Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In bovine aortic smooth muscle, GTP-binding activity was equally distributed in the membrane and cytosol fractions. The most abundant GTP-binding proteins (G proteins) in each fraction were purified to near homogeneity and characterized. The most abundant G protein in the membrane fraction had a Mr value of about 22,000 (m22K G) as estimated on sodium dodecyl sulfate-polyacryl-amide gel electrophoresis (SDS-PAGE). m22K G and the human platelet smg p21, a ras p21 like G protein having the same effector domain as ras p21s, were eluted at the same retention time on C4 reversed-phase high performance liquid chromatography (HPLC). Moreover, m22K G was specifically recognized by an anti-smg p21 polyclonal antibody. m22K G was phosphorylated by cyclic AMP-dependent protein kinase with a stoichiometry of one phosphate/molecule of protein. The most abundant G protein in the cytosol fraction had a Mr value of about 21,000 (c21K G) as estimated on SDS-PAGE. c21K G was ADP-ribosylated by botulinum ADP-ribosyltransferase and about 0.4 mol of ADP-ribose was maximally incorporated into 1 mol of c21K G. c21K G and the bovine brain rhoA p21, another ras p21 like G protein, were eluted at the same retention time on C4 reversed-phase HPLC and migrated at the same position on two-dimensional gel electrophoresis. These results indicate that the major G proteins in the membrane and cytosol fractions of bovine aortic smooth muscle are smg p21 and rhoA p21, respectively. Possible roles of these G proteins in vascular smooth muscle are discussed.
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PMID:Small GTP-binding proteins in bovine aortic smooth muscle. 174 79

The development of IDDM results from the destruction of pancreatic beta cells. Genetic factors, various immune system alterations, and environmental factors have been studied as the possible causes of IDDM. The concordance rate for developing IDDM between monozygotic twins approaches 50%, suggesting that genetic factors are necessary, but nongenetic factors such as various immune system alterations and environmental factors also influence the clinical expression of genetic susceptibility. Environmental factors (e.g., viruses, chemicals, and diet) affecting the induction of diabetes may act as primary injurious agents which damage pancreatic beta cells or as triggering agents of autoimmunity. Certain viruses including EMC-D and Mengo virus 2T can directly infect pancreatic beta cells and replicate in the cells. The replication of viruses in the beta cells results in the destruction of the cells within 3 days, and the infected mice develop a diabeteslike syndrome in 3-4 days without the involvement of autoimmunity. In contrast, rubella virus appears to be somewhat weakly associated with autoimmune IDDM in hamsters. In addition, endogenous retrovirus expressed in pancreatic beta cells is clearly associated with the development of insulitis and diabetes in NOD mice. In man, there appears to be no correlation between the detection of islet cell autoantibodies and anti-Coxsackie B viral antibodies in newly diagnosed IDDM. In contrast, persistent infection of CMV and rubella virus appears to be associated with the presence of autoantibodies in newly diagnosed IDDM patients. It is particularly noteworthy that human CMV can induce islet cell autoantibodies that react specifically with a 38 kDa islet cell protein which may represent islet cell-specific antigens in a proportion of CMV-associated IDDM cases. These observations suggest that the association of diabetes with Coxsackie B viruses might be due to cytolytic infection of the beta cells with no link to autoimmunity, while both rubella virus and CMV are probably associated with autoimmune IDDM. A number of structurally diverse chemicals including alloxan, streptozotocin, chlorozotocin, Vacor, and cyproheptadine are diabetogenic mainly in rodents and sometimes in man. Possible mechanisms for beta cell destruction by these chemicals include (a) generation of oxygen free radicals and alteration of endogenous scavengers of these reactive species; (b) breakage of DNA and a consequent increase in the activity of poly-ADP-ribose synthetase, an enzyme depleting nicotinamide adenine dinucleotide in beta cells; and (c) inhibition of active calcium transport and calmodulin-activated protein kinase activity. (ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of viruses and environmental factors in the induction of diabetes. 207 86

