EC:2.7.11.13 - FACTA Search

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)

Arachidonic acid (AA) directly activates protein kinases C (PKC) and may thereby serve as a regulatory signal during cell stimulation. The effect, however, requires a > or =20 microm concentration of the fatty acid. We find that human polymorphonuclear neutrophils (PMN) equilibrated with a ligand for the diacylglycerol receptor on PKC, [(3)H]phorbol dibutyrate (PDB), increased binding of [(3)H]PDB within 15 s of exposure to > or =10-30 nm AA. Other unsaturated fatty acids, but not a saturated fatty acid, likewise stimulated PDB binding. These responses, similar to those caused by chemotactic factors, resulted from a rise in the number of diacylglycerol receptors that were plasma membrane-associated and therefore accessible to PDB. Unlike chemotactic factors, however, AA was fully active on cells overloaded with Ca(2+) chelators. The major metabolites of AA made by PMN, leukotriene B(4) and 5-hydroxyicosatetraenoate, did not mimic AA, and an AA antimetabolite did not block responses to AA. AA also induced PMN to translocate cytosolic PKCalpha, beta(II), and delta to membranes. This response paralleled PDB binding with respect to dose requirements, time, Ca(2+)-independence, resistance to an AA antimetabolite, and induction by another unsaturated fatty acid but not by a saturated fatty acid. Finally, HEK 293 cells transfected with vectors encoding PKCbeta(I) or PKCdelta fused to the reporter enhanced green fluorescent protein (EGFP) were studied. AA caused EGFP-PKCbeta translocation from cytosol to plasma membrane at > or =0.5 microm, and EGFP-PKCdelta translocation from cytosol to nuclear and, to a lesser extent, plasma membrane at as little as 30 nm. We conclude that AA induces PKC translocations to specific membrane targets at concentrations 2-4 orders of magnitude below those activating the enzymes. These responses, at least as they occur in PMN, do not require changes in cell Ca(2+) or oxygenation of the fatty acid. AA seems more suited for signaling the movement than activation of PKC.
...
PMID:Protein kinases C translocation responses to low concentrations of arachidonic acid. 1132 12

We have previously shown that interleukin-1 receptor-generated ceramide induces growth arrest in smooth muscle pericytes by inhibiting an upstream kinase in the extracellular signal-regulated kinase (ERK) cascade. Here, we now report the mechanism by which ceramide inhibits ERK activity. Ceramide renders the human embryonic kidney 293 cells (HEK 293) resistant to the mitogenic actions of growth factors and activators of protein kinase C (PKC). A role for PKC to mediate ceramide inhibition of growth factor-induced ERK activity and mitogenesis is suggested, as exogenous ceramide directly inhibits both immunoprecipitated and recombinant PKC-epsilon activities. To confirm that PKC-epsilon is necessary for ceramide-inhibited ERK activity, HEK 293 cells were transfected with a dominant-negative mutant of PKC-epsilon (DeltaPKC-epsilon). These transfected cells respond to insulin-like growth factor I (IGF-I) with a significantly decreased ERK activity that is not further reduced by ceramide treatment. Coimmunoprecipitation studies reveal that the treatment with IGF-I induces the association of ERK with PKC-epsilon but not with PKC-zeta. Ceramide treatment significantly inhibits the IGF-I-induced PKC-epsilon interaction with bioactive phosphorylated ERK. Ceramide also inhibits IGF-I-induced PKC-epsilon association with Raf-1, an upstream kinase of ERK. Together, these studies demonstrate that ceramide exerts anti-mitogenic actions by limiting the ability of PKC-epsilon to form a signaling complex with Raf-1 and ERK.
...
PMID:Inhibitory actions of ceramide upon PKC-epsilon/ERK interactions. 1135 Jul 35

