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)

To determine the role of the stimulatory guanine nucleotide-binding protein, Gs, and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase in the basal metabolism of beta-adrenergic receptors in S49 lymphoma cells, we measured the return of receptor number and function after irreversible blockade of receptors. After inactivation of receptors with the irreversible ligand N8-(bromoacetyl)-N'-[3-(4-indolyoxy)-2-hydroxypropyl]-(2)-1,8-diam ino-p- methane (BIM), beta-adrenergic receptors (defined as [125I]iodocyanopindolol binding sites) reappeared in a biphasic manner, the faster phase having a half-time (t 1/2) of 3-8 h (approximately 50% of the sites) and the slower phase greater than 40 h. Although the slow phase is not readily explained, recovery of binding sites during the first 10 h matched recovery of receptor function after BIM treatment (as measured by stimulation of cAMP accumulation) and recovery of receptor sites after downregulation induced by the agonist isoproterenol. Thus quantifying receptor recovery during the first 10 h after BIM treatment appears to be a reasonable method for examining basal receptor metabolism in S49 cells. Measured in this way, metabolism of beta-adrenergic receptors is very similar in wild-type S49 and the following variant clones: cyc- (absent Gs alpha), UNC and H21a (defective Gs alpha), and kin- (lacking cAMP-dependent protein kinase activity). Although previous data have demonstrated that agonist-promoted downregulation of beta-adrenergic receptors requires functional receptor-Gs coupling, the current data suggest that neither Gs nor cAMP-dependent protein kinase activity plays an important role in the regulation of basal metabolism of beta-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beta-adrenoceptor metabolism in wild-type, Gs, and protein kinase A-variant S49 cells. 197

The addition of thrombopoietin (TPO) to HEL cells, cultured in a chemically defined serum-free medium, induced a rapid and dose-dependent phosphorylation of the transcription factor CREB on serine133 (PSer133), as detected by Western blot analysis. TPO also significantly increased the transactivation of CRE-dependent promoter, as determined in transient transfection experiments. On the other hand, neither erythropoietin (Epo; 1 to 10 U) nor hemin (10 (-7) mol/L) were able to significantly stimulate CREB-PSer133 or to activate CRE-promoter in HEL cells. Although pharmacological inhibitors of protein kinase C (chelerytrine and BIM) and protein kinase A (H-89) failed to block the TPO-mediated CREB phosphorylation, a specific inhibitor of the mitogen-activated protein kinases (PD98059) completely blocked the ability of TPO to stimulate CREB-PSer133. Moreover, PD98059 significantly decreased the ability of TPO to upregulate the surface expression of the alphaIIIbbeta3 megakaryocytic marker in HEL cells. In parallel, primary CD34+ hematopoietic cells were seeded in liquid cultures supplemented with 100 ng/mL of TPO and examined by immunofluorescence for the coexpression of alphaIIIbbeta3 and CREB-PSer133 at various time points. High levels of nuclear CREB-PSer133 were unequivocally demonstrated in alphaIIIbbeta3+ cells, including morphologically recognizable megakaryocytes. Taken together, these data suggest that CREB plays a role in modulating the expression of genes critical for megakaryocyte differentiation and that the TPO-mediated CREB phosphorylation seems to be regulated via mitogen-activated protein kinases.
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PMID:The induction of megakaryocyte differentiation is accompanied by selective Ser133 phosphorylation of the transcription factor CREB in both HEL cell line and primary CD34+ cells. 965 46