The effects of adenosine diphosphate (ADP) ribosylation inhibitors on hematopoietic growth factor-induced proliferation were examined. Significant inhibition of interleukin-3 (IL-3), colony-stimulating factor 1, and lung conditioned media-induced clonal agar growth of normal murine hematopoietic cells by 10 mmol/L nicotinamide (NAM), 10 mmol/L 3-aminobenzamide (3AB), and 5 mmol/L N1-methylnicotinamide (1MN) was noted. Nicotinic acid, a related compound that does not inhibit ADP ribosylation, failed to inhibit the growth factor-mediated proliferation. NAM (10 mmol/L), 3AB (10 mmol/L), and 1MN (5 mmol/L) also prevented IL-3 and phorbol ester-stimulated 3H-thymidine incorporation into the IL-3-responsive FDC-P1 cell line. Exposure of FDC-P1 cells to 10 mmol/L NAM led to a significant decrease in nuclear poly-(ADP-ribose) levels. Exposure of FDC-P1 cells to 5 mmol/L 1MN did not affect the interaction of the phorbol ester receptor, protein kinase-C (PK-C), with the cell membrane as determined by assay of phorbol ester binding in cytosol and membrane preparations. Nor did it affect the catalytic activity of PK-C as determined by assaying the in vitro phosphorylation of histone H1 by cytosolic kinase preparations from FDC-P1 as well as EL4 thymoma cells. 1MN markedly enhanced the inhibitory effects of phorbol esters on DNA synthesis of EL4 cells even at concentrations (1.25 mmol/L) that had no effects on DNA synthesis in the absence of phorbol esters. Our findings demonstrate that (a) active ADP ribosylation inhibitors interfere with growth factor-induced proliferation of murine hematopoietic cells and (b) the inhibition occurs at a step that follows the activation and translocation of PK-C and is more closely linked to DNA synthesis.
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PMID:Inhibition of hemopoietic growth factor-induced proliferation by adenosine diphosphate-ribosylation inhibitors. 295 1

The ADP-ribosylation site of histone H1 from calf thymus by purified hen liver nuclear ADP-ribosyltransferase was determined and effects of the ADP-ribose X histone-H1 adduct on cAMP-dependent phosphorylation of the histone H1 were investigated. ADP-ribosylated histone H1 was prepared by incubation of histone H1, 1 mM [adenylate-32P]NAD and the purified ADP-ribosyltransferase. N-Bromosuccinimide-directed bisection of ADP-ribosylated histone H1 showed that the NH2-terminal fragment (Mr = 6000) was modified and contained serine residue 38, the site of phosphorylation by cAMP-dependent protein kinase. Digestion of the NH2-terminal fragment with cathepsin D and trypsin, and purification of this fragment, using high-performance liquid chromatography, yielded a radiolabelled single peptide corresponding to residues 29-34 of histone H1, containing the arginine residue as the ADP-ribosylation site. These results indicate that ADP-ribosylation of histone H1 occurs at the arginine residue 34, sequenced at the NH2-terminal side of the phosphate-accepting serine residue 38. Phosphorylation of histone H1 from calf thymus by cAMP-dependent protein kinase was markedly reduced when histone H1 was ADP-ribosylated. Kinetic studies of phosphorylation revealed that ADP-ribosylated histone H1 was a linear competitive inhibitor of histone H1 and a linear non-competitive inhibitor of ATP.
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PMID:Amino acid sequence of histone H1 at the ADP-ribose-accepting site and ADP-ribose X histone-H1 adduct as an inhibitor of cyclic-AMP-dependent phosphorylation. 299 55

