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)

Activation of human peripheral blood neutrophils by pathogens or by phorbol myristate acetate (PMA), fMLP, or myeloid growth factors generates a respiratory burst in which superoxide production plays an important role in killing invading microorganisms. Although the increased energy demands of activated neutrophils would be expected to be associated with increased glucose uptake and utilization, previous studies have shown that PMA inhibits 2-deoxyglucose (2-DOG) uptake. In this study, we show that PMA activation of neutrophils, isolated by methods not involving hypotonic lysis, increases the rate of 2-DOG uptake and results in a 1.6-fold to 2.1-fold increase in transporter affinity for glucose without changing Vmax. Increased transporter affinity in response to PMA was also observed with 3-O-methyglucose, which is not phosphorylated, and inclusion of glucose in the activation medium further increased respiratory burst activity. Increased 2-DOG uptake and increased transporter affinity for glucose were also observed with the peptide activator, fMLP, and with granulocyte-macrophage colony-stimulating factor (GM-CSF). The protein kinase C (PKC) inhibitor, calphostin C, and the tyrosine kinase inhibitor, genistein, inhibited both PMA- and fMLP-stimulated 2-DOG uptake. In contrast, genistein inhibited fMLP-induced superoxide production, but had little effect on the PMA-induced response, while staurosporine differentially inhibited PMA-induced superoxide production. These results show that neutrophil activation involves increased glucose transport and intrinsic activation of glucose transporter molecules. Both tyrosine kinases and PKC are implicated in the activation process.
 ...
PMID:Acute regulation of glucose transport after activation of human peripheral blood neutrophils by phorbol myristate acetate, fMLP, and granulocyte-macrophage colony-stimulating factor. 942 21

In an attempt to understand the subcellular signals after activation of adenosine A-1 receptors, paeoniflorin was employed to incubate with rat white adipocytes in vitro. Translocation of protein kinase C (PKC) beta-subtype from cytosol to membrane was enhanced by an incubation with paeoniflorin in a concentration-dependent manner similar to that of porcine insulin. Also, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) inhibited this action of paeoniflorin in a concentration-related fashion and it markedly attenuated the action of paeoniflorin at a concentrations sufficient to block the action of adenosine. Moreover, chelerythrine inhibited the paeoniflorin-stimulated translocation of PKC in a way similar to that stimulated by porcine insulin. Subcellular inhibition is considered because stimulation of porcine insulin was not modified by DPCPX at concentrations sufficient to block adenosine A-1 receptors. Similar results were also observed in adipocytes regarding the translocation of glucose transporter (GLUT4) from cytosol to membrane. Thus, we found that paeoniflorin can activate adenosine A-1 receptors to increase the translocations of PKC and GLUT4, two major signals for glucose uptake, from cytosol to membrane of the white adipocytes in rats.
 ...
PMID:Stimulatory effect of paeoniflorin on adenosine A-1 receptors to increase the translocation of protein kinase C (PKC) and glucose transporter (GLUT 4) in isolated rat white adipocytes. 958 41

We have used differential display to identify genes whose expression is altered in type 2 diabetes thus contributing to its pathogenesis. One mRNA is overexpressed in fibroblasts from type 2 diabetics compared with non-diabetic individuals, as well as in skeletal muscle and adipose tissues, two major sites of insulin resistance in type 2 diabetes. The levels of the protein encoded by this mRNA are also elevated in type 2 diabetic tissues; thus, we named it PED for phosphoprotein enriched in diabetes. PED cloning shows that it encodes a 15 kDa phosphoprotein identical to the protein kinase C (PKC) substrate PEA-15. The PED gene maps on human chromosome 1q21-22. Transfection of PED/PEA-15 in differentiating L6 skeletal muscle cells increases the content of Glut1 transporters on the plasma membrane and inhibits insulin-stimulated glucose transport and cell-surface recruitment of Glut4, the major insulin-sensitive glucose transporter. These effects of PED overexpression are reversed by blocking PKC activity. Overexpression of the PED/PEA-15 gene may contribute to insulin resistance in glucose uptake in type 2 diabetes.
 ...
PMID:PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. 967 3