The clotting enzyme thrombin is known to cause receptor-mediated contractile effects in isolated blood vessels. In the present studies the influence of protein kinase inhibitors on the contractile response of porcine pulmonary arteries to thrombin (3 U/ml) was investigated. Endothelium-denuded rings (2-3 mm) from small arteries were placed in organ baths for isometric tension recording. The vessels were preincubated for 30 min with the inhibitors before inducing contractions. In the presence of the protein kinase C (PKC)-inhibitors staurosporine, BIM I (bisindolyl-maleimide I), chelerythrine and Ro 31-8220 (1 microM each), the contractile responses to the PKC activator phorbol 12,13-dibutyrate (PDBu; 50 nM) were diminished by 70-100%. However, for inhibition of thrombin-induced contractions generally higher concentrations of the inhibitors were required. Only staurosporine at 1 microM inhibited the thrombin effect by about 75%. The tyrosine kinase inhibitor erbstatin (30 microM) did not significantly alter the thrombin effect, whereas genistein at 10 microM caused a significant inhibition of contractile responses to both thrombin and PGF2alpha. At 100 microM genistein also inhibited the contractile effects of PdBu and KCl. These studies suggest that activation of both PKC and non-receptor tyrosine kinases seems to be involved in the signal transduction pathways of thrombin-induced contractile effects in isolated vessels.
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PMID:Inhibition of thrombin-induced contractile responses by protein kinase inhibitors in porcine pulmonary arteries. 978 29

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation, thus optimizing gas exchange. NADPH oxidase-related superoxide anion generation has been suggested as part of the signaling response to hypoxia. Because protein kinase (PK) C activation can occur during hypoxia and PKC activation is known to be critical for NADPH oxidase stimulation in different cell types, we probed the role of PKC in hypoxic vasoconstriction in intact rabbit lungs. Control vasoconstrictor responses were elicited by angiotensin II (ANG II) and the stable thromboxane analog U-46619. Portions of the experiments were performed while NO synthesis and prostanoid generation were blocked with NG-monomethyl-L-arginine and acetylsalicylic acid to avoid confounding effects due to interference with these vasoactive mediators. The PKC inhibitor H-7 (10-50 microM) caused dose-dependent inhibition of HPV, but this agent lacked specificity because ANG II- and U-46619-induced vasoconstrictions were correspondingly suppressed. In contrast, low concentrations of the specific PKC inhibitor bisindolylmaleimide I (BIM; 1-15 microM) strongly inhibited the hypoxic vasoconstriction without any interference with the responses to the pharmacological agents. Superimposable dose-inhibition curves were also obtained for BIM when lung NO synthesis and prostanoid generation were blocked throughout the experiments. Under either condition, BIM did not affect normoxic vascular tone. The PKC activator farnesylthiotriazole (FTT), ascertained to stimulate rabbit NADPH oxidase by provocation of alveolar macrophage superoxide anion generation in vitro, caused rapid-onset, transient pressor responses in normoxic lungs. After FTT, the hypoxic vasoconstrictor response was totally suppressed, in contrast to the largely maintained pressor responses to ANG II and U-46619. The lungs became refractory even to delayed hypoxic challenges after FTT application. In conclusion, these data support the concept that activation of PKC is involved in the transduction pathway forwarding pulmonary vasoconstriction in response to alveolar hypoxia.
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PMID:Evidence for a role of protein kinase C in hypoxic pulmonary vasoconstriction. 988 60

Epithelio-mesenchymal transition, which involves the re-organisation of cell-cell adhesion molecules and the actin cytoskeleton, can be induced in embryonic neural epithelium in vitro by protein kinase-C inhibitors. A non-inhibitory analogue, BIM V, and potent inhibitors of other kinases are not active. This suggests a central role for C-kinases, although the powerful specific C-kinase inhibitors BIM I and Ro 31-8220 show lower than expected activity. Co-inhibition by several kinases is unlikely to account for this, since no potentiation occurs when these are combined with potent inhibitors of other kinases. BIM I and Ro 31-8220 strongly inhibit only conventional calcium-regulated C-kinases; this and the lack of effect of TMB-8, which inhibits calcium release, suggests that novel and/or atypical isoforms are involved. Various potentiators and activators of conventional and novel C-kinases have no obvious effect alone and fail to reduce the effect of staurosporine, suggesting that atypical C-kinases are critical. The presence of C-kinase isoforms in the E2 embryonic neural tissues has been probed on Western blots, revealing immunoreactivity for the atypical isoforms iota (or lambda) and zeta and the alpha, gamma, epsilon and mu isoforms. Immunofluorecent localisation on sections of embryos has shown the widespread distribution of conventional and novel isoforms but only the atypical isoforms lambda and zeta are enriched at the apical margins of the neural and other epithelia; they overlap with the cell-cell adhesion molecule N-cadherin and with F-actin. Thus, epithelio-mesenchymal transition in the embryonic neural epithelium in vitro is induced by inhibiting protein kinase activity, probably via an atypical protein kinase-C; atypical protein kinase-C isoforms are present in the tissue at the appropriate developmental stage and subcellular site in cells capable of epithelio-mesenchymal transition.
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PMID:Induction of epithelio-mesenchymal transformation of quail embryonic neural cells by inhibition of atypical protein kinase-C. 993 65