Phosphorylation of c-Jun at Ser 63/73 by the c-Jun N-terminal kinase (JNK) potentiates the transactivation function of c-Jun. Protein kinase D (PKD), a downstream effector of protein kinase C (PKC), has been implicated in the attenuation of epidermal growth factor (EGF)-induced activation of JNK. In order to determine whether activated PKD is sufficient to modulate the EGF-JNK-c-Jun pathway, we have developed a cellular model system, utilizing human embryonic kidney cells (HEK 293), in which stably transfected, constitutively active or kinase dead mutants of PKD can be inducibly expressed by the insect hormone, ecdysone. Induced expression of constitutively active, but not kinase dead PKD, suppressed EGF stimulated c-Jun phosphorylation at Ser 63, demonstrating that activated PKD is sufficient to suppress c-Jun phosphorylation. This is the first demonstration that PKD modulates phosphorylation of the proto-oncogene c-Jun at a site critical for its ability to mediate cell proliferation and differentiation.
...
PMID:Protein kinase D is sufficient to suppress EGF-induced c-Jun Ser 63 phosphorylation. 1140 72

The importance of activation loop phosphorylation in the regulation of protein kinase D (PKD/protein kinase C (PKC) mu) activity has become controversial. In order to clarify the mechanism(s) of PKD activation, we developed a novel phosphospecific antibody recognizing phosphorylated Ser(748) in PKD (pS748). Western blot analysis with the pS748 antibody, carried out with a variety of PKD forms and in a variety of cell types including full-length PKD transfected in COS-7 and HEK 293 cells, a green fluorescent protein-PKD fusion protein transfected in either Swiss 3T3 fibroblasts or Madin-Darby canine kidney epithelial cells, and endogenous PKD expressed in A20 lymphocytes and Rat-1 fibroblasts, indicated that Ser(748) phosphorylation was absent from unstimulated cells. In contrast, dramatic increases in Ser(748) phosphorylation were induced by phorbol esters, bombesin, or cross-linking of B lymphocyte antigen receptors or by cotransfection with active PKCepsilon or PKCeta. Western analysis using a second phosphospecific antibody, which primarily recognizes PKD phosphorylated at Ser(744), revealed that Ser(744) phosphorylation accompanies Ser(748) phosphorylation during PKD activation in vivo. Ser(744)/Ser(748) phosphorylation requires PKC but not PKD activity, indicative of transphosphorylation. Our results provide new experimental evidence indicating that activation loop phosphorylation at Ser(744) and Ser(748) occurs during PKD activation in vivo and support the notion of a PKC-PKD phosphorylation cascade.
...
PMID:Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo. 1141 May 86

The involvement of iron (Fe) transporters in the uptake of cadmium (Cd) was examined in Madin-Darby kidney cells (MDCK). The uptake of Cd displayed properties that are associated with the Fe transporter divalent metal transporter 1 (DMT1). For example, the uptake of Cd and Fe was reduced by altering the cell membrane potential. The uptake of Cd was blocked by Fe, and the uptake of Fe was blocked by Cd. Also, the uptake of Cd and Fe was higher in MDCK cells bathed in a buffer at low pH. Increased uptake of Fe and Cd was observed in the HEK-293 cell line overexpressing DMT1. Overnight treatment of MDCK cells with the protein kinase C activator phorbol 12,13-dibutyrate (PDBu) resulted in increased uptake of Cd and Fe and an increase in DMT1 mRNA. An increase in newly transcribed DMT1 mRNA was not observed, suggesting that PDBu does not increase DMT1 mRNA by activating transcription. Rather, the increase was most likely due to greater stability of DMT1 mRNA, because the rate of degradation of DMT1 mRNA was slower in MDCK cells treated with PDBu. Our results suggest that Fe and Cd are transported in MDCK cells by a transporter with biochemical properties similar to those of DMT1.
...
PMID:Involvement of DMT1 in uptake of Cd in MDCK cells: role of protein kinase C. 1150 56