The sphingomyelin derivative ceramide is a signaling molecule implicated in numerous physiological events. Recently published reports indicate that ceramide levels are elevated in insulin-responsive tissues of diabetic animals and that agents which trigger ceramide production inhibit insulin signaling. In the present series of studies, the short-chain ceramide analog C2-ceramide inhibited insulin-stimulated glucose transport by approximately 50% in 3T3-L1 adipocytes, with similar reductions in hormone-stimulated translocation of the insulin-responsive glucose transporter (GLUT4) and insulin-responsive aminopeptidase. C2-ceramide also inhibited phosphorylation and activation of Akt, a molecule proposed to mediate multiple insulin-stimulated metabolic events. C2-ceramide, at concentrations which antagonized activation of both glucose uptake and Akt, had no effect on the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) or the amounts of p85 protein and phosphatidylinositol kinase activity that immunoprecipitated with anti-IRS-1 or antiphosphotyrosine antibodies. Moreover, C2-ceramide also inhibited stimulation of Akt by platelet-derived growth factor, an event that is IRS-1 independent. C2-ceramide did not inhibit insulin-stimulated phosphorylation of mitogen-activated protein kinase or pp70 S6-kinase, and it actually stimulated phosphorylation of the latter in the absence of insulin. Various pharmacological agents, including the immunosuppressant rapamycin, the protein synthesis inhibitor cycloheximide, and several protein kinase C inhibitors, were without effect on ceramide's inhibition of Akt. These studies demonstrate ceramide's capacity to inhibit activation of Akt and imply that this is a mechanism of antagonism of insulin-dependent physiological events, such as the peripheral activation of glucose transport and the suppression of apoptosis.
 ...
PMID:Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. 971 Jun 29

Glucose transport in response to angiotensin II (AII) was assessed in cultured vascular smooth muscle (VSM) cells by measuring the uptake of [3H]-2-deoxyglucose, a radiolabeled non-metabolizable glucose analog. Significant stimulation occurred by 2 hr of exposure with the maximum effect being observed between 6 and 8 hr. All effects were concentration dependent with a threshold response being detected at 0.1 nM. AII-stimulated transport was blocked by saralasin, an AII receptor antagonist, indicating that AII binding to a specific receptor is required for AII to elicit the transport response. AII-stimulated transport was also blocked when cells were incubated with cycloheximide for 6 hr, suggesting that protein synthesis is required for the long-term effects of AII on glucose transport. A specific protein synthesized in response to AII stimulation was the GLUT 1 glucose transporter as assessed by western blot analysis. Inhibition of protein kinase C (PKC) by bisindolylmaleimide and staurosporine did not affect VSM responsiveness to AII, suggesting that AII is capable of stimulating glucose transport through a PKC-independent mechanism; however, VSM responsiveness to AII did appear to be dependent upon the presence of extracellular calcium. The importance of calmodulin in mediating the response of VSM cells to AII was indicated by the inhibition of AII-stimulated glucose transport when VSM cells were incubated in the presence of the calmodulin inhibitors, calmidazolium and W7. Finally, glucose uptake increased with decreasing levels of glucose in the incubation medium. This was accompanied by a corresponding decrease in the relative effectiveness of AII in stimulating glucose uptake.
 ...
PMID:Regulation of glucose transport by angiotensin II and glucose in cultured vascular smooth muscle cells. 973 49

