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

Trypsinization of rat brain protein kinase C (80 kDa) into 50- and 32-kDa fragments occurred without inhibition of [3H]phorbol dibutyrate ([3H]PDBu) binding activity. The 50-kDa fragment, the catalytic domain (Inoue, M., Kishimoto, A., Takai, Y., and Nishizuka, Y. (1977) J. Biol. Chem. 252, 7610-7616), was further degraded by trypsin, whereas the 32-kDa fragment was resistant. Protein kinase activity and the [3H]PDBu binding activity were completely separated upon gel filtration of a solution containing Triton X-100/phosphatidylserine mixed micelles and trypsinized protein kinase C. Pooled fractions of the [3H]PDBu binding activity contained a 32-kDa fragment exclusively. The binding of [3H]PDBu to this fragment was dependent on calcium and phosphatidylserine and was of high affinity (Kd = 2.8 nM) and of essentially identical specificity to that of native protein kinase C. It is concluded that the 32-kDa fragment represents a lipid binding, regulatory domain of protein kinase C.
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PMID:The lipid binding, regulatory domain of protein kinase C. A 32-kDa fragment contains the calcium- and phosphatidylserine-dependent phorbol diester binding activity. 346 1

Protein kinase capable of phosphorylating 40S ribosomal protein S6 on serine residues has been detected in chicken embryo fibroblasts. This activity appears to be regulated in direct response to expression of pp60v-src in chicken embryo fibroblasts infected with a temperature-sensitive transformation mutant of Rous sarcoma virus. Partially purified S6 kinase was highly specific for S6 in 40S ribosomal subunits. The S6 kinase was not inhibited by calcium or by the heat-stable inhibitor of cAMP-dependent protein kinase, nor was it activated by phosphatidylserine, diacylglycerol, and calcium. Thus, it is distinct from protein kinase C and cAMP-dependent protein kinase, which are capable of phosphorylating S6 in vitro. The tumor-promoter phorbol 12-myristate 13-acetate also stimulated ribosomal protein S6 kinase activity in serum-starved chicken embryo fibroblasts, whereas phorbol, the inactive analog of phorbol 12-myristate 13-acetate, had no effect. S6 kinase activity stimulated by expression of pp60v-src, by phorbol 12-myristate 13-acetate, or by serum growth factors exhibited similar chromatographic properties upon ion-exchange chromatography. These results suggest that a common protein kinase may be activated by three diverse stimuli all involved in regulating cell proliferation.
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PMID:Regulation of a ribosomal protein S6 kinase activity by the Rous sarcoma virus transforming protein, serum, or phorbol ester. 393 63

The existence of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C), the effect of gastrin on phospholipid metabolism and guanylate cyclase activity were investigated to elucidate the cellular mechanism of action of gastrin on the corporal mucosa of the canine stomach. Protein kinase activity was determined by measuring the incorporation of [32P] into calf thymus H1-histone from [32P]-ATP. One unit of protein kinase was defined as the amount of enzyme which incorporated 1 pmol of phosphate from ATP into H1-histone. Protein kinase C was found in 100,000xg supernatant of homogenate fractionated by a DEAE-cellulose column chromatography. Characteristics of further purified protein kinase C, such as dependency on divalent cations and phospholipids, were in agreement with those of previously reported protein kinase C in other tissues. Furthermore, the gastric corporal mucosa was found to contain protein kinase C in large quantities. The specific activity of protein kinase C was 26,000 units/mg protein. The phospholipid metabolism was evaluated by the incorporation of [14C]-glycerol-3-phosphate and the change of the radioactivity of [32P] in individual phospholipids. Each phospholipid was extracted from the gastric corporal mucosa and isolated by thin layer chromatography. Guanylate cyclase activity was determined by measuring the cGMP produced, using radioimmunoassay. Gastrin significantly increased the incorporation of [14C]-glycerol-3-phosphate into phosphatidylethanolamine in the presence of acetylcholine (Ach). Ach increased the uptake of the tracer into phosphatidylinositol significantly, and the increase was enhanced by the simultaneous addition of gastrin. In the experiments with [32P]-labeled phospholipids, gastrin increased the incorporation of [32P] into phosphatidylethanolamine significantly. The significant increase of the radioactivity in phosphatidylinositol by Ach failed to be enhanced by gastrin, but that of phosphatidylethanolamine by Ach was enhanced by gastrin. No stimulation of guanylate cyclase activity by gastrin was detected in the dispersed gastric corporal mucosal cells. These results indicate that gastric corporal mucosa was one of the most abundant tissues in which protein kinase C was contained, when compared with various mammalian tissues previously reported by Minakuchi, Nishizuka, et al. Nishizuka et al, recently proposed the novel hypothesis that phosphatidylinositol turnover activated by cAMP-independent agonists will be essentially required to activate protein kinase C. Our results suggest that gastrin can provoke phospholipids turnover including phosphatidylinositol turnover in gastric corporal mucosa. Therefore, our data indicate the possibility that the protein kinase C system plays an important role in the cellular mechanism of action of gastrin on gastric corporal mucosa.
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PMID:[The cellular mechanism of action of gastrin on the corporal mucosa of the canine stomach. (2) Ca2+-activated, phospholipid-dependent protein kinase and phospholipid turnover--possible mediator of gastrin action]. 613 23

