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)

A protein kinase that is activated by calcium and lipid has been partially purified from the plasma membrane of oat roots. This protein kinase cross-reacts with four monoclonal antibodies directed against a soluble calcium-dependent protein kinase from soybean described previously [Putman-Evans, C. L., Harmon, A. C., & Cormier, M. J. (1990) Biochemistry 29, 2488-2495; Harper, J. F., Sussman, M. R., Schaller, G. E., Putnam-Evans, C., Charbonneau, H., & Harmon, A. C. (1991) Science 252, 951-954], indicating that the oat enzyme is a member of this calcium-dependent protein kinase family. Immunoblots demonstrate that the membrane-derived protein kinase is slightly larger than that observed in the cytosolic fraction of oat. Limited digestion of the membrane-derived kinase with trypsin generates a smaller water-soluble kinase that is still activated by calcium but is no longer activated by lipid. When posthomogenization proteolysis is minimized, the bulk of the immunoreactive kinase material is localized in the membrane. These results suggest that a calcium-dependent protein kinase observed in the supernatant fraction of oat extracts may originate in situ from a calcium- and lipid-dependent protein kinase which is associated with the oat plasma membrane. They further indicate that, in contrast to animal cells, the predominant calcium- and lipid-dependent protein kinase associated with the plasma membrane of plant cells has biochemical properties and amino acid sequence unlike protein kinase C.
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PMID:Characterization of a calcium- and lipid-dependent protein kinase associated with the plasma membrane of oat. 173 26

The activities of several hepatic enzymes are preferentially zonated to the periportal or perivenous cells of the liver acinus. Employing dual-digitonin-pulse perfusion of rat liver in the study of acetyl-CoA carboxylase (ACC), we have identified a heretofore unrecognized feature of hepatic zonation, namely an intrahepatic gradient in enzyme specific activity. ACC activity shows a relative periportal localization in normally feeding rats, even when corrected for ACC protein mass. In contrast with results previously reported by us [Evans, Quistorff & Witters (1989) Biochem. J. 259, 821-829], the total mass of both hepatic ACC isoenzymes was not found to differ between the two hepatic zones in the present study. In perfusion eluates from fed animals, periportal ACC displays enhanced citrate reactivity and two kinetic components of acetyl-CoA reactivity; the largest periportal/perivenous gradient (5-fold) is accounted for by a species with a lower Km for acetyl-CoA. The zonal gradient in ACC maximal velocity, measured in eluates from fed rats, does not persist after ACC purification, although the isolated periportal enzyme, like dephosphorylated ACC, has a lower activation constant for citrate. Total ACC protein phosphatase activity is higher in periportal eluates, but no differences in the activities of either a 5'-AMP-activated ACC kinase or the cyclic-AMP-dependent protein kinase are noted between the hepatic zones. The induction of total hepatic ACC mass and specific activity, on fasting/refeeding with a high-carbohydrate diet, abolishes the periportal/perivenous activity gradient, largely owing to a selective activation of perivenous enzyme. Nutritional induction is also accompanied by a marked alteration in ACC acetyl-CoA kinetics and abolition of the gradient in total ACC phosphatase. These studies indicate that hepatic enzyme zonation, which is often attributed to differential expression of enzyme protein, may result from zonal variations in enzyme specific activity, owing to differences in allosteric regulation and/or covalent modification.
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PMID:Hepatic zonation of acetyl-CoA carboxylase activity. 197 69

A novel calcium-dependent protein kinase (CDPK) previously reported to be activated by the direct binding of Ca2+, and requiring neither calmodulin nor phospholipids for activity [Harmon, A.C., Putnam-Evans, C.L., & Cormier, M.J. (1987) Plant Physiol. 83, 830-837], was purified to greater than 95% homogeneity from suspension-cultured soybean cells (Glycine max, L. Wayne). Purification was achieved by chromatography on DEAE-cellulose, phenyl-Sepharose, Sephadex G-100, and Blue Sepharose. The purified enzyme (native molecular mass = 52,200 Da) resolved into two immunologically related protein bands of 52 and 55 kDa on 10% SDS gels. Enzyme activity was stimulated 40-100-fold by micromolar amounts of free calcium (K0.5 = 1.5 microM free calcium) and was dependent upon millimolar Mg2+. CDPK phosphorylated lysine-rich histone III-S and chicken gizzard myosin light chains but did not phosphorylate arginine-rich histone, phosvitin, casein, protamine, or Kemptide. Phosphorylation of histone III-S, but not autophosphorylation, was inhibited by KCl. CDPK displayed a broad pH optimum (pH 7-9), and kinetic studies revealed a Km for Mg2(+)-ATP of 8 microM and a Vmax of 1.7 mumol min-1 mg-1 with histone III-S (Km = 0.13 mg/mL) as substrate. Unlike many other protein kinases, CDPK was able to utilize Mg2(+)-GTP, in addition to Mg2(+)-ATP, as phosphate donor. The enzyme phosphorylated histone III-S exclusively on serine; however, CDPK autophosphorylated on both serine and threonine residues. These properties demonstrate that CDPK belongs to a new class of protein kinase.
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PMID:Purification and characterization of a novel calcium-dependent protein kinase from soybean. 233 77

