high levels in the brain display progressive neuronal degeneration and gliosis. Gliosis developed in parallel with the onset of postnatal transgene expression and led to a dramatic increase in the number of astrocytes positive for GFAP, vimentin, and possibly tau. Interestingly, vimentin is normally expressed only in immature or neoplastic astrocytes, but appears to be induced to high levels in Mos-transgenic, mature astrocytes. Mos can activate mitogen activated protein kinase (MAPK) and MAPK has been implicated in Alzheimer-type tau phosphorylation. In the Mos-transgenic brain we found increased levels of phosphorylation at one epitope on tau containing serines 199 and 202 (numbering according to human tau), a pattern similar but not identical to that found in Alzheimer's disease. In addition, Mos-transgenic mice express a novel neurofilament-related protein that might be a proteolytic neurofilament heavy chain degradation product. These results suggest that activation of protein phosphorylation in neurons can result in changes in cytoskeletal proteins that might contribute to neuronal degeneration.
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PMID:Neurodegenerative changes including altered tau phosphorylation and neurofilament immunoreactivity in mice transgenic for the serine/threonine kinase Mos. 874 4

Ser55 within the head domain of neurofilament light chain (NF-L) is transiently phosphorylated by protein kinase A, and phosphorylation of this residue is thought to regulate assembly of neurofilaments. To understand how Ser55 phosphorylation influences NF-L assembly, wild-type and mutant NF-L genes in which Ser55 was mutated to alanine, so as to prevent phosphorylation, or to aspartate, so as to mimic permanent phosphorylation, were transfected into mammalian cells that contain or do not contain an endogenous intermediate filament network. Wild-type and mutant NF-Ls localised to the Triton X-100-insoluble fraction, which suggests that phosphorylation of Ser55 does not inhibit assembly of NF-L and NF-L/ vimentin polymers at or below the tetrameric stage. Immunofluorescence microscopy of transfected cells demonstrated that the wild-type and mutant NF-Ls all colocalised with vimentin to produce similar filamentous arrays. However, in cells lacking an endogenous intermediate filament network, the aspartate mutant produced a pattern of staining different from that of the wild-type or alanine mutant. These results suggest that phosphorylation of NF-L Ser55 is not a mechanism that precludes assembly of neurofilaments from monomers into intermediate filament structures but that phosphorylation/dephosphorylation of this residue might confer more subtle characteristics on neurofilament assembly properties and architecture.
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PMID:Assembly properties of neurofilament light chain Ser55 mutants in transfected mammalian cells. 876 98

Myofibroblasts of the lamina propria of human seminiferous tubules were studied in testes having normal or slightly reduced spermatogenesis by means of electron microscopy, confocal laser microscopy and immunocytochemistry. Myofibroblasts are large, flat individual cells braced in a network of microfibrils and collagen fibrils in the tubular wall. They are arranged in discontinuous cell layers with interposed layers of an extracellular matrix. Myofibroblasts of the lamina propria exhibit an unique cell shape with the peripheral cytoplasm split up in two or more layers. After FITC-phalloidin staining and by means of confocal laser microscopy, actin filaments of variable orientation are visible in their cytoplasm. The thickness and preferential direction of actin filaments differ in the outer and innermost cell layers. The myofibroblasts express both antigens of smooth muscle cells (alpha-smooth muscle actin, pan-actin, desmin, GB 42, smooth muscle myosin), and of connective tissue cells (vimentin, fibroblast surface protein). The variable expression of these antigens evidenced the existence of different phenotypes of myofibroblasts. Immunoreactivity for basic fibroblast growth factor and transforming growth factor beta as well as for components of the extracellular matrix indicate that these agents may be important for the phenotypic differentiation of the lamina propria cells. The detection of CNPase-and galactocerebroside-immunoreactivity in a number of lamina propria cells and some cells of the intertubular tissue gives rise to the hypothesis that components of the testicular tissue share some structural similarities with glia cells of the nervous system. Finally, immunoreactivities for the neuronal and endothelial nitric oxide synthase, soluble guanylyl cyclase, cyclic GMP, calmodulin, calcium-dependent protein kinase II and glutamate indicate that the contractility of myofibroblasts in the lamina propria of human seminiferous tubules may be in part modulated by the NO/cGMP-system.
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PMID:Myofibroblasts in the lamina propria of human semi-niferous tubules are dynamic structures of heterogeneous phenotype. 879 Aug 58

The rate of steroid synthesis is regulated by the rate of transport of cholesterol to mitochondria. The transport process involves two elements of the cytoskeleton (microfilaments and intermediate filaments) and Ca2+/ calmodulin. Electron microscopy and immunofluorescence reveal that lipid droplets in which steroidogenic cholesterol is stored in the cytoplasm are tightly attached to vimentin intermediate filaments. Mitochondria are also attached to intermediate filaments. Ca2+/calmodulin is known to be essential for the steroidogenic response to ACTH and acts to increase transport of cholesterol to mitochondria. Ca2+/ calmodulin promotes phosphorylation of two important adrenal proteins: vimentin via its protein kinase and myosin light chain via the calmodulin-dependent light-chain kinase. In permeabilized adrenal cells Ca2+/calmodulin causes an ATP-dependent contraction of the cells. Phosphorylation of vimentin is known to cause breakdown of intermediate filaments. Electron microscopy reveals that actin filaments cross-link intermediate filaments in adrenal cells. It is proposed that ACTH has at least two second messengers, Ca2+/calmodulin and cAMP. Ca2+/calmodulin causes breakdown of vimentin filaments and activates a contractile event dependent on ATP and myosin light chain. These changes reorganize the cytoskeleton in such a way as to facilitate the interaction of lipid droplets with mitochondria, resulting in transport of cholesterol to these organelles and hence increased steroid synthesis.
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PMID:The roles of calmodulin, actin, and vimentin in steroid synthesis by adrenal cells. 902 35


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