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 order to elucidate the signal transduction pathway from external mechanical stress to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK) and MAP kinases (MAPKs) in neonatal rat cardiac myocytes. Mechanical stretch transiently activated Raf-1 and MAPKK with a peak at 2 and 5 min after stretch, respectively. In addition, MAPKs were maximally activated at 8 min after stretch. Next, the relationship between stretch-induced hypertrophy and the cardiac reninangiotensin system was investigated. When the stretch-conditioned culture medium was transferred to non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type I angiotensin II (AngII) receptor antagonist, CV-11974. Moreover, in in vivo studies using spontaneously hypertensive rats, hypertension-induced cardiac hypertrophy was significantly reduced by treatment with subpressure doses of CV-11974. In addition, CV-11974 reduced the isozymic transition of MHC from VI to V3 and inhibited the accumulation of collagen fibers in the extracellular space of the myocardium. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK and MAPKs. AngII, which is secreted from stretched myocytes, possibly activates these protein kinases. Moreover, it was shown that CV-11974 causes regression of cardiac hypertrophy and has cardioprotective effects on hypertrophied myocardium in vivo.
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PMID:Angiotensin II mediates mechanical stress-induced cardiac hypertrophy. 896 84

To elucidate the signal transduction pathway from external stimuli to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of protein kinases such as Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) in neonatal rat cardiomyocytes. Mechanical stretch rapidly activated Raf-1 and its maximal activation was observed at 1-2 min after stretch. The activity of MAPKK was also increased by stretch, with a peak at 5 min after stretch. In addition, MAPKs and p90rsk were maximally activated at 8 min and at 10-30 min after stretch, respectively. Next, the relationship between mechanical stress-induced hypertrophy and the cardiac renin-angiotensin system was investigated. When the stretch-conditioned culture medium was transferred to the culture dish of non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type 1 angiotensin II receptor antagonist, CV-11974. However, activation of Raf-1 and MAPKs provoked by stretching cardiomyocytes was only partially suppressed by pretreatment with CV-11974. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK, MAPKs and p90rsk, and that angiotensin II, which is secreted from stretched myocytes, activates a part of these protein kinases.
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PMID:Molecular aspects of mechanical stress-induced cardiac hypertrophy. 897 57

Several peptides derived from microtubule-associated tau protein, have been tested as substrates for glycogen synthase kinase 3 (GSK 3). In the absence of cofactors, GSK 3 can modify serines or threonines followed by prolines. In other cases, a phosphorylation in position +4 is required for the phosphorylation of threonine/serine residues. A third type of substrate can be modified by GSK 3 in the presence of heparin. The comparison of GSK 3 with other kinases suggests some similar features of this kinase with proline-directed protein kinases, such as cdc-2 or mitogen-activated protein kinase (MAP Kinases,) and also with casein kinase 2 (CK 2). Thus, all these kinases are specifically inhibited by 5,6-Dichloro-1-(beta-D-ribofuranosyl)-benzimidazole (DRB). However, heparin is an inhibitor of CK 2 whereas it activates the modification of certain substrates by GSK 3. A possible explanation for the obtained results is that the consensus sequence for GSK 3 phosphorylation is a serine/threonine adjacent to a proline or other beta-turn former residue and that such recognition could be favoured by the presence of adjacent negative charges or the addition of polyanions.
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PMID:Glycogen synthase kinase 3 phosphorylation of different residues in the presence of different factors: analysis on tau protein. 897 80

The inhibitory effect of actin on protein phosphorylation by three distinct protein kinases (CK-II, A-kinase and MAP-kinase) was examined in vitro. It was found that: (i) actin inhibits the activities of alpha-monomeric CK-II (CK-IIalpha) as well as oligomeric CK-II (alpha2beta2) in a dose-dependent manner, but has no effect on the activities of the two other kinases; and (ii) actin-induced inhibition of CK-II activity is due to the binding of actin to the alpha-subunit of CK-II and is non-competitive with its phosphate acceptors. In addition, it is demonstrated that actin binds directly to CK-II: both actin and CK-II are coprecipitated by anti-serum against Drosophila CK-IIbeta or by specific IgG against Ascaris suum muscle actin. The results presented here suggest that actin can suppress CK-II-mediated signal transduction.
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PMID:An inhibitory effect of actin on casein kinase II activity in vitro. 897 30

