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)

We used proximal tubule-derived opossum kidney (OK) cells to determine the dependence of albumin endocytosis on regulation by protein kinases and on the cytoskeleton. Uptake was observed only across the apical but not the basolateral membrane and exceeded uptake in collecting duct-derived Madin-Darby canine kidney cells 14-fold. Inhibition of endocytosis via clathrin-coated vesicles but not via caveolae abolished uptake. Cytochalasin D reduced uptake to < 5% of control, and inhibition of microtubule polymerization by nocodazole reduced uptake to approximately 55% of control. Activation of protein kinase A (PKA) by adenosine 3',5'-cyclic monophosphate, forskolin, or parathyroid hormone (PTH) reduced uptake to approximately 65% of control. Protein kinase C (PKC) activation did affect uptake to a similar extent as PKA activation but with a certain delay. Stimulation of PKG by guanosine 3',5'-cyclic monophosphate did not affect albumin endocytosis. The inhibitor of tyrosine kinases (TRK), genistein, induced an increase of uptake to approximately 160% of control. Reexocytosis of albumin was enhanced by PKC activation but not by PKA activation. TRK inhibition reduced the rate of reexocytosis. We conclude that albumin endocytosis in OK cells requires the integrity of the actin cytoskeleton. Microtubules facilitate endocytosis. Uptake is regulated by PKA, PKC, and TRK, yet with different time course and by different mechanisms, e.g., reexocytosis. Possibly TRK activity serves in a negative feedback loop to limit albumin endocytosis via a stimulation of reexocytosis.
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PMID:Albumin endocytosis in OK cells: dependence on actin and microtubules and regulation by protein kinases. 917 79

Krabbe's disease (globoid cell leukodystrophy) is a progressive cerebral degenerative disease of infancy characterized by severe myelin loss and the presence of globoid bodies in the white matter. Previous studies have suggested that psychosine is the causative agent for the pathogenesis of Krabbe's disease. In the present study, we investigated psychosine-induced injury and cell death of oligodendrocytes in enriched cultures of oligodendrocytes prepared from 3-week-old rat brain. The psychosine concentration sufficient to induce 50% cell death in oligodendrocytes was 30 micrograms/ml in the medium containing serum and 10 micrograms/ml in the serum-free medium. When oligodendrocytes were exposed to psychosine in the presence of phorbol esters, insulin, insulin-like growth factor I (IGF-I), demethylsulfoxide, or serum albumin, the survival of oligodendrocytes was greatly increased. These results indicate that psychosine cytotoxicity against oligodendrocytes is blocked by phorbol esters, insulin, and IGF-I through activation of protein kinase-C, by dimethylsulfoxide through activation of beta-galactosidase, and by albumin through its binding to psychosine.
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PMID:Tissue culture model of Krabbe's disease: psychosine cytotoxicity in rat oligodendrocyte culture. 921 77

Myosin light chain (MLC) phosphorylation catalyzed by the Ca(2+)- calmodulin-dependent MLC kinase (MLCK) is critical to thrombin-mediated endothelial cell gap formation and barrier dysfunction. We have tested the hypothesis that the Ca2+ ionophore ionomycin stimulates MLCK-dependent endothelial cell contraction and permeability. Ionomycin significantly increased albumin clearance and decreased electrical resistance across confluent bovine pulmonary microvascular and macrovascular endothelial cell monolayers in a concentration-dependent manner that was temporally similar to that produced by thrombin. In contrast, however, ionomycin produced a significant Ca(2+)-dependent reduction in the levels of phosphorylated MLC with evidence of serine/threonine phosphatase activation. Potential MLCK-independent mechanisms of endothelial cell permeability were examined with little evidence to support a role for stimulated nitric oxide synthase or phospholipase A2 activities. Importantly, ionomycin produced 1) reductions in the activities of the barrier protective adenylate cyclase and the adenosine 3',5'-cyclic monophosphate-dependent protein kinase A, 2) dramatic dose- and time-dependent inhibition of endothelial cell tyrosine kinase activities, and 3) marked decreases in the phosphotyrosine content of the p125 focal adhesion kinase. These data indicate that ionomycin produces endothelial cell barrier dysfunction by mechanisms that are independent of MLCK activation and may involve reductions in endothelial cell tethering forces via inhibition of protein kinase A and tyrosine kinase activities, especially the p125 focal adhesion kinase.
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PMID:Mechanisms of ionomycin-induced endothelial cell barrier dysfunction. 925 54

