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)

Exposure of mammalian cells to ionizing radiation causes a delay in progression through the cycle at several checkpoints. Cells from patients with ataxia-telangiectasia (A-T) ignore these checkpoint controls postirradiation. The tumour suppressor gene product p53 plays a key role at the G1/S checkpoint preventing the progression of cells into S phase. The induction of p53 by radiation is reduced and/or delayed in A-T cells, which appears to account for the failure of delay at the G1/S checkpoint. We have investigated further this defect in radiation signal transduction in A-T. While the p53 response was defective after radiation, agents that interfered with cell cycle progression such as mimosine, aphidicolin and deprivation of serum led to a normal p53 response in A-T cells. None of these agents caused breaks in DNA, as determined by pulse-field gel electrophoresis, in order to elicit the response. Since this pathway is mediated by protein kinases, we investigated the activity of several of these enzymes in control and A-T cells. Ca+2-dependent and -independent protein kinase C activities were increased by radiation to the same extent in the two cell types, a variety of serine/threonine protein kinase activities were approximately the same and anti-tyrosine antibodies failed to reveal any differences in protein phosphorylation between A-T and control cells. It is not evident what is the nature of the defect in signal transduction in A-T cells. However, it is clear that the p53 response is normal in these cells after exposure to some agents and it is mediated through protein kinase C or another serine/threonine kinase.
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PMID:Defect in radiation signal transduction in ataxia-telangiectasia. 753 Jul 54

Protein tyrosine kinases (PTKs) are closely related to cell growth, proliferation and differentiation. In keratinocytes, various growth factor receptors and cytosolic proteins, including the EGF and IGF receptors, the proteins of the src family and others, exhibit PTK activity. In psoriatic epidermis an increased level of EGF receptors and their ligand TGF-alpha has been found, and this is thought to be one reason for the pathological hyperproliferation of keratinocytes in this disease. Oral treatment with cyclosporin A (CsA) and FK506 or topical treatment with dithranol lead to an improvement in psoriasis. In the present study we examined the effect of these three drugs on the cellular content of phosphorylated tyrosines in highly proliferative HaCaT keratinocytes. HaCaT keratinocytes can be used as a model for highly proliferative epidermis, e.g. psoriatic epidermis. CsA had no effect whereas FK506 and dithranol reduced the phosphorylation of tyrosine residues in HaCaT keratinocytes. The activation of serine/threonine protein kinase C (PKC) is known to downregulate PTKs. Therefore we incubated keratinocytes with the selective PKC inhibitor Ro 31-8220 in addition to the other drugs. Only after the addition of Ro 31-8220 to FK506-treated keratinocytes was the phosphotyrosine (p-tyr) level elevated, but this was only one-third of the increase measured without additional therapeutic drugs. We assume that an induction of PKC alone is not responsible for the reduced p-tyr level after treatment with dithranol and FK506.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclosporin A, FK506 and dithranol after tyrosine-specific protein phosphorylation in HaCaT keratinocytes. 754 Nov 91

A rice (Oryza sativa) seed plasma-membrane calcium-dependent serine/threonine protein kinase (CDPK) has been partially purified. Comparing results in seeds that were treated with and without the plant hormone gibberellin (GA) for 10 min showed that rice CDPK was highly induced by GA. After separating solubilized membrane proteins by sodium dodecyl sulfate-gel electrophoresis, followed by renaturation, a radiolabeled phosphoprotein band of approximately 58 kD was detected, and it was apparently produced by autophosphorylation. There are five aspects of the rice CDPK that show similarity to mammalian protein kinase C (PKC) and to other plant CDPKs: (a) Histone IIIS and PKC peptide-ser25 (19-31) are phosphorylated by rice CDPK. (b) The phosphorylation reaction is strictly dependent on calcium. (c) The activity of the rice CDPK is inhibited by either staurosporine or the PKC inhibitory peptide (19-36). (d) Addition of calmodulin has no effect on the activity of the enzyme; however, the CDPK is inhibited by the calmodulin antagonists trifluoperazine and W-7. (e) The rice CDPK reacts with a mammalian anti-PKC antibody in immunoblotting analysis. However, there is one major difference between the rice CDPK and other CDPKs: the rice CDPK is induced by GA, whereas no mammalian PKC or other plant CDPKs are known to be induced by any hormone.
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PMID:A rice membrane calcium-dependent protein kinase is induced by gibberellin. 761 Jan 67

