Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C theta (PKC theta) is unique among PKC isozymes in its translocation to the center of the immune synapse in T cells and its unique downstream signaling. Here we show that the hematopoietic protein tyrosine phosphatase (HePTP) also accumulates in the immune synapse in a PKC theta-dependent manner upon antigen recognition by T cells and is phosphorylated by PKC theta at Ser-225, which is required for lipid raft translocation. Immune synapse translocation was completely absent in antigen-specific T cells from PKC theta-/- mice. In intact T cells, HePTP-S225A enhanced T-cell receptor (TCR)-induced NFAT/AP-1 transactivation, while the acidic substitution mutant was as efficient as wild-type HePTP. We conclude that HePTP is phosphorylated in the immune synapse by PKC theta and thereby targeted to lipid rafts to temper TCR signaling. This represents a novel mechanism for the active immune synapse recruitment and activation of a phosphatase in TCR signaling.
 ...
PMID:Lipid raft targeting of hematopoietic protein tyrosine phosphatase by protein kinase C theta-mediated phosphorylation. 1647

The Mg(2+)-inhibited cation (MIC) current (I(MIC)) in cardiac myocytes biophysically resembles currents of heterologously expressed transient receptor potential (TRP) channels, particularly TRPM6 and TRPM7, known to be important in Mg(2+) homeostasis. To understand the regulation of MIC channels in cardiac cells, we used the whole cell voltage-clamp technique to investigate the role of intracellular ATP in pig, rat, and guinea pig isolated ventricular myocytes. I(MIC), studied in the presence or absence of extracellular divalent cations, was sustained for >or=50 min after patch rupture in ATP-dialyzed cells, whereas in ATP-depleted cells I(MIC) exhibited complete rundown. Equimolar substitution of internal ATP by its nonhydrolyzable analog adenosine 5'-(beta,gamma-imido)triphosphate failed to prevent rundown. In ATP-depleted cells, inhibition of lipid phosphatases by fluoride + vanadate + pyrophosphate prevented I(MIC) rundown. In contrast, under similar conditions neither the inhibition of protein phosphatases 1, 2A, 2B or of protein tyrosine phosphatase nor the activation of protein kinase A (forskolin, 20 microM) or protein kinase C (phorbol myristate acetate, 100 nM) could prevent rundown. In ATP-loaded cells, depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)) by prevention of its resynthesis (10 microM wortmannin or 15 microM phenylarsine oxide) induced rundown of I(MIC). Finally, loading ATP-depleted cells with exogenous PIP(2) (10 microM) prevented rundown. These results suggest that PIP(2), likely generated by ATP-utilizing lipid kinases, is necessary for maintaining cardiac MIC channel activity.
 ...
PMID:ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes. 1670 55

The ubiquitously expressed protein tyrosine phosphatase PTP1B is involved in the regulation of numerous cellular signaling pathways. PTP1B is anchored to the ER membrane while many of its substrates are localized to the plasma membrane. This spatial separation raises the question how PTP1B can interact with its targets. In our study we demonstrate direct interaction of PTP1B with the Ser/Thr kinase PKCdelta, the non-receptor tyrosine kinase Src and the insulin receptor which all are key enzymes in cellular signaling cascades. Protein complex formation was visualized in vivo using Bimolecular Fluorescence Complementation (BiFC). We demonstrate that complex formation of PTP1B with plasma membrane-anchored proteins is possible without detachment of PTP1B from the ER. Our data indicate that the dynamic ER membrane network is in constant contact to the plasma membrane. Local attachments of the two membrane systems enable a direct communication of ER- and plasma membrane-anchored proteins. The reported formation of membrane junctions is an important step towards the understanding of signal transmissions between the ER and the plasma membrane.
 ...
PMID:Direct interaction between ER membrane-bound PTP1B and its plasma membrane-anchored targets. 1709 89

The ability of vitamin E to modulate signal transduction and gene expression has been observed in numerous studies; however, the detailed molecular mechanisms involved are often not clear. The eight natural vitamin E analogues and synthetic derivatives affect signal transduction with different potency, possibly reflecting their different ability to interact with specific proteins. Vitamin E modulates the activity of several enzymes involved in signal transduction, such as protein kinase C, protein kinase B, protein tyrosine kinases, 5-, 12-, and 15-lipoxygenases, cyclooxygenase-2, phospholipase A2, protein phosphatase 2A, protein tyrosine phosphatase, and diacylglycerol kinase. Activation of some these enzymes after stimulation of cell surface receptors with growth factors or cytokines can be normalized by vitamin E. At the molecular level, the translocation of several of these enzymes to the plasma membrane is affected by vitamin E, suggesting that the modulation of protein-membrane interactions may be a common theme for vitamin E action. In this review the main effects of vitamin E on enzymes involved in signal transduction are summarized and the possible mechanisms leading to enzyme modulation evaluated. The elucidation of the molecular and cellular events affected by vitamin E could reveal novel strategies and molecular targets for developing similarly acting compounds.
 ...
PMID:Modulation of signal transduction by vitamin E. 1732 Jan 64