L-type pyruvate kinase (EC 2.7.1.40) purified from pig liver was ADP-ribosylated by incubation with NAD and ADP-ribosyltransferase purified from hen liver nuclei. Maximal incorporation of the ADP-ribose moiety from NAD into the L-type pyruvate kinase was 0.98 mol/mol of subunit. The Km values for NAD and L-type pyruvate kinase were 0.17 mM and 9.7 microM, respectively. ADP-ribosylation of the L-type pyruvate kinase resulted in suppression of the subsequent phosphorylation catalyzed by cAMP-dependent protein kinase. The ADP-ribosylation-induced suppression of phosphorylation of the L-type pyruvate kinase also resulted in suppression of the phosphorylation-induced inactivation. Amino acid analysis, after exhaustive sequential digestion of ADP-ribosyl-L-type pyruvate kinase with pepsin, aminopeptidase M and carboxy-peptidase B showed arginine to be the ADP-ribose-accepting amino acid. These results together with finding of the ADP-ribosyltransferase activity in mammalian liver cytosol (Moss, J. and Stanley, S.J. (1981) J. Biol. Chem. 256, 7830-7833) suggest that ADP-ribosylation may participate in the regulation of the L-type pyruvate kinase activity through changes in the rate of phosphorylation.
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PMID:ADP-ribosylation suppresses phosphorylation of the L-type pyruvate kinase. 334 9

Phosphorylation of whole histones from calf thymus by the catalytic subunit of cyclic AMP-dependent protein kinase was markedly reduced when the histones were ADP-ribosylated. NAD, nicotinamide or free ADP-ribose molecule did not suppress the phosphorylation. Urea gel electrophoretic analyses of the phosphorylated histones which had already been ADP-ribosylated revealed that the suppression of phosphorylation occurred in both H1 and core histones. Therefore, the possibility that ADP-ribosylation may regulate the phosphorylation of histones phosphorylation in nuclei warrants further investigation.
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PMID:ADP-ribosylation regulates the phosphorylation of histones by the catalytic subunit of cyclic AMP-dependent protein kinase. 630 64

The effect of cyclic AMP (cAMP)-dependent phosphorylation and ADP-ribosylation on the activities of the rat liver bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2), was investigated in order to determine the role of the N-terminus in covalent modification of the enzyme. The bifunctional enzyme was demonstrated to be a substrate in vitro for arginine-specific ADP-ribosyltransferase: 2 mol of ADP-ribose was incorporated per mol of subunit. The Km values for NAD+ and PFK-2/FBPase-2 were 14 microM and 0.4 microM respectively. A synthetic peptide (Val-Leu-Gln-Arg-Arg-Arg-Gly-Ser-Ser-Ile-Pro-Gln) corresponding to the site phosphorylated by cAMP-dependent protein kinase was ADP-ribosylated on all three arginine residues. Analysis of ADP-ribosylation of analogue peptides containing only two arginine residues, with the third replaced by alanine, revealed that ADP-ribosylation occurred predominantly on the two most C-terminal arginine residues. Sequencing of the ADP-ribosylated native enzyme also demonstrated that the preferred sites were at Arg-29 and Arg-30, which are just N-terminal to Ser-32, whose phosphorylation is catalysed by cAMP-dependent protein kinase (PKA). ADP-ribosylation was independent of the phosphorylation state of the enzyme. Furthermore, ADP-ribosylation of the enzyme decreased its recognition by liver-specific anti-bifunctional-enzyme antibodies directed to its unique N-terminal region. ADP-ribosylation of PFK-2/FBPase-2 blocked its phosphorylation by PKA, and decreased its PFK-2 activity, but did not alter FBPase-2 activity. In contrast, cAMP-dependent phosphorylation inhibited the kinase and activated the bisphosphatase. These results demonstrate that ADP-ribosylation of arginine residues just N-terminal to the site phosphorylated by PKA modulate PFK-2 activity by an electrostatic and/or steric mechanism which does not involved uncoupling of N- and C-terminal interactions as seen with cAMP-dependent phosphorylation.
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PMID:Role of the N-terminal region in covalent modification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: comparison of phosphorylation and ADP-ribosylation. 761 45