MBA-2, bone marrow-derived endothelial stromal cells, express platelet-derived growth factor (PDGF) A and B chain mRNAs and secrete PDGF activity that is induced by TGF-beta. Either chain of the PDGF molecule could modulate hematopoiesis and stromal cell growth. Intracellular pathways that regulate PDGF expression in the marrow microenvironment are unknown. In the present study, we examined the mechanisms that mediate PDGF A and B chain mRNA induction by TGF-beta and the role of protein kinase C (PKC) and cyclic AMP in PDGF regulation. TGF-beta was tested in parallel with PMA, an activator of phorbol ester-dependent PKC isoforms. Both PMA (10(-7)M) and TGF-beta (2.5 ng/ml) increased PDGF A and B chain mRNA levels. The serine/threonine protein kinase inhibitor, H7, blocked PDGF A and B chain mRNA induction in response to TGF-beta. However, down-regulation of PKC by prolonged incubation with PMA failed to abolish TGF-beta induction of PDGF A and B chain mRNAs. These findings indicate that induction of PDGF A and B chain mRNAs can be mediated via phorbol ester-dependent PKC pathway. In contrast, H7-sensitive protein kinase(s) other than phorbol ester-sensitive protein kinase C mediate the effect of TGF-beta. Agents that increase cAMP were also tested for their effect on PDGF gene expression. TGF-beta-mediated induction of PDGF A and B chain mRNAs was markedly inhibited by cAMP. cAMP also blocked stimulation of PDGF A chain mRNA by PMA. The positive and negative signaling mechanisms involved in modulating PDGF in the microenvironment may be important for determining hematopoietic and stromal cell responses in vivo.
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PMID:Regulation of platelet-derived growth factor A and B chain gene expression in bone marrow stromal cells. 762 89

Gq is the heterotrimeric guanine nucleotide-binding protein that activates the beta isoforms of phosphatidyl-inositol-specific phospholipase C (PI-PLC). The Gq alpha-subunit polypeptide (alpha qa) was N-terminally modified by addition of a 9-aa sequence, YPYDVPDYA. Placement of the 9-aa epitope tag at the N terminus allowed expression of functional alpha q polypeptides and selective identification of plasmid-expressed wild-type and mutant G-protein alpha subunits. Mutation of glutamine-209 to leucine in the N-terminally epitope-tagged alpha q (N(epi) alpha qQ209L) inhibited GTPase activity and persistently activated PI-PLC, resulting in high steady-state levels of inositol phosphates. The elevated levels of inositol phosphates resulting from N(epi) alpha qQ209L expression were similar to those obtained with carbachol activation of the M1 muscarinic acetylcholine receptor. The Gq-coupled M1 receptor, which stimulates PI-PLC activity, and phorbol esters, acting via protein kinase C, activate the cytoplasmic mitogen-activated protein kinase in COS cells. However, the constitutive activation of PI-PLC enzymatic activity resulting from expression of GTPase-deficient alpha q was unable to persistently activate this kinase. The results indicate that persistent PI-PLC activation is insufficient to sustain the stimulation of a cytoplasmic serine/threonine protein kinase regulated by Gq-coupled receptor signal-transduction pathways.
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PMID:Epitope-tagged Gq alpha subunits: expression of GTPase-deficient alpha subunits persistently stimulates phosphatidylinositol-specific phospholipase C but not mitogen-activated protein kinase activity regulated by the M1 muscarinic acetylcholine receptor. 768 19

The pim-1 gene encodes a serine/threonine protein kinase with expression restricted primarily to cells of hematopoietic lineage and is thought to play a role in the signal transduction events associated with lymphocyte activation. A rapid increase in pim-1 mRNA levels was found after stimulation of normal unseparated PBMCs with phorbol ester (PMA) and a calcium ionophore (ionomycin) with the peak level occurring 4 hr poststimulation. Treatment of PBMCs with ionomycin alone caused only a minimal increase in pim-1 mRNA, whereas treatment with PMA alone induced a large increase in pim-1 mRNA, suggesting that the activation of a signaling pathway involving protein kinase C is responsible for the accumulation of this transcript. In enriched subpopulations of resting alpha/beta-T cells, gamma/delta-T cells, and B cells, pim-1 expression was found to be constitutively expressed, albeit at lower levels in T cells. This basal level of pim-1 expression could be increased by stimulation of alpha/beta-T cells (approx fivefold) and gamma/delta-T cells (approximately sevenfold) with PMA plus ionomycin. In contrast, pim-1 expression was not inducible in B cells. In PBMCs, half-life determination studies showed that turnover of pim-1 mRNA was markedly prolonged as a result of message stabilization induced by PMA plus ionomycin treatment. In addition, stable pim-1 transcripts were also observed in all transformed lymphoid cell lines examined. Taken together, these results suggest that the stability of pim-1 transcripts may be linked to the regulation of cell growth and represent the first direct demonstration that pim-1 expression is indeed regulated in a cell-type-specific manner.
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PMID:Expression of the pim-1 protooncogene: differential inducibility between alpha/beta- and gamma/delta-T cells and B cells. 770