An affinity column, prepared by immobilizing phosphatidylserine and cholesterol in polyacrylamide, was utilized in the purification of protein kinase C. Protein kinase activity and phorbol ester binding were monitored by assaying Ca2+ plus phosphatidylserine-dependent phosphorylation of histone H1 and [3H]phorbol dibutyrate binding, respectively. Both activities were present in a cytosolic extract of rabbit renal cortex, eluted together from a DEAE-cellulose column, bound to the affinity column in the presence of Ca2+, and eluted symmetrically upon application of EGTA. Recovery from the affinity column was high (30-50%) and resulted in as much as a 6000-7700-fold purification, depending on the region of the DEAE-cellulose peak that was applied. Following affinity column purification, protein kinase and phorbol ester binding activity eluted symmetrically upon gel filtration, with a molecular weight of approximately 80 kDa. A protein of the same size was present in silver-stained gels following sodium dodecyl sulfate-polyacrylamide gel electrophoresis of affinity column purified samples from the DEAE-cellulose peak. From 2-4 other, smaller proteins were also present, their number and relative amounts depending on the region of the DEAE-cellulose peak used. These data indicate that Ca2+-dependent/binding to a polyacrylamide-immobilized phospholipid provides a useful technique for purification of protein kinase C as well as other, unidentified proteins exhibiting a Ca2+ plus phospholipid-dependent interaction.
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PMID:Affinity chromatography of protein kinase C-phorbol ester receptor on polyacrylamide-immobilized phosphatidylserine. 623 25

The transmembrane glycoprotein CD34 shows a highly restricted expression on a crucial subset of hematopoietic cells. We show here that engagement of particular determinants of CD34 can lead to signal transduction and to enhanced adhesiveness of CD34+ hematopoietic cells. Monoclonal antibodies (MoAbs) directed against O-sialoglycoprotease-sensitive epitopes of CD34 (QBEND10, ICH3, BI.3C5, MY10) but not MoAbs against O-sialoglycoprotease-resistant epitopes (9F2, 8G12) induce actin polymerization in KG-1a and KG-1 cells and strongly enhanced cytoadhesiveness. The capacity to induce adhesion requires cellular energy, divalent cations, and intact cytoskeleton but not de novo protein synthesis. The observed cytoadhesion seems at least in part to be caused by a concomitant activation of the beta 2 integrin cytoadhesion pathway. It can be significantly inhibited with lymphocyte function-associated antigen-1 and intercelluar adhesion molecule-1 antibodies. Protein kinase inhibition analyses suggest that the pathways initiated by engagement of the CD34 molecule with certain CD34 MoAbs involves protein tyrosine kinases but that protein kinase C is not critically involved.
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PMID:Signaling and induction of enhanced cytoadhesiveness via the hematopoietic progenitor cell surface molecule CD34. 750 53

