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)

Rapid inhibition of acetyl-CoA carboxylase (ACC) activity in rat liver in response to 6 h starvation and rapid re-activation in response to 2-6 h of re-feeding chow were shown to be due to changes in the expressed activity of existing enzyme. Decreases and increases in ACC concentration occurred at later stages of the transitions, i.e. 6-48 h starvation and 8-24 h re-feeding respectively. The decrease in expressed activity of ACC was due primarily to changes in its phosphorylation state, demonstrated by a significantly decreased Vmax. and significantly increased Ka for citrate of enzyme purified by avidin-Sepharose chromatography from 6 h- or 48 h-starved rats. These effects were totally reversed within 2-4 h of chow re-feeding. Changes in the activity of purified ACC closely correlated with reciprocal changes in the activity of AMP-activated protein kinase (AMP-PK) over the fed to starved to re-fed transition. Increases in the activity ratio of cyclic-AMP-dependent protein kinase in response to starvation lagged behind the increase in AMP-PK and the decrease in ACC activity. Changes in AMP-PK and ACC activities of rat liver closely correlated with changes in plasma insulin concentration in response to time courses of starvation and re-feeding.
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PMID:The short-term regulation of hepatic acetyl-CoA carboxylase during starvation and re-feeding in the rat. 168 93

To evaluate the possibility that some of the metabolic effects of GH in rat adipose tissue depend upon phosphorylation-dephosphorylation reactions, we examined the effects of the isoquinoline sulfonamide family (H-7, H-8, and HA-1004) of protein kinase inhibitors on the actions of GH. In the course of these studies it became clear that these compounds may also block RNA synthesis. In the concentration range of 50-200 microM, H-7, H-8, and HA-1004 completely blocked lipolysis in response to the combination of 100 ng/ml dexamethasone and 30 ng/ml human GH in segments of epididymal fat from normal rats, but were less effective in blocking lipolysis in response to either 1 mM (Bu)2cAMP or 1 ng/ml isoproterenol, which are known to depend upon activation of protein kinase-A. Activation of protein kinase-C with phorbol myristate nearly doubled the rate of glucose oxidation in segments of normal adipose tissue, and this insulin-like response was completely inhibited with 200 microM H-7. At concentrations as high as 500 microM, H-7, H-8, and HA-1004 failed to inhibit the insulin-like response to GH in tissue segments of either normal or hypophysectomized rats. However, when 200 microM H-7 or H-8, but not HA-1004, was present during the first 3 h of treatment with GH, it prolonged the duration of the insulin-like response (acceleration of glucose oxidation) from its normal termination within 2-3 h to more than 4 h. Identical results were obtained with 5 micrograms/ml actinomycin-D. The effect of H-7 or H-8 was reversible and required the continuous presence of these agents, whereas actinomycin-D was required only during the first 60 min after GH. Termination of the insulin-like response normally is followed by a period of several hours in which the tissues are refractory to further insulin-like stimulation by GH. When actinomycin-D, H-7, H-8, or HA-1004 was added to tissues of hypophysectomized rats 60 min after GH, the insulin-like response terminated at its normal time, but the tissues were not refractory to insulin-like stimulation upon reexposure to GH. These agents also prevented GH from sustaining refractoriness in normal adipose tissue.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The isoquinoline sulfonamide inhibitors of protein phosphorylation, H-7, H-8, and HA-1004, also inhibit RNA synthesis: studies on responses of adipose tissue to growth hormone. 168 12