In dopaminergic neurons, chondroitin sulfate (CS) proteoglycans play important roles in neuronal development and regeneration. However, due to the complexity and heterogeneity of CS, the precise structure of CS with biological activity and the molecular mechanisms underlying its influence on dopaminergic neurons are poorly understood. In this study, we investigated the ability of synthetic CS oligosaccharides and natural polysaccharides to promote the neurite outgrowth of mesencephalic dopaminergic neurons and the signaling pathways activated by CS. CS-E polysaccharide, but not CS-A, -C or -D polysaccharide, facilitated the neurite outgrowth of dopaminergic neurons at CS concentrations within the physiological range. The stimulatory effect of CS-E polysaccharide on neurite outgrowth was completely abolished by its digestion into disaccharide units with chondroitinase ABC. Similarly to CS-E polysaccharide, a synthetic tetrasaccharide displaying only the CS-E sulfation motif stimulated the neurite outgrowth of dopaminergic neurons, whereas a CS-E disaccharide or unsulfated tetrasaccharide had no effect. Analysis of the molecular mechanisms revealed that the action of the CS-E tetrasaccharide was mediated through midkine-pleiotrophin/protein tyrosine phosphatase zeta and brain-derived neurotrophic factor/tyrosine kinase B receptor pathways, followed by activation of the two intracellular phospholipase C (PLC) signaling cascades: PLC/protein kinase C and PLC/inositol 1,4,5-triphosphate/inositol 1,4,5-triphosphate receptor signaling leading to intracellular Ca(2+) concentration-dependent activation of Ca(2+)/calmodulin-dependent kinase II and calcineurin. These results indicate that a specific sulfation motif, in particular the CS-E tetrasaccharide unit, represents a key structural determinant for activation of midkine, pleiotrophin and brain-derived neurotrophic factor-mediated signaling, and is required for the neuritogenic activity of CS in dopaminergic neurons.
 ...
PMID:Activation of phospholipase C pathways by a synthetic chondroitin sulfate-E tetrasaccharide promotes neurite outgrowth of dopaminergic neurons. 1768 Sep 89

The present study was designed to explore whether L-carnitine (CA) regulates insulin signaling and modulates the changes in liver in a well-characterized insulin resistant rat model. Adult male Wistar rats were divided into 4 groups. Groups I and IV animals received starch-based control diet, while groups II and III rats were fed a high fructose-diet (60 g/100 g). Groups III and IV animals additionally received CA (300 mg/kg/day i.p). After a period of 60 days hepatic tyrosine phosphorylation status was determined by assaying protein tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK) activities. Oxidative damage was monitored by immunohistochemical localization of 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT) and dinitrophenol (DNP)-protein adducts. In addition protein kinase C beta II (PKC beta II) expression, propidium iodide staining of isolated hepatocytes and histology of liver tissue were determined to examine liver integrity. Fructose-fed rats displayed reduced insulin action, increased expression of PKC beta II, altered histology, fragmentation of hepatocyte nuclear DNA, and accumulation of oxidatively modified proteins. Simultaneous treatment with CA alleviated the abnormalities associated with fructose feeding. In summary the data suggest that elevated oxidative damage and PKC expression could in part induce insulin resistance and CA has beneficial impact on liver during insulin resistance with modulatory effects at the post-receptor level.
 ...
PMID:Beneficial impact of L-carnitine in liver: a study in a rat model of syndrome X. 1771 46

Signal transduction exerted by the microenvironment around the primary tumor locus may trigger tumor metastasis especially at the migration stage. Sustained mitogen activated protein kinase (MAPK) signaling involved in uncontrolled tumor cell migration rely on the cross talks between integrin, receptor tyrosine kinase (RTK) and protein kinase C (PKC). The molecular mechanisms for cross talking between these migration-related signal cascades leading to sustained cell migration are reviewed, focusing on the focal adhesion scaffold protein paxillin as the platform for signal integration. We proposed reactive oxygen species (ROS) as the critical signal messenger sustaining these signal cascades. For the cross talk of integrin with RTK, ROS may suppress paxillin-associated protein tyrosine phosphatase (PTP-PEST) relieving its negative regulatory effects. For the cross talk of integrin with PKC, PKC itself may phosphorylate integrin or paxillin-associated focal adhesion proteins to induce generation of ROS which may reactivate PKC. In the future, ROS will be validated as the promising therapeutic targets for prevention of tumor metastasis.
 ...
PMID:Signal cross talks for sustained MAPK activation and cell migration: the potential role of reactive oxygen species. 1829 6

