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)

The product of the c-raf-1 proto-oncogene is a cytoplasmic serine/threonine protein kinase that appears to be activated in signal transduction from a variety of cell-surface receptors. The mechanism of c-Raf activation upon stimulation of cell-surface receptors is not clear, but there seem to exist multiple pathways of activation which involve tyrosine and/or serine phosphorylation of the c-Raf protein in vivo. The activated state of Raf is reflected in an increased apparent molecular weight of the Raf protein in sodium dodecyl sulfate-polyacrylamide gels owing to hyperphosphorylation. The tumor promoter 12-O-tetradecanoyl phorbol 13-acetate (TPA) is one of the agents able to induce this hyperphosphorylation of Raf in vivo, suggesting that protein kinase C (PKC) may be involved in the activation of c-Raf in particular situations. Using recombinant baculoviruses expressing PKC and Raf polypeptides, we show here that conventional PKC types (alpha, beta, gamma) but not novel types (delta, zeta, eta) or the unrelated Mos kinase are able to activate c-Raf in a TPA-dependent manner upon coexpression in insect cells. Direct phosphorylation of the Raf protein with PKC in vitro also enhanced the kinase activity of c-Raf, suggesting that c-Raf acts immediately downstream of PKC in a protein kinase cascade which is triggered by TPA and may lead to transcriptional activation of TPA-inducible genes and tumor promotion.
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PMID:Activation of the c-Raf protein kinase by protein kinase C phosphorylation. 143 48

We have analyzed the in vitro phosphorylation of tau protein by Ca2+/calmodulin-dependent protein kinase, casein kinase II, and proline-directed serine/threonine protein kinase. These kinases phosphorylate tau protein in sites localized in different regions of the molecule, as determined by peptide mapping analyses. Focusing on the phosphorylation of tau by protein kinase C, it was calculated as an incorporation of 4 mol of phosphate/mol of tau. Limited proteolysis assays suggest that the phosphorylation sites could be located within the tubulin-binding domain. Direct phosphorylation of synthetic peptides corresponding to the cysteine-containing tubulin-binding region present in both fetal and adult tau isoforms demonstrates that serine 313 is modified by protein kinase C. Phosphorylation of the synthetic peptide by protein kinase C diminishes its binding to tubulin, as compared with the unphosphorylated peptide.
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PMID:Microtubule-associated protein tau is phosphorylated by protein kinase C on its tubulin binding domain. 163 8

Transforming growth factor-beta 1 (TGF-beta 1) rapidly increases the expression of junB transcription factor and plasminogen activator inhibitor-1 (PAI-1) and prevents the cell cycle-dependent phosphorylation of the RB retinoblastoma susceptibility gene product during late G1 phase in Mv1Lu lung epithelial cells. These responses are shown in this report to be blocked by the potent serine/threonine protein kinase inhibitor, H7, added with TGF-beta 1. Added alone, H7 does not alter the basal junB or PAI-1 mRNA levels, the deposition of PAI-1 into the extracellular matrix, or the phosphorylation of RB in late G1 phase, suggesting that this inhibitor does not have a general nonspecific effect on the cell. The analogs H8 and H9, which are preferential inhibitors of cyclic nucleotide-dependent protein kinases, are fivefold less potent than H7 as inhibitors of the TGF-beta response. The PAI-1 response to TGF-beta 1 is not affected by the simultaneous addition of staurosporine, which is a protein kinase C inhibitor, or by the prolonged preincubation of cells with phorbol 12-myristate 13-acetate, which down-regulates protein kinase C. The results suggest the possibility that H7 and its analogs block various early TGF-beta responses by inhibiting a protein serine/threonine kinase(s).
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PMID:Evidence for the involvement of protein kinase activity in transforming growth factor-beta signal transduction. 172 3

A novel serine/threonine protein kinase (termed rac-PK) has recently been identified and cloned from cDNA libraries derived from the human cell lines MCF-7 and WI38. A second form of this protein kinase, termed rac protein kinase beta, has been identified from cDNAs derived from the same cell lines. These two closely related forms show 90% homology, although the beta form with a predicted Mr 60,200 has a carboxyl terminal extension of 40 amino acids in comparison to the alpha form. This extension has a high serine content with 11 serine residues in the last 30 amino acids. The beta form of the protein has been shown by both in vitro translation and bacterial expression to be approximately 5000 Da larger than the alpha form. rac protein kinase beta is encoded by a 3.4-kb transcript and the alpha form is encoded by a 3.2-kb mRNA. Using gene-specific probes both transcripts were detected in all cell types analyzed, although levels of expression were different for the two forms. The catalytic domain of rac protein kinase beta shows a high degree of homology to both the protein kinase C and cyclic AMP-dependent protein kinase families, and hence rac protein kinases appear to represent a new subfamily of the second messenger serine/threonine protein kinases.
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PMID:Molecular cloning of a second form of rac protein kinase. 180 21