Steady-state levels of mRNAs that encode specific Fc gamma R and Ia antigen genes have been measured in macrophages treated with interferons (IFNs) to examine the induction of these markers at the molecular level. Our previous studies suggested requirement for protein kinase C (PKC) in the IFN induction of these macrophage surface markers, although a difference in PKC dependence was found between IFN-alpha/beta- and IFN-gamma-induced Fc gamma R expression. The protein kinase antagonist H7, used previously to distinguish between the surface induction of Fc gamma R by IFN-alpha/beta and IFN-gamma, also distinguishes between the IFN-alpha and IFN-gamma in the induction of Fc gamma RI mRNA and Fc gamma RI surface expression. Protein kinase inhibitors blocked the IFN-gamma induction of Ia mRNA in a manner similar to that reported previously for cell surface Ia expression. It is concluded that Fc gamma RI is induced by both IFN-alpha and IFN-gamma through distinct biochemical pathways, whereas IFN-gamma utilizes distinct pathways to induce the two macrophage activation markers, Ia antigen and Fc gamma RI.
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PMID:Multiple pathways of interferon-induced gene expression in murine macrophages. 768 67

Stimulus-induced insulin secretion involves the activation of several protein kinases within the beta cell. Most prominent are protein kinase A, protein kinase C and calcium/calmodulin-dependent protein kinases. Protein kinase action is functionally antagonized by protein phosphatases. The four ubiquious serine/threonine protein phosphatases are termed PP-1, PP-2A, -2B and -2C. PP-1 and PP-2A are in vivo parts of major protein complexes. These complexes presumably regulate the phosphatase activity and direct the enzyme to its site of action. Therefore, PP-1 and -2A could play an important role in controlling intracellular signal transmission. Two different toxins, okadaic acid and calyculin A, both from marine invertebrates, were recently discovered and identified as potent and highly specific inhibitors of PP-1 and PP-2A. Both compounds emerged as very useful tools for studying intracellular phosphorylation events. We took advantage of these substances to investigate the significance of protein phosphatase action in stimulus-induced insulin secretion. To avoid major complexity, we confined our study to the cAMP and the phosphoinositide signal pathway. Okadaic acid alone evoked virtually no secretory response. cAMP-dependent secretion was markedly enhanced by 1 microM okadaic acid. The stimulatory effect of okadaic acid was strongly dependent on the concentration of cAMP analoga. In contrast, insulin release caused by the cholinergic agonist carbachol was not influenced by okadaic acid. Calyculin A (10 nM) slightly increased cAMP-induced secretion, but its high toxicity prohibited accurate interpretation of the data. Our findings support the idea that serine/threonine phosphatases act as important regulators in stimulus response coupling.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Okadaic acid indicates a major function for protein phosphatases in stimulus-response coupling of RINm5F rat insulinoma cells. 781 3

The mechanism of the regulation of Ca++ influx via Na(+)-Ca++ exchange in response to Na+ deprivation was studied in bovine adrenal medullary cells. Protein kinase inhibitors staurosporine and (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl2,3,9,10-te trahydro-8, 11-epoxy-1H,8H, 11H-2,7b, 11a-triazadibenzo[a,g]cycloocta[c,d,e]trinden- 1-one depressed Na+ deprivation-induced 45Ca++ uptake and catecholamine secretion in a concentration-dependent manner. However, 1 mM dibutyryl cyclic AMP and 1 microM forskolin, an activator of adenylate cyclase, had little effect on Na+ deprivation-induced 45Ca++ uptake and catecholamine secretion. Dibutyryl cyclic GMP (1 mM) and muscarine (30 microM), which increased intracellular cyclic GMP level via stimulation of muscarinic receptors, had also little effect on the responses. Although the phorbol esters 12-O-tetradecanoyl-phorbol-13-acetate and phorbol 12,13-dibutyrate, activators of protein kinase C, enhanced Na+ deprivation-induced catecholamine secretion, these compounds failed to affect Na+ deprivation-induced 45Ca++ uptake. On the other hand, a variety of calmodulin antagonists such as calmidazolium, trifluoperazine, pimozide and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide inhibited Na+ deprivation-induced 45Ca++ uptake and catecholamine secretion in a concentration-dependent manner. Furthermore, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpipera zin e, which is known as an inhibitor of Ca++/calmodulin-dependent protein kinase II, also reduced Na+ deprivation-induced 45Ca++ uptake and catecholamine secretion. Chelation of intracellular Ca++ with Quin-2 acetoxymethyl ester resulted in a decrease in Na+ deprivation-induced 45Ca++ uptake. However, these compounds that inhibited the Na+ deprivation-induced responses in the cells did not cause solely nonspecific and direct inhibition on Na(+)-Ca++ exchanger. These pharmacological observations suggest that Ca++/calmodulin-dependent protein kinase is involved in the regulation of Na(+)-Ca++ exchange in bovine adrenal medullary cells.
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PMID:Pharmacological evidence for regulation of Na(+)-Ca++ exchange by Ca++/calmodulin-dependent protein kinase in isolated bovine adrenal medullary cells. 803 5