The plasminogen activator system is known to play a crucial role in the angiogenesis process by modulating the adhesive properties of endothelial cells to the extracellular matrix and cell-cell interaction. In the present study, we demonstrated that the urokinase-type plasminogen activator (u-PA) induced neovascular growth in the avascular rabbit cornea and dose-dependently promoted growth, chemotaxis, and matrix invasion of cultured endothelial cells. Interaction between u-PA and its receptor appears to be mandatory for the angiogenic effect of u-PA because monoclonal antibodies anti-u-PA and anti-u-PA receptor (u-PAR) blocked the proangiogenic effects of u-PA at the endothelial cell level. We then assessed the signaling pathway activated in endothelial cells by u-PA. u-PAR activation by u-PA produced de novo synthesis of diacylglycerol (DAG) from glucose by a cytochalasin B-inhibitable mechanism, indicating the involvement of a specific glucose transporter (GLUT). Endothelial cells expressed GLUT2, whose activation was tyrosine kinase-dependent and protein kinase C (PKC)-independent. The increase of glucose uptake led to DAG production, which resulted in PKC activation/translocation. Impairment of u-PAR availability by monoclonal antibodies and by antisense oligonucleotides (aODN) against u-PAR mRNA inhibited glucose uptake, DAG neosynthesis, and PKC activation, resulting in the blockade of endothelial cell proliferation, chemotaxis, and chemoinvasion. These data suggest that u-PAR activation consequent to the binding of u-PA can be regarded as an "angiogenic switch" and disclose the possibility that an anti-u-PAR aODN strategy may efficiently target endothelial cell function to control angiogenesis in vivo.
 ...
PMID:Urokinase-dependent angiogenesis in vitro and diacylglycerol production are blocked by antisense oligonucleotides against the urokinase receptor. 975 55

Phosphoinositide (PI) 3-kinase contributes to a wide variety of biological actions, including insulin stimulation of glucose transport in adipocytes. Both Akt (protein kinase B), a serine-threonine kinase with a pleckstrin homology domain, and atypical isoforms of protein kinase C (PKCzeta and PKClambda) have been implicated as downstream effectors of PI 3-kinase. Endogenous or transfected PKClambda in 3T3-L1 adipocytes or CHO cells has now been shown to be activated by insulin in a manner sensitive to inhibitors of PI 3-kinase (wortmannin and a dominant negative mutant of PI 3-kinase). Overexpression of kinase-deficient mutants of PKClambda (lambdaKD or lambdaDeltaNKD), achieved with the use of adenovirus-mediated gene transfer, resulted in inhibition of insulin activation of PKClambda, indicating that these mutants exert dominant negative effects. Insulin-stimulated glucose uptake and translocation of the glucose transporter GLUT4 to the plasma membrane, but not growth hormone- or hyperosmolarity-induced glucose uptake, were inhibited by lambdaKD or lambdaDeltaNKD in a dose-dependent manner. The maximal inhibition of insulin-induced glucose uptake achieved by the dominant negative mutants of PKClambda was approximately 50 to 60%. These mutants did not inhibit insulin-induced activation of Akt. A PKClambda mutant that lacks the pseudosubstrate domain (lambdaDeltaPD) exhibited markedly increased kinase activity relative to that of the wild-type enzyme, and expression of lambdaDeltaPD in quiescent 3T3-L1 adipocytes resulted in the stimulation of glucose uptake and translocation of GLUT4 but not in the activation of Akt. Furthermore, overexpression of an Akt mutant in which the phosphorylation sites targeted by growth factors are replaced by alanine resulted in inhibition of insulin-induced activation of Akt but not of PKClambda. These results suggest that insulin-elicited signals that pass through PI 3-kinase subsequently diverge into at least two independent pathways, an Akt pathway and a PKClambda pathway, and that the latter pathway contributes, at least in part, to insulin stimulation of glucose uptake in 3T3-L1 adipocytes.
 ...
PMID:Requirement of atypical protein kinase clambda for insulin stimulation of glucose uptake but not for Akt activation in 3T3-L1 adipocytes. 981 85

Exposure of Clone 9 cells, a rat liver cell line, to hydrogen peroxide (H2O2) resulted in a striking and rapid stimulation of glucose transport (8- to 10-fold in 1 h). A comparable response was found in 3T3-L1 preadipocytes, C2C12 myoblasts, and NIH 3T3 fibroblasts, which, similar to Clone 9 cells, express only the Glut 1 glucose transporter isoform. The enhancement of glucose transport in Clone 9 cells in response to H2O2 was significantly attenuated by genistein and the phospholipase C (PLC) inhibitor, U73122. Exposure to H2O2 resulted in a rise in cell sn-1,2-diacylglycerol content, and the rise was significantly inhibited by U73122. Moreover, the H2O2-induced stimulation of glucose transport was significantly blocked by thapsigargin. Neither staurosporine nor a 24-h preincubation in the presence of phorbol-12-myristate-13-acetate (TPA) affected the stimulatory effect of hydrogen peroxide on glucose transport. The activity of big mitogen-activated kinase (BMK1) and of stress-activated protein kinase (SAPK), both members of mitogen-activated protein kinases, were enhanced in response to exposure to H2O2; however, neither protein kinase appeared to be linked to the enhancement of glucose transport by H2O2. It is concluded that the stimulation of glucose transport in response to H2O2 is independent of changes in PKC, BMK1, and SAPK activity, and is mediated, at least in part, through H2O2-induced stimulation of protein tyrosine kinase and PLC pathways.
 ...
PMID:Mechanism of stimulation of glucose transport by H2O2: role of phospholipase C. 991 35