Protein kinase assays that use recombinant pp90rsk as a substrate were developed in an attempt to identify growth-regulated enzymes responsible for the phosphorylation and activation of pp90rsk S6 phosphotransferase activity. With this assay we have ientified a pp60v-src-, growth factor-, phorbol ester-, and vanadate-regulated serine/threonine protein kinase activity that is not related to two other cofactor-independent, growth-regulated protein kinases, pp70-S6 protein kinase and pp90rsk. The pp90rsk-protein kinase activity (referred to as rsk-kinase) is also not related to cofactor-dependent signal transducing protein kinases such as the cyclic AMP-dependent protein kinases, members of the protein kinase C family, or other Ca2(+)-dependent protein kinases. In vitro, partially purified rsk-kinase phosphorylates several of the sites (serine and threonine) that are phosphorylated in growth-stimulated cultured cells. A detailed examination of the mitogen-regulated activation kinetics of rsk-kinase and pp90rsk activities demonstrated that they are coordinately regulated. In addition, protein kinase C is not absolutely required for epidermal and fibroblast growth factor-stimulated activation of rsk-kinase, whereas, like pp90rsk, platelet-derived growth factor- and vanadate-stimulated rsk-kinase activity exhibits a greater dependence on protein kinase C-mediated signal transduction. The characterization and future purification of the rsk-kinase(s) will improve our understanding of the early signaling events regulating cell growth.
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PMID:Coordinate regulation of pp90rsk and a distinct protein-serine/threonine kinase activity that phosphorylates recombinant pp90rsk in vitro. 182 43

Recombinant monocyte-chemotactic and activating factor (rMCAF; alternative acronyms MCP-1, TDCF, human JE) induced migration of human monocytes across polycarbonate or nitrocellulose filters. Maximal induction of migration was observed at a concentration of 10 ng/ml (10(-9) M). Checkerboard analysis revealed that rMCAF elicited true gradient-dependent chemotactic migration, although a gradient independent chemokinetic effect was observed at low concentrations (1-5 ng/ml). rMCAF caused a rapid (less than 5 s) and transient (approximately 1.5 min) increase of free cytosolic Ca2+ ions, as assessed by the fura-2 probe. No Ca2+ increase was detected in neutrophils or lymphocytes stimulated by rMCAF. Studies conducted in the absence of extracellular Ca2+ or in the presence of Ni2+ (an inhibitor of Ca2+ influx) suggested that the increase of intracellular Ca2+ induced by rMCAF is dependent on the influx of extracellular Ca2+ through plasma membrane channels. Bordetella pertussis toxin inhibited the intracellular Ca2+ elevation and chemotaxis caused by rMCAF. The possible involvement of Ca(2+)-dependent protein kinases in rMCAF signaling pathway(s) was explored using inhibitors. Inhibitors of GMP-dependent kinase and myosin L chain kinase had no effect on rMCAF-induced monocyte migration. In contrast, protein kinase C/cAMP-dependent kinase inhibitors (such as, C-I, H-7, HA-1004, KT5720, and Staurosporine) markedly decreased rMCAF induced chemotaxis suggesting the involvement of a serine/threonine protein kinase, possibly protein kinase C, in rMCAF signaling pathway.
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PMID:The signal transduction pathway involved in the migration induced by a monocyte chemotactic cytokine. 191 57

A new class of serine/threonine protein kinase inhibitors was designed by associating, in the same structure, mimics of both the ATP binding site and a protein substrate. Among the several potent antagonists which were obtained, the most active consists of isoquinoline-5-sulfonamide, as ATP mimic, and Ser-Arg6, as peptidic moiety, bound by a-NH(CH2)2NH(CH2)2CO-linker. This compound, with a Ki of 0.1 microM toward protein kinase C (PKC) and 0.004 microM toward cyclic AMP dependent protein kinase (PKA), is respectively 60- and 750-fold more active than the commercial inhibitor H-7.
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PMID:Design of potent protein kinase inhibitors using the bisubstrate approach. 199 55