The activity of several proteins involved in the development of antitumor drug resistance is regulated by protein phosphorylation. These proteins include the mdr-1-encoded P-glycoprotein (Pgp) and topoisomerase II (topo II). The corresponding evidence is reviewed and attempts to modulate multidrug resistance (MDR) by protein kinase C inhibitors are described. The expression of several proteins which are essential in drug resistance is regulated at the transcriptional level, involving protein phosphorylation by members of the protein kinase C (PKC) family, casein kinase II (CKII), and others. These proteins include mdr-1-encoded P-glycoprotein, metallothionein, glutathione S-transferase (GST), dTMP synthase, and the proteins Fos and Jun. The corresponding genes are under positive regulation of ras, which in turn requires the activation of a protein kinase cascade for its function. Protein kinases are therefore potentially useful targets in reducing the expression of proteins involved in the development of multifactorial drug resistance caused by the expression of transforming ras-genes. Attempts to inhibit the ras-induced fos expression by an inhibitor of protein kinase C (ilmofosine) are described. Protein kinase inhibitors are also able to synergistically enhance the cytotoxicity of cis-platinum, which is discussed as resulting from a reduction of PKC-dependent fos expression.
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PMID:Role of protein kinases in antitumor drug resistance. 806 Nov 7

Changes in the activities of protein kinase A (cAMP-dependent), protein kinase C (Ca2+/phospholipid-dependent), and protein kinase M (Ca2+/calmodulin-dependent) in dog heart and liver were studied 4 hr following endotoxin injection. Protein kinases A and C were extracted and partially purified by DEAE-cellulose chromatography. Protein kinase M was extracted and partially purified by DEAE-cellulose, DEAE-Sephacel, and calmodulin-Sepharose chromatography. The results indicate that in the heart, both type I (eluted at low ionic strength) and type II (eluted at high ionic strength) protein kinase A activities were unchanged after endotoxin administration. Cardiac cytosolic protein kinase C activity was increased by 50% (p < 0.05) while the membrane-associated protein kinase C activity remained unaltered following endotoxin injection. Cardiac protein kinase M activity was decreased by 38.5% (p < 0.01) post endotoxin. In the liver, type I protein kinase A activity was unaffected while type II protein kinase A activity was decreased by 34% (p < 0.01) following endotoxin injection. Hepatic cytosolic and membrane-associated protein kinase C activities were inhibited by 37% (p < 0.01) and 53% (p < 0.01), respectively, 4 hr postendotoxin. Hepatic protein kinase M activity was decreased by 61% (p < 0.01) after endotoxin administration. These data indicate that the activities of various protein kinases in the heart and liver were modified by endotoxin administration. Since protein kinases regulate cell function through phosphorylation of various substrate proteins, a modification on protein kinase activities may contribute to the development of organ dysfunction in endotoxin shock.
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PMID:Changes in the activities of protein kinases A, C, and M in dog heart and liver following endotoxin administration. 815 40


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