The effects of cationic polyamino acids on phosphorylation of the insulin and insulin-like growth factor 1 receptor kinases were studied and the following observations were made. (a) Polylysine stimulated both tyrosine and serine phosphorylation of the insulin receptor and of additional proteins present in lectin-purified membrane preparations from rat liver. (b) Polylysine synergized with insulin to enhance phosphorylation of the insulin receptor and of additional proteins (pp40 and pp110). (c) Polylysine effects were more pronounced upon increasing the polylysine chain length. (d) The effect of polylysine was biphasic with an optimum at 100 micrograms/ml. (e) Polylysine was found ineffective in stimulating the phosphorylation of immobilized insulin receptors. Taken together, these findings support the notion that the action of polylysine involves conformational changes and presumably aggregation of soluble receptors. The same effects of polylysine were obtained with highly purified insulin receptor preparations. Under these conditions polylysine enhanced both serine and tyrosine phosphorylation of the insulin receptor, suggesting that polylysine stimulates the activity of the insulin receptor kinase, and of a serine kinase that is tightly associated with the insulin receptor.
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PMID:Basic polycations activate the insulin receptor kinase and a tightly associated serine kinase. 170 86

Activation of protein synthesis is required for quiescent cells to transit the cell cycle, and seems to be mediated in part by phosphorylation of the 40S ribosomal protein, S6. A mitogen-activated S6 kinase of relative molecular mass 70,000 (70K) has been isolated from mouse fibroblasts as well as from avian, rat and rabbit tissues. Comparison of complementary DNA sequences shows that this enzyme is distinct from S6 kinase II (92K) found in Xenopus eggs and fibroblasts. Both kinases are activated by serine/threonine phosphorylation, suggesting that at least one serine/threonine kinase links receptor tyrosine kinases with S6 kinases. A candidate for this link is MAP2 kinase, which is rapidly activated by tyrosine/threonine phosphorylation following mitogenic stimulation. Incubation of MAP2 kinase from insulin-treated 3T3-L1 adipocytes with phosphatase-inactivated S6 kinase II from Xenopus leads to partial reactivation and phosphorylation of the enzyme. These and other findings have led to the suggestion that MAP2 kinase also activates the 70K S6 kinase. Here we refute this idea by showing that the two kinases lie on distinct signalling pathways.
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PMID:MAP2 kinase and 70K S6 kinase lie on distinct signalling pathways. 170 81

Quiescent Swiss 3T3 cells can be stimulated to reenter the cell cycle by various mitogens used in synergistic combinations with insulin-like growth factors (IGFs). The cells constitutively secrete an IGF-binding protein (IGFBP), which can modulate the interaction of IGFs with their receptors and could, therefore, alter cellular responsiveness to IGFs. We have now characterized the IGFBP secreted by Swiss 3T3 cells and tested whether its secretion is regulated by heterologous mitogens. Ligand blotting using [125I]IGF-I revealed a major IGFBP of 40,000 mol wt, and treatment of the cells with tunicamycin reduced the mol wt of this protein to about 32,000. mRNA from Swiss 3T3 cells hybridized to a 32P-labeled oligonucleotide (50-mer) complementary to rat IGFBP-3. Taken together, these results indicate that the principal IGFBP secreted by Swiss 3T3 cells is probably the N-glycosylated IGFBP-3. Production of this IGFBP by Swiss 3T3 cells was stimulated by 50-150% by the mitogens bombesin, vasopressin, platelet-derived growth factor, epidermal growth factor, and 12-O-tetradecanoylphorbol 13-acetate and also by IGF-I. The increased production of IGFBP was first detected after 4-6h of incubation and was then maintained for 48-72 h. Agents that elevate intracellular cAMP and the glucocorticoid dexamethasone reduced IGFBP output. In cells in which protein kinase-C had been down-modulated, the stimulation of IGFBP output by 12-O-tetradecanoylphorbol 13-acetate was abolished, but the stimulation induced by the other mitogens was not prevented. Thus, the production of IGFBP by Swiss 3T3 cells can be regulated by a number of different signalling pathways.
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PMID:Mitogens regulate the production of insulin-like growth factor-binding protein by Swiss 3T3 cells. 170 79