The activity ratio of hepatic cyclic AMP-dependent protein kinase has been found to change with increasing age in male, Long-Evans rats. In rats 35 days old (135 g), the activity ratio (cyclic AMP-dependent protein kinase activity measured in the absence and presence of exogenous cyclic AMP) was 0.76, it increased to 0.92 in rats 75 days old (315 g) and to 0.98 in rats 305 days old (646 g). This change in the activity ratio seems to correlate with the ability of aging animals to respond to a stimulus, and may be a primary mechanism in the biochemistry of aging.
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PMID:Altered activation of rat hepatic cyclic AMP-dependent protein kinases with increasing age. 628 36

Between the catalytic and regulatory domains of calmodulin-like domain protein kinase, CDPK, is a junction domain which has some identity to the autoinhibitory domain of calmodulin-dependent protein kinase type II (Harper, J. F., Sussman, M. R., Schaller, G. E., Putnam-Evans, C., Charbonneau, H., & Harmon, A. C. (1991) Science 252, 951-954). To investigate whether CDPK's junction domain also functions as an autoinhibitory domain, we determined the effect of synthetic peptides, corresponding to sequences within the junction domain, on the activity of native soybean CDPK. Three peptides, corresponding to residues 310-332, 318-332, 302-317, were competitive inhibitors with respect to syntide-2 and had Ki values of 5, 25, and 85 microM, respectively. These peptides were uncompetitive inhibitors with respect to ATP and had Ki values of 24, 220, and 510 microM, respectively. A fourth peptide, CDPK alpha 302-332, inhibited activity by a mixed mechanism with respect to both syntide-2 (Ki = 1.9 microM; K'i = 5.0 microM) and ATP (Ki = 15 microM; K'i = 4.5 microM). Three of the peptides, CDPK alpha 302-332, 310-332, and 318-332, formed complexes with soybean calmodulin during electrophoresis in native polyacrylamide gels and were able to inhibit calmodulin-dependent protein kinases. Given the similarity between CDPK's calmodulin-like domain and calmodulin (40% sequence identity), it was possible that these peptides could inhibit activity through interaction with the calmodulin-like domain rather than the catalytic domain. To address this possibility, a cDNA encoding the first 312 residues of soybean CDPK alpha was constructed and expressed in Escherichia coli. This enzyme, which is missing most of the junction domain and all of the calmodulin-like domain, was active in the presence and absence of calcium. Peptide CDPK alpha 310-332 inhibited this truncated enzyme competitively with respect to syntide-2 (Ki = 4 microM). These results show that the junction domain is capable of functioning as an autoinhibitory domain, possibly through a pseudosubstrate site located between residues 310 and 332.
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PMID:Pseudosubstrate inhibition of CDPK, a protein kinase with a calmodulin-like domain. 800 91