Previous studies have indicated that PKCepsilon behaves as an oncogene when overproduced in rodent fibroblasts (Cacace et al., 1993; Mishak et al., 1993). In the present study, Western blot analysis revealed that the hyperphosphorylated form of Raf kinase was present at a high level in PKCepsilon overproducing R6 rat fibroblasts but not in R6 fibroblasts overproducing PKCalpha or beta1. Extracts from the PKCepsilon overproducing cells also exhibited a marked increase in Raf-1 kinase and MAP-kinase activity. To investigate the significance of these findings, dominant negative mutants of ras (N17) or raf (301-1) were stably expressed in early passage control and PKCepsilon-transformed R6 fibroblasts, by transduction using retrovirus-derived constructs. Dominant negative raf expressing clones exhibited a flat morphology, a decreased saturation density, and decreased growth in soft agar. In addition, these reverted clones exhibited decreased Raf kinase activity. In contrast, dominant negative ras expressing clones remained highly transformed. In addition, PKCepsilon was detected in Raf-1 immunoprecipitates indicating that PKCepsilon forms a complex with Raf-1 in vivo. Taken together, these results suggest that PKCepsilon functions as an oncogene in R6 cells by enhancing activation of the Raf-1 kinase.
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PMID:PKC epsilon functions as an oncogene by enhancing activation of the Raf kinase. 900 Jan 26

The influence of aniso-osmolarity on the activity of the MAP kinases Erk-1 and Erk-2 was studied in C6 glioma cells. Hypo-osmotic treatment (205 mosmol/l) led to an increased activity of Erk-1 and Erk-2 within 3 min, which became maximal at 10 min and returned to basal level within 120 min. In contrast, Erk activity was reduced under hyper-osmotic conditions (405 mosmol/l), compared to the normo-osmotic control (305 mosmol/l). Erk activation was accompanied by a mobility shift of Raf-1. Hypo-osmotic exposure increased the cytosolic Ca2+ concentration ([Ca2+]i). Absence of extracellular Ca2+ largely abolished the [Ca2+]i response to hypo-osmolarity, whereas Erk activation following hypo-osmotic stimulation remained unaffected, suggesting a Ca2+ independence of the osmosignalling pathway to the MAP kinases. Both the Ca2+ response as well as the Erk activation following hypo-osmotic exposure were maintained in the presence of the phospholipase C inhibitor U73122. Application of 8-CPT cAMP, forskolin/isobutylmethylxanthine or isoproterenol blocked Erk activation following hypo-osmotic treatment of the cells, suggesting a role of the Ras/Raf pathway upstream from Erk-1 and Erk-2. Protein kinase C (PKC) is unlikely to play a role in the hypo-osmolarity- induced signalling towards MAP kinases, as revealed by inhibition of PKC with Go6850. Inhibition of pertussis- or cholera toxin-sensitive G-proteins as well as inhibition of tyrosine kinases with genistein and of PI3 kinase by wortmannin had no effect on the Erk response to hypo-osmolarity. It is concluded that osmosignalling in C6 glioma cells differs upstream of the MAP kinases from that observed in primary rat astrocytes, H4IIE rat hepatoma cells and isolated rat hepatocytes.
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PMID:Osmosignalling in C6 glioma cells. 900 90

Taxol, a natural product with significant anti-tumor activity, stabilizes microtubules and arrests cells in the G2/M phase of the cell cycle. It has been reported that taxol has additional effects in cells, including an increase in tyrosine phosphorylation of proteins and activation of MAP kinase. We investigated a possible effect of taxol on tyrosine phosphorylation of Shc and on formation of the Shc/Grb-2 complex in the murine macrophage-like cell line RAW 264.7. Shc, an SH2 domain containing adaptor protein, was immunoprecipitated from lysates of taxol-treated cells with anti-phosphotyrosine antibody and its identity determined by Western blotting with anti-Shc antibody. Non-denatured Shc containing protein complexes were immunoprecipitated with anti-Shc antibody, and analysis with an anti-Grb2 antibody revealed the presence of the 24-kDa Grb2 protein. Taxol also activated Raf-1 kinase and ERK1/ERK2 MAP kinases in these cells. These results demonstrate that taxol affects tyrosine phosphorylation of Shc and this may result in the activation of the Raf-1/MAPK cascade.
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PMID:Taxol induces tyrosine phosphorylation of Shc and its association with Grb2 in murine RAW 264.7 cells. 900 67