Protein phosphorylation is an important mechanism for regulation of cell processes. Bilirubin inhibits phosphorylation of several peptides/proteins by a number of different kinases, and this may contribute to the toxic effects of bilirubin on cells, particularly neurons. Bilirubin binds to lysine residues on both albumin and ligandin. The ATP-binding subdomain II on protein kinases contains an invariant lysine, which might hypothetically be involved in mediation or modulation of bilirubin-inhibition of protein phosphorylation. We have studied the ability of lysine-containing peptides to modulate the effects of bilirubin, using phosphorylation of a phospholemman peptide catalyzed by protein kinase A as a model system. Addition of bilirubin (50 microM) decreased the activity of the catalytic subunit of protein kinase A by 75%. A synthetic lysine-containing decapeptide which mimicked part of subdomain II on the protein kinase family was partially able to prevent the bilirubin effects. Similar effects were not observed with two other decapeptides in which lysine had been replaced by arginine or alanine. Polylysine (100 microM) completely prevented the inhibitory effect of 50 microM bilirubin, whereas polyglutamate and polyarginine did not have this effect. Poly-D-lysine and poly-L-lysine appeared to be equivalent in their ability to prevent the bilirubin effect. These data support the notion that binding of bilirubin to lysine may play a role in the mediation and/or modulation of bilirubin neurotoxicity.
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PMID:Modulation of the effect of bilirubin on protein phosphorylation by lysine-containing peptides. 935 33

Our previous studies have shown that inflammatory mediators increase microvascular permeability through a phospholipase C-nitric oxide synthase (NOS)-guanylate cyclase cascade. The aim of this study is to delineate in more detail the signaling pathway leading to microvascular hyperpermeability. Endothelial cytosolic calcium and the apparent permeability coefficient of albumin (Pa) were measured in isolated and perfused coronary venules. Histamine stimulated a rapid increase in cytosolic calcium followed by a transient elevation in Pa. The NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) and the guanosine 3',5'-cyclic monophosphate-dependent protein kinase G (PKG) inhibitor KT-5823 abolished the hyperpermeability but did not affect the calcium response to histamine. Similarly, the calcium ionophore ionomycin produced a calcium spike preceding venular hyperpermeability. Blockage of the NOS-PKG cascade inhibited the increase in Pa, whereas the endothelial calcium was still elevated on administration of ionomycin. Furthermore, the relationship between protein kinase C (PKC) and the calcium-NOS-PKG pathway in modulation of venular permeability was investigated. Stimulation of PKC with phorbol 12-myristate 13-acetate (PMA) dramatically increased basal Pa without significantly changing the cytosolic calcium level. The selective PKC inhibitor bisindolylmaleimide abolished the effect of PMA but did not alter the effect of histamines on Pa. In contrast, both L-NMMA and KT-5823 were able to greatly attenuate the increase in Pa caused by PMA. These results suggest that 1) elevation of endothelial cytosolic calcium is an early signaling event preceding nitric oxide (NO) synthesis in the transduction of endothelial hyperpermeability, and 2) activation of PKC may alter the endothelial barrier function partially through the modulation of NO production.
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PMID:Interaction of PKC and NOS in signal transduction of microvascular hyperpermeability. 937 83