Intrinsic expression of the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) may be regulated by reactive oxygen species (ROS). A transient expression of Pgp was observed during the growth of multicellular tumor spheroids. Maximum Pgp expression occurred in tumor spheroids with a high percentage of quiescent, Ki-67-negative cells, elevated glutathione levels, increased expression of the cyclin-dependent kinase inhibitors p27Kip1 and p21WAF-1 as well as reduced ROS levels and minor activity of the mitogen-activated kinase (MAPK) members c-Jun amino-terminal kinase (JNK), extracellular signal-regulated kinase ERK1,2, and p38 MAPK. Raising intracellular ROS by depletion of glutathione with buthionine sulfoximine (BSO) or glutamine starvation resulted in down-regulation of Pgp and p27Kip1, whereas ERK1,2 and JNK were activated. Down-regulation of Pgp was furthermore observed with low concentrations of hydrogen peroxide and epidermal growth factor, indicating that ROS may regulate Pgp expression. The down-regulation of Pgp following BSO treatment was abolished by agents interfering with receptor tyrosine kinase signaling pathways, i.e. the protein kinase C inhibitors bisindolylmaleimide I (BIM-1) and Ro-31-8220, the p21ras farnesyl protein transferase inhibitor III, the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1,2 activation. ROS involved as second messengers in receptor tyrosine kinase signaling pathways may act as negative regulators of Pgp expression.
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PMID:Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. 1127 18

The effect of parathyroid hormone (PTH) and activation of protein kinase C (PKC) and protein kinase A (PKA) on transepithelial P(i) transport was examined in monolayers of chick proximal tubule cells in primary culture (PTCs). Acute exposure of the PTCs to PTH (10(-9) M, basolateral side) significantly decreased the net reabsorption of P(i) by approximately 66%. There was no effect after the addition of PTH to the luminal side. Activation of PKC by phorbol 12-myristate 13-acetate (PMA; 0.1 microM) dramatically decreased net P(i) reabsorption by approximately 60%. Bisindolylmaleimide I (BIM; 1 microM), a highly selective PKC inhibitor, prevented PMA-induced inhibition. Activation of adenylate cyclase/PKA by forskolin (10 microM) mimicked the effect of PTH by significantly reducing net P(i) reabsorption by one-half. Addition of H-89 (10 microM), a potent inhibitor of PKA, abolished forskolin-induced inhibition. PTH inhibition was blocked by either BIM or H-89. Tissue electrophysiology remained stable after all treatments. There was a decreased immunoreactivity of the luminal Na+-P(i) cotransporter NaPi-IIa after PTH treatment. These data indicate that PTH inhibition of P(i) reabsorption in this in vitro system is mediated by PKC and PKA.
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PMID:Regulation of transepithelial phosphate transport by PTH in chicken proximal tubule epithelium. 1174 32