Protein kinases are involved in signal transduction pathways and play important roles in the regulation of cell functions. cDNA clones encoding a novel serine/threonine protein kinase sequence, designated as DBK, were isolated from cDNA libraries made from human endothelial cells. The compiled nucleotide sequence is 1636 base pairs long, consisting of an open reading frame encoding a 479-amino-acid protein with a calculated molecular mass of 53 kDa. The deduced amino acid sequence contains a protein kinase catalytic domain of 263 residues which includes all the characteristic features of a serine/threonine protein kinase. The invariant amino acid residues scattered throughout the catalytic domain of almost all known protein kinases are also found in DBK. Sequence comparison of DBK catalytic domain shows approximately 51% sequence identities to that of human protein kinase C family members. DBK shares the highest sequence identity, 53%, to that of Drosophila PKC. Northern blot analysis of various human tissues and cultured cell lines with a DBK gene-specific cDNA probe demonstrated a single band of 2.0 kb that is expressed in all tissues and cell lines examined. Although the expression of DBK kinase was detected in all human tissues analyzed, the levels of expression varied significantly, with the highest expression detected in lung and heart, and the lowest expression found in brain and liver. Anti-DBK peptide-specific rabbit antisera were prepared, and were capable of immunoprecipitating DBK protein from COS cells transfected with DBK cDNA. The DBK gene is a single-copy gene, and is highly conserved across species from human to yeast. Using somatic cell hybrids, the DBK gene has been localized to human chromosome 14. The ubiquitous expression and high degree of conservation of DBK across species suggest that DBK may play an important role in cell functions.
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PMID:Identification and characterization of DBK, a novel putative serine/threonine protein kinase from human endothelial cells. 795 85

We have investigated the possibility of a protein kinase participating in the signal transduction mechanisms of the interleukin-1 (IL-1) type I receptor (IL-1RI). Our data show that a protein kinase was co-precipitated with the IL-1RI from the two murine T helper cell lines D10N and EL-4. The kinase activity was detected in an in vitro kinase assay performed with the immuno beads in the presence of exogenous substrates. IL-1 treatment of the cells resulted in a rapid activation of this protein kinase in a concentration-dependent manner. Both forms of IL-1, IL-1 alpha and IL-1 beta, induced this kinase activity, whereas the IL-1 receptor antagonist (IL-1ra) was inactive. In excess IL-1ra competitively antagonized IL-1 stimulation. In the in vitro kinase assay the exogenous substrates myelin basic protein and histone H1 were phosphorylated, whereas casein or heat-shock protein HSP27 were not accepted, reflecting a certain selectivity of this protein kinase. The IL-1RI co-precipitable protein kinase showed a serine/threonine specificity and was inhibited by staurosporine, but not by inhibitors specific for protein tyrosine kinase or protein kinase C. These results show that a serine/threonine protein kinase directly interacts with the IL-1RI at the plasma membrane level of T helper cells forming a novel type of IL-1 inducible signaling complex. This protein kinase may resemble the link coupling the plasma membrane IL-1 receptor to cytosolic downstream elements in the IL-1 signaling pathway.
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PMID:Interleukin-1-induced activation of a protein kinase co-precipitating with the type I interleukin-1 receptor in T cells. 802 18

A serine/threonine protein kinase that binds phorbol esters and diacylglycerol (named protein kinase D, PKD) has been identified. PKD contains membrane localization signals and a cysteine-rich repeat sequence homologous to that seen in the regulatory domain of protein kinase C (PKC). A bacterially expressed N-terminal domain of PKD exhibited high-affinity phorbol ester binding activity (Kd = 35 nM). The diacylglycerol analog 1-oleoyl-2-acetylglycerol inhibited phorbol ester binding in a dose-dependent manner. The catalytic domain of PKD contains all characteristic sequence motifs of serine protein kinases but shows only a low degree of sequence similarity to PKCs. The highest identity is with the catalytic domain of myosin light-chain kinase from Dictyostelium (41%). The bacterially expressed catalytic domain of PKD efficiently phosphorylated the exogenous peptide substrate syntide 2 in serine but did not catalyze significant phosphorylation of a variety of other substrates used by PKCs and other major second messenger regulated kinases. PKD may be an unusual component in the transduction of diacylglycerol and phorbol ester signals.
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PMID:Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain. 807 25

The Lymantria dispar multinucleocapsid nuclear polyhedrosis virus (LdMNPV) gene encoding vPK has been cloned and sequenced. LdMNPV vPK shows a 24% amino acid identity to the catalytic domains of the eucaryotic protein kinases nPKC from rabbits, HSPKCE from humans, APLPKCB from Aplysia californica, and dPKC98F from Drosophila melanogaster, and homology to several other protein kinases from yeasts, mice, and bovines. The homology suggests that vPK is a serine/threonine protein kinase as defined by Hanks et al. (S.K. Hanks, A.M. Quinn, and T. Hunter, Science 241:42-52, 1988). Temporal expression studies indicate that vPK is expressed throughout the infection cycle beginning at 4 h postinfection, first as a delayed-early gene and subsequently as a late gene. Sequence analysis and primer extension reactions confirm the presence of distinct early and late transcription initiation regions. Expression of vPK with a rabbit reticulocyte system generated a 31-kDa protein, which is in close agreement with the predicted size of 32 kDa from the amino acid sequence. Phosphorylation activity of in vitro-expressed vPK was demonstrated by using calf thymus histones.
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PMID:Identification and characterization of a protein kinase gene in the Lymantria dispar multinucleocapsid nuclear polyhedrosis virus. 810 34


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