Protein kinase C (PKC)-mediated phosphorylation has been implicated in neuronal growth and differentiation [R.S. Turner, R.L. Mazzei, G.J. Raynor, P.R. Girard, J.F. Kuo, Proc. Natl. Acad. Sci. U.S.A., 81 (1984) 3143-3147.]. We examined effects of gestational exposure to the neurotoxicant, methylmercury (CH3Hg), on the developmental profile of immunoreactivity (IR) for alpha, beta, gamma and epsilon PKC isoforms and cytosolic PKC activity. Long-Evans dams were dosed on gestational days (GD)6-15 (p.o.) with 0, 1, or 2 mg kg-1 day-1 CH3Hg dissolved in saline. Pups were sacrificed and perfused with buffered paraformaldehyde on post-natal days (PND) 1, 4, 10, 21, 45 and 85. The brains were sectioned sagittally, stained immunohistochemically, and examined throughout the medial to lateral extent. IR in neuronal cell bodies for PKC isoforms alpha, beta, gamma, and epsilon was densest in the olfactory bulb, hippocampus, shell of the inferior colliculus, pons, cerebral, piriform, and cerebellar cortex, whereas axonal staining was prominent in the brainstem, internal capsule, corpus callosum, anterior commissure, fornix and olfactory tract. In controls, the PKC alpha and epsilon IR was highest on PND1-4, decreased dramatically by PND10, and decreased further by PND21. In the neonate, the regional and cellular distributions of alpha and epsilon IR were similar. The PKC gamma IR was greater at post-weaning ages (PND21-85) with the greatest regional density apparent in the hippocampus, cortex, and cerebellum. Only the highest dose of CH3Hg (2 mg kg-1 day-1; GD6-15) produced a persistent decrease in regional alpha and epsilon, but not beta or gamma IR during the post-natal period. These regional and time-dependent changes in PKC isoforms were complemented by the examination of PKC activity in cortex, olfactory bulb, cerebellum and brainstem. Cytosolic PKC activity increased from PND1 to 10 in cortex, olfactory bulb, and cerebellum. On PND21, PKC activity decreased in the cortex and olfactory bulb, but remained high in the cerebellum. By contrast, PKC activity in the brainstem was highest on PND1 and 4 and decreased dramatically by PND21. CH3Hg (2 mg kg-1 day-1) significantly decreased PKC activity on PND1 and 4 in the cortex. The present results characterize the cellular and regional ontogeny of PKC isoenzymes alpha, beta, gamma and epsilon, and indicate that developmental exposure to CH3Hg can alter the ontogeny of specific isoforms and regional PKC activity.
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PMID:Effects of gestational methylmercury exposure on immunoreactivity of specific isoforms of PKC and enzyme activity during post-natal development of the rat brain. 970 89

This study tests the hypothesis that activation of protein kinase C (PKC) is a critical step for early recovery from spontaneous nystagmus after unilateral ablation of the vestibular periphery. Halothane-NO(2)-O(2)-anesthetized Long-Evans rats received a 5-microl intracerebroventricular bolus of vehicle (distilled water, six rats), PKC inhibitor [Iso-H-7 (10 mM, four rats; 50 mM, five rats) or bisindolemaleimide I (Bis-I, 10 microM six rats)], PKG and PKA inhibitor (A-3, 1 mM, six rats), or the serine-threonine protein kinase inhibitor H-7 (1 mM, five rats; 10 mM, five rats). Surgical unilateral labyrinthectomy (UL) was completed within 15 min. Sham control groups showed no nystagmus. Bis-I and Iso-H-7 significantly retarded the disappearance of spontaneous nystagmus quick phases for 8 h after UL (p<0.05). The effects of Iso-H-7 were dose-dependent: more nystagmus quick phases (p<0.05) were present in the 50 mM than the 10 mM group at 7 and 8 h post-UL. The rats given A-3 showed a delayed retardation of nystagmus loss, which differed significantly (p<0.05) from controls at 4-8 h after labyrinthectomy. The number of nystagmus quick phases was significantly greater than controls (p<0. 05) in the 10 mM H-7 group at 4, 5, 6 and 48 h post-UL, but only at 6 and 24 h post-UL in the 1 mM H-7 group. Thus, PKC activation is an important early requirement for vestibular compensation during the acute post-labyrinthectomy period, while cyclic-nucleotide dependent kinases may be important in a later time frame.
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PMID:Protein kinase C inhibition blocks the early appearance of vestibular compensation. 1052 48