We questioned the mechanism of the increase in pulmonary endothelial permeability induced by tumour necrosis factor-alpha (TNF-alpha), a cytokine implicated in the pathogenesis of adult respiratory distress syndrome. As a measure of permeability, we determined the albumin transferred across cultured pulmonary endothelial monolayers prepared on a porous filter. The agents evaluated included protein kinase inhibitors H-7 and H-8, a calmodulin antagonist W-7, and protein kinase C (PKC) activators, phorbol myristate acetate (PMA) and SC-9. H-7, more potent in inhibiting PKC than H-8, failed to attenuate the increase in permeability induced by TNF-alpha. Neither PMA nor SC-9 increased permeability. However, H-8, which is a potent inhibitor of cyclic nucleotide-dependent protein kinases, prevented the increase in permeability induced by TNF-alpha. These results suggest that protein kinase other than PKC are involved in the signal transduction in endothelial permeability increase induced by TNF-alpha. Calmodulin pathway may not be implicated in the increase in permeability induced by TNF-alpha.
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PMID:Protein kinase inhibitor attenuates an increase in endothelial monolayer permeability induced by tumour necrosis factor-alpha. 942 6

A cyclic AMP (cAMP)-inducible enhancer in the pig urokinase-type plasminogen activator gene located 3.4 kb upstream of the transcription initiation site is composed of three protein-binding domains, A, B, and C. Domains A and B each contain a CRE (cAMP response element)-like sequence but require the adjoining C domain for full cAMP responsiveness. A tissue-specific transcription factor, LFB3/HNF1beta/vHNF1, binds to the C domain. Mutation analyses suggest that the imperfect CRE and LFB3-binding sequences are required for tight coupling of hormonal and tissue-specific regulation. CREB and ATF1 bind to domains A and B, and this binding is enhanced upon phosphorylation by cAMP-dependent protein kinase (protein kinase A [PKA]). Analysis in a mammalian two-hybrid system revealed that CREB/ATF1 and LFB3 interact and that transactivation potential is enhanced by PKA activation. Interestingly, however, phosphorylation of CREB at Ser-133 does not contribute to its interaction with LFB3. The region of LFB3 involved in its interaction with CREB/ATF1 lies, at least partly, between amino acids 400 and 450. Deletion of this region removed the ability of LFB3 to mediate cAMP induction of the ABC enhancer but did not impair its basal transactivation activity on the albumin promoter. Thus, the two activities are distinct functions of LFB3.
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PMID:Role of tissue-specific transcription factor LFB3 in a cyclic AMP-responsive enhancer of the urokinase-type plasminogen activator gene in LLC-PK1 cells. 967 80

Heavy metal ions can be released by corroding metallic implants into the surrounding tissue. When they enter blood vessels some of them are carried by proteins like albumin and can be taken up by endothelial cells lining the vessels. To study their involvement in the inflammatory response we investigated heavy metal ion induced effects in cultured human vascular endothelial cells (HUVECs). NiCl2 and CoCl2 upregulate, especially in concentrations of 1 mM, the expression of adhesion molecules (e.g., E-selectin and intercellular adhesion molecule-1), as well as the cytokines IL-6 and IL-8, as shown by enzyme immunoassay and Northern blot analysis. In addition, possible signal transduction mechanisms were elucidated. The HUVECs were treated with various selective inhibitory drugs followed by the incubation of metal ions before measuring the expression of the above-mentioned endothelial factors. Two protein kinase inhibitors (H-7 and H-8) strongly repressed Ni2+ and Co2+ enhanced expression, as did the phospholipase A2 inhibitor quinacrine. Other selective inhibitors of protein kinases C or A, or cGMP-dependent protein kinases, as well as calcium antagonists like 1,2-bis(2-aminophenoxy)ethan-N,N,N',N'-tetraacetic acid and 3,4,5-trimethoxybenzosaure 8-(diethylamino)-octylester and inhibitors of receptor mediated endocytosis (primary amines), had no influence. We showed that NiCl2 and CoCl2 activate the translocation of the transcription factor nuclear factor (NF)-kappaB into the cell nucleus and enhance its binding to a NF-kappaB consensus sequence as shown by mobility shift analysis. Furthermore, we demonstrated the activation of AP-1. Despite the repression of heavy metal induced adhesion molecule synthesis, we did not detect any inhibition of NF-kappaB translocation by H-7 or H-8. Therefore, it must be concluded that heavy metal ions like Ni2+ and Co2+ activate two or more signal transduction pathways in endothelial cells. We clearly showed that there is one pathway in which H-7 and H-8 sensitive protein kinases are involved and a second pathway leading to NF-kappaB activation, which is insensitive to H-7 and H-8. Our results demonstrate that heavy metal ions induce mechanisms of gene activation in endothelial cells as do proinflammatory mediators, indicating that corroding metal ion containing biomaterials can provoke inflammatory reactions by known, as well as by yet unknown, intracellular signaling pathways.
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PMID:Mechanisms of cell activation by heavy metal ions. 1088 Jan