In this work, we show that erythropoietin and inositolphosphate-glycan activate Raf-1 and the mitogen-activated protein kinases (MAP kinases) in normal erythropoietin-responsive cells. Using a protein kinase C (PKC) activator such as the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate and the PKC inhibitor GF109203X, we investigated a possible involvement of PKC during activation of Raf-1 and MAP kinase by erythropoietin or inositolphosphate-glycan. We found that erythropoietin increased MAP kinase level with a maximum stimulation reached at 5-10 min. Inositolphosphate-glycan and 12-O-tetradecanoyl-phorbol-13-acetate increased MAP kinase activity in the same manner. This activity was inhibited by cell preincubation with GF109203X. Two MAP kinase isoforms were present in erythroid progenitor cells, the 44 and 42 kDa proteins. We report here that erythropoietin, inositolphosphate-glycan, and 12-O-tetradecanoyl-phorbol-13-acetate activated only the p44 form (erk-1) of MAP kinase and the Raf-1 protein. GF109203X was used at a concentration which inhibited by 50% erythroid colonie (CFU-E) proliferation and differentiation induced by erythropoietin or inositolphosphate-glycan. These results support the hypothesis that erythropoietin and inositolphosphate-glycan activate Raf-1 and MAP kinases in normal erythroid progenitor cells and suggest that this activation involves PKC.
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PMID:Activation of Raf-1 and mitogen-activated protein kinases by erythropoietin and inositolphosphate-glycan in normal erythroid progenitor cells: involvement of protein kinase C. 906 28

MEK kinase 1 (MEKK1) shares sequence identity with the yeast kinases Ste11 and Byr2, and is capable of phosphorylation and activation of both mitogen-activated protein/extracellular signal-related protein kinase (MAP/ERK) kinase (MEK) and stress-activated protein kinase (SAPK)/ERK kinase (SEK) in vitro. In vivo, however, MEKK1 predominantly activates the SEK/SAPK kinase cascade. Mechanisms of activation of MEKK1 are unclear. We have identified a major site of autophosphorylation (Thr-575) within the 'activation loop' of MEKK1 between the kinase subdomains VII and VIII. Phosphatase treatment of a constitutively active MEKK1 decreased kinase activity by 59%. Dephosphorylated T575 was rapidly re-(auto)phosphorylated by MEKK1. Mutation of T575 to alanine decreased MEKK1 transphosphorylation activity with a SEK substrate to approx. 30% of wild-type. Mutation of a second threonine residue (Thr-587) to alanine eliminated the phosphorylation of MEK or SEK substrate but not autophosphorylation. MEKK1 autophosphorylation is an intramolecular reaction because active MEKK1 cannot transphosphorylate a kinase-inactive MEKK1. Inactive MEKK1 was not phosphorylated on Thr-575 within cells, suggesting that the phosphorylation of Thr-575 in vivo results from autophosphorylation rather than phosphorylation by an upstream kinase. Autoactivation of MEKK1 via autophosphorylation of Thr-575 might be an immediate response to initial kinase activation through non-phosphorylation mechanisms.
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PMID:Regulation of the activity of MEK kinase 1 (MEKK1) by autophosphorylation within the kinase activation domain. 907 60

Stimulation of the ERK family of protein kinases ('extracellular signal regulated kinases', also known as MAP kinases) plays an important role in the activation of many cell types, including T lymphocytes. ERKs are activated when they are phosphorylated by an upstream activator, the dual-specific protein kinase MEK. To see if aging leads to an impairment of MEK activation in mouse T cells, we used a mobility shift assay in which activation of MEK leads to phosphorylation and altered mobility of ERK-2 kinase. Similarly, we monitored mobility of pp90rsk, a known ERK substrate, as an indication of ERK function. We found an age-related decline in the ability of mouse T cells to activate both MEK and ERK function in response to stimulation by antibodies to the CD3 chain of the T cell receptor. Aging did not alter the kinetics of enzyme activation, but did diminish (by about 2-fold) the maximal level of substrate converted into the slower migrating form. Naive and memory CD4 T cells from young mice were equally able to convert ERK2 to its slower migrating form, suggesting that the decline in MEK function is not likely to be attributable to the shift, with age, from naive to memory T cell predominance. Our data suggest that age-dependent declines in gene activation, including genes for key cytokines like IL-2, may be due to declines in the upstream signals that lead to activation of the MEK/ERK protein kinase cascade.
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PMID:Diminished activation of the MAP kinase pathway in CD3-stimulated T lymphocytes from old mice. 914 61


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