Inhibition of calcium channels by G-protein-coupled receptors depends on the nature of the Galpha subunit, although the Gbetagamma complex is thought to be responsible for channel inhibition. Ca currents in hypothalamic neurons and N-type calcium channels expressed in HEK-293 cells showed robust inhibition by G(i)/G(o)-coupled galanin receptors (GalR1), but not by Gq-coupled galanin receptors (GalR2). However, deletions in the C terminus of alpha(1B-1) produced Ca channels that were inhibited after activation of both GalR1 and GalR2. Inhibition of protein kinase C (PKC) also revealed Ca current modulation by GalR2. Imaging studies using green fluorescent protein fusions of the C terminus of alpha(1B) demonstrated that activation of the GalR2 receptor caused translocation of the C terminus of alpha(1B-1) to the membrane and co-localization with Galphaq and PKC. Similar translocation was not seen with a C-terminal truncated splice variant, alpha(1B-2). Immunoprecipitation experiments demonstrated that Galphaq interacts directly with the C terminus of the alpha(1B) subunit. These results are consistent with a model in which local activation of PKC by channel-associated Galphaq blocks modulation of the channel by Gbetagamma released by Gq-coupled receptors.
...
PMID:The C terminus of the Ca channel alpha1B subunit mediates selective inhibition by G-protein-coupled receptors. 1156 49

The endocytosis of GABA(A) receptors was investigated in HEK 293 cells expressing receptor alpha1beta2- and alpha1beta2gamma2-subunit combinations. For assessment of internalized receptors by radioimmunoassay or immunofluorescence, a triple c-myc epitope was introduced into the amino terminus of the beta2 subunit. An assay based on biotin inaccessibility was used for alpha1 subunits. GABA(A) alpha1beta2- and alpha1beta2gamma2-subunit receptors were internalized with a t(1/2) of 5.5 min at 37 degrees C. With both subunit combinations, phorbol 12-myristate 3-acetate enhanced internalization by nearly 100%. Treatment of the cells with hypertonic sucrose prevented both the basal and phorbol ester-induced endocytosis of GABA(A) receptors. GF 109203X, an inhibitor of protein kinase C, blocked the stimulation by phorbol ester but had no detectable effect on basal receptor endocytosis. Coexpression with a dominant-negative mutant of dynamin (K44A) led to a 100% enhancement of GABA(A) receptor internalization, while the endocytosis of beta(2)-adrenergic receptors was completely prevented. The results indicate that the endocytosis of GABA(A) alpha1beta2-subunit receptors in HEK cells is constitutive, positively modulated by activation of protein kinase C, and occurs by a mechanism that requires neither the participation of a GABA(A) receptor gamma2 subunit nor a clathrin-mediated pathway.
...
PMID:Clathrin-independent endocytosis of GABA(A) receptors in HEK 293 cells. 1170 95

Albert Renold strived to gain insight into the abnormalities of human diabetes by defining the pathophysiology of the disease peculiar to a given animal. He investigated the Israeli desert-derived spiny mice (Acomys cahirinus), which became obese on fat-rich seed diet. After a few months hyperplasia and hypertrophy of beta-cells occurred leading to a sudden rupture, insulin loss and ketosis. Spiny mice were low insulin responders, which is probably a characteristic of certain desert animals, protecting against insulin oversecretion when placed on an abundant diet. We have compared the response to overstimulation of several mutant diabetic species and nutritionally induced nonmutant animals when placed on affluent diet. Some endowed with resilient beta-cells sustain long-lasting oversecretion, compensating for the insulin resistance, without lapsing into overt diabetes. Some with labile beta cells exhibit apoptosis and lose their capacity of coping with insulin resistance after a relatively short period. The wide spectrum of response to insulin resistance among different diabetes prone species seems to represent the varying response of human beta cells among the populations. In search for the molecular background of insulin resistance resulting from overnutrition we have studied the Israeli desert gerbil Psammomys obesus (sand rat), which progresses through hyperinsulinemia, followed by hyperglycemia and irreversible beta cell loss. Insulin resistance was found to be the outcome of reduced activation of muscle insulin receptor tyrosine kinase by insulin, in association with diminished GLUT4 protein and DNA content and overexpression of PKC isoenzymes, notably of PKCepsilon. This overexpression and translocation to the membrane was discernible even prior to hyperinsulinemia and may reflect the propensity to diabetes in nondiabetic species and represent a marker for preventive action. By promoting the phosphorylation of serine/threonine residues on certain proteins of the insulin signaling pathway, PKCepsilon exerts a negative feedback on insulin action. PKCepsilon was also found to attenuate the activity of PKB and to promote the degradation of insulin receptor, as determined by co-incubation in HEK 293 cells. PKCepsilon overexpression was related to the rise in muscle diacylglycerol and lipid content, which are prevalent on lascivious nutrition especially if fat-rich. Thus, Psammomys illustrates the probable antecedents of the development of worldwide diabetes epidemic in human populations emerging from food scarcity to nutritional affluence, inappriopriate to their metabolic capacity.
...
PMID:Albert Renold memorial lecture: molecular background of nutritionally induced insulin resistance leading to type 2 diabetes--from animal models to humans. 1179 38