Amplification found in a number of cyclin genes, especially in cyclin D and E, is an important event process that takes place in cancers, including hepatocellular carcinoma (HCC). The activities of a wide range of cell cycle-related kinases remain obscure in HCC. The purpose of the present study is to determine the cyclins and kinase activities of HCC in Long-Evans Cinnamon (LEC) rats. Cyclin D1, E, A, H, Cdk1(cyclin-dependent kinase; Cdc2), Cdk4, and Cdk6 protein levels were determined by Western blot analysis at different pathologic stages of liver tissues exhibiting HCC. Enzymatic activities of cyclin D1, E, A, Cdk4, Cdk6, Cdc2, Cdk7, and Wee1 kinase were measured by in-gel kinase assay. Protein levels and kinase activities of cyclin D1, E, Cdk4, cyclin A, and Wee1 increased proportionally with the development of HCC, especially in the transition process from chronic hepatitis to HCC. Although Cdc2 kinase activity was found to increase slightly from normal liver to chronic hepatitis, its activity remained unchanged in the process from chronic hepatitis to HCC. Cdk6 and Cdk7 activities remained unchanged in the process from normal liver to HCC. These data suggest that the increase in Cdc2 kinase may play a role in the process from normal liver to chronic hepatitis, whereas the predominant increase in cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 suggests involvement not only in the process from normal liver to chronic hepatitis, but also during transition into HCC.
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PMID:Hepatocellular carcinoma cell cycle: study of Long-Evans cinnamon rats. 1100 14

Mammalian cell cycle progression is regulated by the combined action of cyclins/cyclin-dependent kinases (CDKs) and CDK inhibitors. Abnormal expression as well as interaction of these proteins may result in malignant transformation of cells. To further address the role of these cell cycle proteins in hepatocellular carcinomas, we analyzed the expression of cyclin E and CDK2. A panel of livers with human hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis were used as a human experimental system. The inbred LEC (Long-Evans with a cinnamon-like coat color) rats were used as an animal experimental HCC model. Immunohistochemical staining of serial paraffin sections was performed using antibodies to cyclin E and CDK2. The results showed that cyclin E and CDK2 were concurrently overexpressed in hepatocellular carcinomas both in human and rat livers. Western blot analysis and CDK2 kinase assay demonstrated expression levels of cyclin E and CDK2 and CDK2 kinase activity, respectively, and both were shown to increase along with the development of hepatocellular carcinomas. Analysis of the correlation between expression of cyclin E and CDK2 and clinicopathological parameters revealed a significant correlation between expression of cyclin E and tumor grade (P=0.013), and PCNA index (P=0.006) as well as CDK2 expression (P=0.015). Overexpression of CDK2 tended to be associated with poorly differentiated HCCs. The results suggest that overexpression of cyclin E and CDK2 plays an important role in the development of hepatocellular carcinoma.
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PMID:Overexpression of cyclin E and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas. 1147 Jun 26

ATP causes relaxation of the K(+)-contracted rat vas deferens. Possible sites of action were investigated. ATP and adenosine relaxed the vas deferens precontracted with 80 mM K(+); EC(50) values and maximal relaxations averaged, respectively, 760 microM and 56% for ATP and 74 microM and 30% for adenosine. The adenosine P1 receptor antagonist 8-(para-sulfophenyl)theophylline (8-SPT) reduced relaxations caused by adenosine and low concentrations of ATP, as did the Rp-diastereomer of adenosine 3',5'-cyclic phosphorothioate (Rp-cAMPS), an inhibitor of protein kinase A. The phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) augmented responses to adenosine and low concentrations of ATP. alpha,beta-Methylene ADP, an inhibitor of 5'-nucleotidase, reduced relaxations caused by ATP to a similar extent as did 8-SPT. In the presence of an almost saturating concentration of adenosine, ATP caused further relaxation. Conversely, in the presence of ATP, adenosine had little effect. Like ATP, UTP and other nucleoside triphosphates relaxed the vas deferens. The P2 receptor antagonists reactive blue 2, acid blue 25 and 4,4'-diisothiocyanotostilbene-2,2'-disulphonate (DIDS) attenuated the relaxation caused by ATP; suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulphonate (PPADS), Evans blue, trypan blue, reactive red 2 and brilliant blue G had no effect. Three non-selective inhibitors of protein kinases, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), staurosporine and (8R*,9S*,11S*)-(-)-9-hydroxy-9-carboxy-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one (K-252b), markedly reduced the relaxation caused by ATP. The results indicate that adenosine, derived from enzymatic dephosphorylation, contributes to the relaxant effect of ATP, presumably by activation of a smooth muscle adenosine receptor linked to the accumulation of cAMP and activation of protein kinase A. Yet, the main part of the response to ATP is mediated by a site distinct from the adenosine receptor. The pharmacological properties of this site differ from known P2 receptor subtypes. Possibly, the nucleotide-evoked relaxation is due to a phosphoryl transfer catalyzed by an ecto-protein kinase.
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PMID:Nucleotide-evoked relaxation of rat vas deferens: possible mechanisms. 1183 57


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