Exercise-induced airway obstruction is thought to involve evaporative water loss and hyperosmolarity of the airway surface liquid. Hyperosmolar challenge of the epithelium of isolated, perfused guinea pig trachea rapidly alters transepithelial potential difference (V(t)), and it elicits smooth muscle relaxation mediated by epithelium-derived relaxing factor (EpDRF). In many cell types, protein kinases mediate responses to hyperosmolarity and regulatory volume increase. In this study, inhibitors were used to investigate the involvement of kinases and phosphatases in bioelectric responses of epithelium to hyperosmolarity and their possible relationship to EpDRF-mediated relaxation. After contraction of the perfused trachea with extraluminal methacholine, D-mannitol applied intraluminally (< or = 80 mosM) increased V(t) and elicited dilation of the smooth muscle with a similar concentration-dependence; higher concentrations decreased V(t). In tracheas exposed to 30 mosM D-mannitol (approximately EC(50)), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580) and SKF 86002 [6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridyl)imidazo[2,1-b]thiazole] (p38 inhibitors) potentiated the dilation, whereas SP 600125 [anthra[1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone] and dicumarol [c-Jun NH(2)-terminal kinase (JNK) inhibitors], chelerythrine [nonselective protein kinase C (PKC) inhibitor], and NaAsO(2) (mitogen-activated protein kinase stress inducer) and Na(3)VO(4) (protein tyrosine phosphatase inhibitor) inhibited the hyperpolarization. Large increases in the phosphorylation of p38 and JNK occurred at concentrations higher than those needed to elicit functional responses. The phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002) and Na(3)VO(4) did not affect the V(t) responses, but they inhibited methacholine-induced constriction; SP 600125 and dicumarol potentiated, and chelerythrine inhibited, methacholine-induced epithelial hyperpolarization. These results suggest that JNK, PKC, and phosphatase(s) are involved in hyperosmolarity-induced hyperpolarization of the tracheal epithelium but that p38 is involved in EpDRF-mediated relaxation.
 ...
PMID:Hyperosmolarity-induced dilation and epithelial bioelectric responses of guinea pig trachea in vitro: role of kinase signaling. 1841 57

Inhibitory killer Ig-like receptors (KIR), expressed by human natural killer cells and effector memory CD8(+) T-cell subsets, bind HLA-C molecules and suppress cell activation through recruitment of the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1). To further analyze the still largely unclear role of inhibitory KIR receptors on CD4(+) T cells, KIR2DL1 transfectants were obtained from a CD4(+) T-cell line and primary cells. Transfection of CD4(+) T cells with KIR2DL1 dramatically increased the T-cell receptor (TCR)-induced production of interleukin-2 independently of ligand binding but inhibited TCR-induced activation after ligation. KIR-mediated costimulation of TCR activation involves intact KIR2DL1-ITIM phosphorylation, SHP-2 recruitment, and PKC- phosphorylation. Synapses leading to activation were characterized by an increase in the recruitment of p-Tyr, SHP-2, and p-PKC-, but not of SHP-1. Interaction of KIR2DL1 with its ligand led to a strong synaptic accumulation of KIR2DL1 and the recruitment of SHP-1/2, inhibiting TCR-induced interleukin-2 production. KIR2DL1 may induce 2 opposite signaling outputs in CD4(+) T cells, depending on whether the KIR receptor is bound to its ligand. These data highlight unexpected aspects of the regulation of T cells by KIR2DL1 receptors, the therapeutic manipulation of which is currently being evaluated.
 ...
PMID:Two opposite signaling outputs are driven by the KIR2DL1 receptor in human CD4+ T cells. 1857 28

The inward l-dihydroxyphenylalanine (L-dopa) transport supplies renal proximal tubule cells (PTCs) with the precursor for dopamine synthesis. We have previously described insulin-induced stimulation of L-dopa uptake into PTCs. In the present paper we examined insulin-related signaling pathways involved in the increase of l-dopa transport into isolated rat PTCs. Insulin (50-500 microU/ml) increased L-dopa uptake by PTCs, reaching the maximal increment (60% over the control) at 200 microU/ml. At this concentration, insulin also increased insulin receptor tyrosine phosphorylation. Both effects were abrogated by the tyrosine kinase inhibitor genistein (5 microM). In line, inhibition of the protein tyrosine phosphatase by pervanadate (0.2-100 microM) caused a concentration-dependent increase in both the uptake of L-dopa (up to 400%) and protein tyrosine phosphorylation. A synergistic effect between pervanadate and insulin on L-dopa uptake was observed only when threshold (0.2 microM), but not maximal (5 microM), concentrations of pervanadate were assayed. Insulin-induced stimulation of L-dopa uptake was also abolished by inhibition of phosphatidylinositol 3-kinase (PI3K; 100 nM wortmannin, and 25 microM LY-294002) and protein kinase C (PKC; 1 microM RO-318220). Insulin-induced activation of PKC-zeta was confirmed in vitro by its translocation from the cytosol to the membrane fraction, and in vivo by immunohistochemistry studies. Insulin caused a wortmannin-sensitive increase in Akt/protein kinase B (Akt/PKB) phosphorylation and a dose-dependent translocation of Akt/PKB to the membrane fraction. Our findings suggest that insulin activates PKC-zeta, and Akt/PKB downstream of PI3K, and that these pathways contribute to the insulin-induced increase of L-dopa uptake into PTCs.
 ...
PMID:Signaling cascade of insulin-induced stimulation of L-dopa uptake in renal proximal tubule cells. 1884 30


<< Previous 1 2 3 4 5 6 7 8 9 10