We have studied activation by phorbol derivatives of TRPV4 channels, the human VRL-2, and murine TRP12 channels, which are highly homologous to the human VR-OAC, and the human and murine OTRPC4 channel. 4alpha-Phorbol 12,13-didecanoate (4alpha-PDD) induced an increase in intracellular Ca(2+) concentration, [Ca(2+)](i), in 1321N1 cells stably transfected with human VRL-2 (hVRL-2.1321N1) or HEK-293 cells transiently transfected with murine TRP12, but not in nontransfected or mock-transfected cells. Concomitantly with the increase in [Ca(2+)](i), 4alpha-PDD activated an outwardly rectifying cation channel with an Eisenman IV permeation sequence for monovalent cations that is Ca(2+)-permeable with P(Ca)/P(Na) = 5.8. Phorbol 12-myristate 13-acetate also induced an increase in [Ca(2+)](i) but was approximately 50 times less effective than 4alpha-PDD. EC(50) for Ca(2+) increase and current activation was nearly identical (pEC(50) approximately 6.7). Similar effects were observed in freshly isolated mouse aorta endothelial cells which express TRP12 endogenously. By using 4alpha-PDD as a tool to stimulate TRP12, we showed that activation of this channel is modulated by [Ca(2+)](i); an increase in [Ca(2+)](i) inhibits the channel with an IC(50) of 406 nm. Ruthenium Red at a concentration of 1 microm completely blocks inward currents at -80 mV but has a smaller effect on outward currents likely indicating a voltage dependent channel block. We concluded that the phorbol derivatives activate TRPV4 (VR-OAC, VRL-2, OTRPC4, TRP12) independently from protein kinase C, in a manner consistent with direct agonist gating of the channel.
...
PMID:Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. 1182 75

Bradykinin (BK) is an inflammatory mediator that plays a pivotal role in pain and hyperalgesia to heat in inflamed tissues by exciting nociceptors and sensitizing them to heat through activation of protein kinase C (PKC). It has been suggested that the capsaicin receptor (VR1), a nociceptor-specific cation channel sensitive to noxious heat, protons, and capsaicin, is a channel that is modified by BK in these effects. In this study, we examined how BK modulates the activity of VR1. We measured VR1 currents using the patch-clamp technique in human embryonic kidney-derived (HEK293) cells expressing VR1 and B2 BK receptor. We found that BK lowered the threshold temperature for activation of VR1 currents in HEK cells down to well below the physiological body temperature in a concentration-dependent manner through PKC activation. We also demonstrated that in capsaicin-sensitive dorsal root ganglion (DRG) neurons the activation threshold of heat-induced current, which is considered to be VR-1 mediated, was lowered by BK and that this effect was also mediated by PKC. These data further support the supposition that modulation of VR1 is a mechanism for the BK-induced excitation of nociceptors and their sensitization to heat.
...
PMID:Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. 1209 79

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