The atrial natriuretic peptide (ANP)-C receptor is generally believed to clear ANP; however, the ANP-C receptor may serve to reduce cAMP by inhibiting adenylate cyclase. ANP decreases endothelial permeability in coronary endothelial cell monolayers. We tested the hypothesis that part of this effect might be mediated by the ANP-C receptor. We used an endothelial cell monolayer from rat coronary endothelium and measured albumin flux. We applied either ANP or a ring-deleted ANP (C-ANP), which only stimulates the ANP-C receptor. ANP and C-ANP both decreased permeability from 100 pM to 100 nM by 60 and 30%, respectively. ANP increased endothelial cGMP contents 5.5-fold, whereas C-ANP had no effect. ANP reduced endothelial cAMP contents by 75%, which was only partly blocked by pertussis toxin. C-ANP also reduced cAMP; however, this effect was completely blocked by pertussis toxin. Protein kinase G inhibition blocked the ANP-mediated decrease in permeability by 50%. In contrast, pretreatment with pertussis toxin, in the face of protein kinase G inhibition, blocked the effect completely. C-ANP decreased permeability by half the amount of ANP. This C-ANP effect was completely blocked by pertussis toxin but not by protein kinase G inhibition. Isoproterenol (10 microM) increased permeability by almost 50%, which was completely blocked by ANP but only partially blocked by C-ANP. The C-ANP effect was blocked completely by pertussis toxin. Isoproterenol increased cAMP threefold, which was abolished by ANP. C-ANP reduced the isoproterenol-induced increase in cAMP by 50%. Isoproterenol had no effect on cGMP. We conclude that agonist binding to the ANP-C receptor inhibits cAMP production via a Gi protein-coupled signaling system. This inhibition may contribute to the decreased endothelial permeability evoked by ANP in this system.
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PMID:Atrial natriuretic peptide clearance receptor participates in modulating endothelial permeability. 981 90

Butyrolactone I is a selective inhibitor of the cyclin-dependent kinase (cdk) family, cdk2 and cdc2 kinase. In the present study, the effect of butyrolactone I on expression of the albumin and alpha-fetoprotein (AFP) genes was investigated in HuH-7 human hepatoma cells. Butyrolactone I inhibited cell growth and arrested cells predominantly in G2/M phase. By Northern blot analysis, the levels of both albumin and AFP mRNA were suppressed dose-dependently by butyrolactone I. In transient chloramphenicol acetyltransferase plasmid transfection experiments, the albumin promoter activity and the AFP promoter and enhancer activities were suppressed by butyrolactone I. Consistent with this, the transcripts of hepatocyte nuclear factor-1 (HNF-1), a liver-specific transcription factor which transactivates these promoter and enhancer regions were reduced by butyrolactone I in a dose-dependent manner. These results indicate that butyrolactone I down-regulates both the albumin and the AFP gene transcription through the reduction of HNF-1 expression.
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PMID:Suppression of albumin and alpha-fetoprotein gene expression by butyrolactone I, a selective inhibitor of the cdk family, in HuH-7 human hepatoma cells. 989 85


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