Exposure of Clone 9 cells, a nontransformed rat liver cell line expressing only the Glutl glucose transporter isoform, to the guanylyl cyclase inhibitor LY-83583 was found to stimulate the rate of glucose transport (approximately 7- to 8-fold in 1 h). A similar response to LY-83583 was found in NIH 3T3 fibroblasts, 3T3-L1 pre-adipocytes, and C2C12 myoblasts. Neither the rate of glucose transport in cells under control conditions nor the effect of LY-83583 on glucose transport was altered by 10, 50, or 100 microM 8-bromo-cGMP or by addition of cGMP phosphodiesterase inhibitors, zaprinast, or dipyridamole suggesting that glucose transport and the response to LY-83583 is independent of cGMP levels. In addition, the effect of LY-83583 on glucose transport was not mediated by inhibition of oxidative phosphorylation, since exposure to the agent resulted in no increase in lactate production. Incubation of Clone 9 cells in the presence of the phospholipase C inhibitor U73122, however, attenuated the glucose transport response to LY-83583. Moreover, exposure to LY-83583 resulted in a rise in cell diacylglycerol content, and preincubation with U73122 significantly diminished this rise as well as the glucose transport response to LY-83583. The stimulatory effect of LY-83583 on glucose transport was significantly blocked by thapsigargin. Down-regulation of protein kinase C activity, resulting from 24 h pre-incubation in the presence of 160 nM phorbol-12-myristate 13-acetate, did not attenuate the glucose transport response to LY-83583. It is concluded that the stimulation of glucose transport in response to LY-83583 is independent of changes in cGMP levels, is not mediated by inhibition of oxidative phosphorylation, and is mediated, at least in part, through stimulation of the phospholipase C pathway.
 ...
PMID:LY-83583 stimulates glucose transporter-1-mediated glucose transport independent of changes in cGMP levels. 1006 58

The combined effect of arachidonic acid and cAMP on glucose transport was examined in 3T3-L1 adipocytes. In cells pre-treated with arachidonic acid and increasing concentrations of 8-bromo cAMP for 8 h, although either agent alone enhanced glucose uptake, the simultaneous presence of both agents dramatically increased 2-deoxyglucose uptake in a synergistic fashion. Insulin-stimulated glucose transport, on the other hand, was only slightly affected. The synergistic effect of these two agents was abolished in the presence of cycloheximide. Immunoblot analysis revealed that the contents of ubiquitous glucose transporter (GLUT1) in total cellular and plasma membranes were similarly augmented in cells pre-treated with both arachidonic acid and 8-bromo cAMP, to a greater extent than the additive effect of each agent alone. The content of GLUT4, on the other hand, was not altered under the same experimental conditions. In cells pre-treated with 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA) for 24 h to down-regulate protein kinase C (PKC), the subsequent synergistic effect of arachidonic acid and 8-bromo cAMP was greatly inhibited. In addition, pre-treatment with both PMA and 8-bromo cAMP enhanced glucose transport in a similarly synergistic fashion. Thus the present study seems to indicate that arachidonic acid may act with cAMP in a synergistic way to increase glucose transport by a PKC-dependent mechanism. The increased activity may be accounted for by increased GLUT1 synthesis.
 ...
PMID:Synergistic effect of arachidonic acid and cyclic AMP on glucose transport in 3T3-L1 adipocytes. 1020 45


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