It has now become clear that protein kinase C (PKC) plays a fundamental role in cellular growth control in higher eukaryotes. In addition, since PKC has also been shown to be the high-affinity intracellular receptor for several classes of tumor promoters, the study of PKC has also become a central focus of current work in cancer research. We have isolated cDNA clones encoding several forms of this enzyme, and we have used these clones to begin to study in detail the role of PKC in growth control and tumor promotion. The complete primary structure of one of these forms, designated PKC beta 1, exhibits structural and functional characteristics which are shared among all of the currently identified forms of PKC. These include an amino terminal cysteine-rich domain which mediates Ca2+ and phospholipid binding, tumor promoter binding, and membrane association, and a carboxy terminal catalytic domain which possesses serine/threonine protein kinase activity. To further characterize the function of PKC, we have generated a series of rat fibroblast cell lines which stably overexpress a full-length cDNA encoding the beta 1 form of this enzyme. These cell lines contain a 20- to 53-fold increase in PKC activity, and also have an increase in high affinity phorbol ester receptors, relative to control cells. They also exhibit dramatically enhanced morphologic changes in response to treatment with the tumor promoter 12-0-tetradecanoyl phorbol-13-acetate (TPA). These cell lines grow to a higher saturation density in monolayer culture and, when maintained at post-confluence, develop small, dense foci. In contrast to the control cells, which display complete anchorage dependence, the cell lines that overproduce PKC form small colonies in soft agar in the absence of TPA, and larger colonies in the presence of TPA. Thus, the mere overproduction of a single form of PKC is sufficient to confer anchorage independent growth and other growth abnormalities in rat fibroblasts. Taken together, these results provide direct evidence that PKC plays a critical role in normal cellular growth control and that it mediates several, and perhaps all of the cellular effects of the phorbol ester tumor promoters.
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PMID:Structural and functional studies of protein kinase C. 306 83

The inhibitory potencies of bioflavonoids on various tyrosine protein kinases and serine/threonine protein kinases were investigated. The phosphotransferase activity of an oncogene product, pp130fps, and a growth factor receptor, insulin receptor, were inhibited by myricetin, a derivative of quercetin. However, tyrosine kinase activity in the particulate fraction from human platelets (PM-TPK) was resistant to myricetin. Apparent Ki values of myricetin for tyrosine protein kinases of pp130fps and insulin receptor were 1.8 and 2.6 microM, respectively. The Ki values for serine/threonine kinase activities of myosin light chain kinase (MLC-kinase), casein kinase I, casein kinase II, cAMP-dependent protein kinase, and protein kinase C were 1.7 microM, 9.0 microM, 0.6 microM, 27.5 microM, and 12.1 microM, respectively. Lineweaver-Burk plots revealed that myricetin competitively inhibits pp130fps tyrosine kinase, myosin light chain kinase, casein kinase I and II with ATP, but does not inhibit other protein kinases. Since myricetin is a hydroxylated derivative of quercetin, the inhibitory effects of a series of seven flavonoids with various numbers of hydroxy residues were examined. Structure activity studies exhibited that the inhibitory potencies of the flavonoids for tyrosine kinases of pp130fps and insulin receptor correlated with the number of hydroxy residues on the flavone rings (gamma = 0.974 and 0.926, respectively), whereas the hydroxylation influenced to a lesser extent the inhibitory potencies for serine/threonine protein kinase. The hydroxy residues at position 3' and 5' did not affect the activities of cAMP-dependent protein kinase, and protein kinase C, and the hydroxylation at position 5' is detrimental for the inhibition of MLC-kinase, and casein kinase I and II. Thus, flavonoids may be useful tools to elucidate the active site of tyrosine and serine/threonine protein kinases.
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PMID:Differential effects of flavonoids as inhibitors of tyrosine protein kinases and serine/threonine protein kinases. 316 98

We have isolated cDNA clones encoding protein kinase C by using a 53-base-pair synthetic oligonucleotide probe corresponding to a peptide that we obtained from the rat brain enzyme. We also have isolated several closely related clones using the same oligonucleotide probe. Nucleotide sequence analysis of one of the protein kinase C clones, RP41, identifies a 224-amino-acid carboxyl-terminal region with approximately equal to 40% homology to the carboxyl-terminal catalytic domains of both the cAMP-dependent and cGMP-dependent protein kinases. The levels of mRNA homologous to RP41 are very high in brain, whereas much lower levels are present in heart and liver. Nucleotide sequence analysis of a second cDNA clone, RP16, identifies a deduced amino acid sequence that shares 65% homology with the corresponding region of the protein kinase C clone RP41. The levels of mRNA corresponding to RP16 are also high in rat brain, but the transcript sizes and tissue-specific expression patterns differ from those of RP41. These and additional results provide evidence that the gene encoding protein kinase C is a member of a novel serine/threonine protein kinase multigene family.
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PMID:Isolation of cDNA clones encoding protein kinase C: evidence for a protein kinase C-related gene family. 346 47


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