Expression of tissue factor (TF) by activated monocytes may initiate thrombotic episodes associated with diseases, such as thrombosis and atherosclerosis. In this study, steps in the regulatory pathways of lipopolysaccharide (LPS)-induced monocyte TF activity and released TNF-alpha in human whole blood were probed for using an array of inhibitors, comprising specific inhibitors of cytosolic phospholipase A(2) (PLA(2)) (AACOCF(3)), secretory PLA(2) (SB-203347), protein kinase (PK) (staurosporine), PKC (GF-109203; BIM), and serine protease (Pefabloc SC), antagonists of thromboxane prostanoid (TP) receptor (R) (SQ-29548), platelet activating factor (PAF) R (BN-52021), leukotriene B(4) R (SC-41930), serotonin R (cyproheptadine), fibronectin/fibrinogen R (RGDS), and finally, creatine phosphate/creatine phosphokinase (CP/CPK) which removes ADP. Whereas when added alone neither of these agents significantly inhibited LPS-induced TF or TNF-alpha, when presented as a reference cocktail comprising all the agents, TF activity and TNF-alpha were reduced by 77% and 49%, respectively. By subsequently testing a series of incomplete inhibitory cocktails equal to the reference except for deleted single agents or combinations of two or three active agents, the inhibitory effect of the reference cocktail could be shown to depend on the presence of the protease inhibitor and the thromboxane A(2) and PAF antagonists.
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PMID:The central role of thromboxane and platelet activating factor receptors in ex vivo regulation of endotoxin-induced monocyte tissue factor activity in human whole blood. 1223 Sep 18

Cells of the vasculature, including macrophages, smooth muscle cells, and endothelial cells, exhibit apoptosis in culture upon treatment with oxidized low density lipoprotein, as do vascular cells of atherosclerotic plaque. Several lines of evidence support the hypothesis that the apoptotic component of oxidized low density lipoprotein is one or more oxysterols, which have been shown to induce apoptosis through the mitochondrial pathway. Activation of the mitochondrial pathway of apoptosis is regulated by members of the BCL family of proteins. In this study, we demonstrate that, in the murine macrophage-like cell line P388D1, oxysterols (25-hydroxycholesterol and 7-ketocholesterol) induced the degradation of the prosurvival protein kinase AKT (protein kinase B). This led, in turn, to the activation of the BCL-2 homology-3 domain-only proteins BIM and BAD and down-regulation of the anti-apoptotic multi-BCL homology domain protein BCL-xL. These responses would be expected to activate the pro-apoptotic multi-BCL homology domain proteins BAX and BAK, leading to the previously reported release of cytochrome c observed during oxysterol-induced apoptosis. Somewhat surprisingly, small interfering RNA knockdown of BAX resulted in a complete block of the induction of apoptosis by 25-hydroxycholesterol.
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PMID:AKT/protein kinase B regulation of BCL family members during oxysterol-induced apoptosis. 1455 20

The effects of somatostatin (SRIF, somatotropin release inhibiting factor) on the release of glutamate have been investigated using superfused mouse cerebrocortical synaptosomes. SRIF-14 inhibited the K+ (12 mM)-evoked overflow of preaccumulated [3H]D-aspartate as well as that of endogenous glutamate. Cyanamid 154806, a selective sst2 receptor antagonist, but not BIM-23056, an antagonist at sst5 receptors, prevented the SRIF-14 effect. Octreotide and L779976, selective agonists at sst2 receptors, mimicked SRIF-14, whereas L797591, L796778, L803087 and L362855, selective agonists at sst1, sst3, sst4 and sst5 receptor subtypes, were inactive. Activation of sst2 receptors seems to involve inhibition of the adenylyl cyclase-protein kinase A pathway present in glutamatergic terminals since the adenylyl cyclase inhibitor MDL-12,330A and the protein kinase A inhibitor H89 prevented the K+-evoked [3H]D-aspartate overflow. Consistent with the involvement of adenylyl cyclase, depolarization with 12 mM K+ increased synaptosomal cyclic AMP (cAMP) content, while forskolin, an adenylyl cyclase activator, potentiated basal [3H]D-aspartate release in an octreotide-, MDL-12,330A- and H89-sensitive manner. To conclude, glutamatergic cerebrocortical nerve endings possess release-inhibiting sst2 receptors which represent potential targets for new drugs able to mitigate the effects of excessive glutamate transmission.
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PMID:Somatostatin inhibits glutamate release from mouse cerebrocortical nerve endings through presynaptic sst2 receptors linked to the adenylyl cyclase-protein kinase A pathway. 1497 94


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