The reason for different phosphorylation of topoisomerase I in two sublines of L5178Y murine lymphoma (LY cells) was investigated. Camptothecin-resistant LY-S cells show increased poly(ADP-ribose) level and lowered topoisomerase I phosphorylation compared to camptothecin-sensitive LY-R cells. In this study diminished phosphorylation of LY-S topoisomerase I was observed for sites recognized by casein kinase 2 but not for those phosphorylated by protein kinase C. Tryptic digests of LY-S topoisomerase I labeled in vitro by casein kinase 2 indicated that phosphorylation was similarly lowered at different sites. Activity of casein kinase 2 measured in nuclear extracts was about 1.7 times lower for LY-S than LY-R cells. This difference was diminished or eliminated by increasing casein concentration, diluting the extract or increasing the ionic strength. Activity of poly(ADP-ribose) polymerase was 5.3 times higher in LY-S than in LY-R nuclei. When the activity of the polymerase was inhibited by treatment of LY-S cells with benzamide, casein kinase 2-catalyzed phosphorylation of topoisomerase I increased. This was accompanied by an increase in sensitivity to camptothecin as reflected in the diminished viability of LY-S cells.
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PMID:Phosphorylation of topoisomerase I in L5178Y-S cells is associated with poly(ADP-ribose) metabolism. 863 Nov 20

In the present study, we describe a role for cyclic GMP (cGMP) in the signalling pathway that leads from alpha-adrenergic receptor activation to intracellular Ca2+ mobilization in rat lacrimal acinar cells. The alpha-adrenergic agonist, phenylephrine, stimulates intracellular Ca2+ release which is blocked by inhibitors of guanylate cyclase and cGMP-dependent protein kinase Ia. The membrane-permeable cGMP analogues, dibutyryl-cGMP and 8-bromo-cGMP, potentiate ( approximately 5-fold) the Ca2+ response to submaximal phenylephrine stimulation. In contrast, the same cGMP analogues have no effect on cyclic ADP-ribose-evoked Ca2+ release from permeabilized lacrimal acinar cells. Collectively, these findings suggest that cGMP, via cGMP-dependent protein kinase I alpha , is required for intracellular Ca2+ release following alpha-adrenergic receptor activation in lacrimal acinar cells.
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PMID:Cyclic GMP potentiates phenylephrine but not cyclic ADP-ribose-evoked calcium release from rat lacrimal acinar cells. 870 97

The role of the basal activity of the serine/threonine protein kinase, protein kinase C (PKC) in the regulation of anti-CD95-induced apoptosis in Jurkat T cells was investigated. The PKC-specific inhibitor GF 109203X and the proposed cPKC-specific inhibitor Go 6976, in a concentration-dependent manner, increased the percentage of cells undergoing apoptosis induced by anti-CD95 mAb as demonstrated by propidium iodide (PI) staining, TUNEL assay and DNA fragmentation by gel electrophoresis. Furthermore, Go 6976 and GF 109203X abrogated phorbol myristate acetate-induced inhibition of anti-CD95-induced apoptosis. To examine the molecular mechanism by which PKC modulates anti-CD95-induced apoptosis, the effects of Go 6976 on known effector and regulatory molecules of cell death were studied. Increased recruitment of cells undergoing apoptosis was associated with enhanced anti-CD95-induced proteolytic cleavage of the most receptor-proximal cysteine protease caspase-8, subsequent cleavage and activation of the machinery protease caspase-3, and cleavage of the caspase substrates DNA-dependent protein kinase catalytic subunit, poly-(ADP-ribose) polymerase and lamin B1. CD95 and FADD protein levels in Jurkat T cells were not altered by Go 6976 treatment. In addition, Go 6976 did not alter protein levels and subcellular distribution of the anti-apoptotic molecules Bcl-2 and Bcl-xL. These data suggest indirectly that basal PKC activity acts at an early stage in the anti-CD95-induced caspase pathway to attenuate subsequent activation of downstream effector molecules and associated apoptosis in Jurkat T cells.
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PMID:Inhibition of the protein kinase C pathway promotes anti-CD95-induced apoptosis in Jurkat T cells. 970 Oct 26


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