Insulin receptors from rat brain and liver were purified. Brain purified receptor exhibited protein bands of apparent Mr = 135,000 and 95,000 molecular weight corresponding to alpha- and beta-subunits, retained a tyrosine specific protein kinase activity and demonstrated phosphorylation that is hormonally sensitive. Antisera were raised against both insulin receptor preparations and enzyme-linked immunosorbent assay was developed. The comparison of two insulin receptors was based on a displacement enzyme-linked immunosorbent assay where antisera were interchanged on predetermined optimal dilutions. This indicated that both insulin receptors possess some unique antigenic determinants thereby implying a structural difference.
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PMID:Purification and immunochemical interrelationship of insulin receptors from rat brain and liver. 170 33

Treatment of BC3H1 myocytes or 3T3-L1 fibroblasts with fluoroaluminate (AlF4-), a direct activator of G proteins, increased the tyrosine phosphorylation of a 42-kDa cytosolic protein. AlF4- induced a parallel increase in protein kinase activity toward myelin basic protein (MBP) in partially purified cell extracts. To test whether AlF4- was activating the 42-kDa MAP (mitogen-activated protein) kinase, extracts from AlF4--treated cells were taken through the chromatographic steps routinely used to purify MAP kinase from growth factor-stimulated cells. Following phenyl-Superose chromatography, a peak of MBP kinase activity eluted at a position characteristic of MAP kinase. Immunoblotting of the active fractions with anti-phosphotyrosine antibodies revealed a single reactive protein band of Mr 42,000. Stimulation of MAP kinase by AlF4- was rapid, peaking within 15 min and persisting for at least 1 h. In contrast, the activation of MAP kinase by insulin was transient, characteristic of its activation by growth factors in other cell types. Although concentrations of sodium fluoride greater than 1 mM also activated MAP kinase, this effect was shown to be dependent upon the simultaneous presence of aluminum ions in the medium. Activation of MAP kinase by AlF4- was not affected by either cellular depletion of protein kinase C or pretreatment of cells with pertussis toxin. Potential sites of action of AlF4- are discussed. These findings suggest that activation of a G protein(s) in intact cells can initiate events that result in tyrosine phosphorylation and activation of MAP kinase.
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PMID:Activation of mitogen-activated protein kinase in BC3H1 myocytes by fluoroaluminate. 170 25

Microtubule-associated protein 2 kinase (MAP kinase), which exists in several forms, is a protein serine/threonine kinase that participates in a growth factor-activated protein kinase cascade in which it activates a ribosomal protein S6 kinase (pp90rsk) while being regulated itself by a cytoplasmic factor (MAP kinase activator). Experiments with recombinant MAP kinase, ERK2, purified from Escherichia coli in a nonactivated form revealed a self-catalyzed phosphate incorporation into both tyrosine and threonine residues. Another MAP kinase, ERK1, purified from insulin-stimulated cells also autophosphorylated on tyrosine and threonine residues. Autophosphorylation of ERK2 correlated with its autoactivation, although both autophosphorylation and autoactivation were slow compared to that occurring in the presence of MAP kinase activator. Therefore, we propose that autophosphorylation is probably involved in the MAP kinase activation process in vitro, but it may not be sufficient for full activation. The specificity toward tyrosine and threonine residues indicates that the MAP kinases ERK1 and ERK2 are members of a group of kinases with specificity for tyrosine as well as serine and threonine residues.
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PMID:Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation. 171 80

In primary cultures of astrocytes, methylmethane, 2-N-methyl 9-hydroxy-ellepticinium acetate, ditercalinium, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1,3 bis (2-chloroethyl)-1-nitrosourea (BCNU) blocked to various extents the activation of S6 kinase by acidic fibroblast growth factor and insulin [or insulin-like growth factor 1 (IGF1)]. The effects of the most active agent, BCNU, were time and concentration dependent. Pretreatment of cells with 50 microM BCNU for 1 hr completely prevented S6 kinase activation by growth factors for at least 2 days. The S6 kinase activity of unstimulated cells was slightly affected. S6 kinase activation by 12-O-tetradecanoylphorbol 13 acetate was also strongly impaired by treating cells with BCNU whereas activation by 8-bromo-cyclic AMP was slightly reduced. Cyclic AMP-dependent protein kinase and phospholipid and Ca(2+)-dependent protein kinase were unaffected. BCNU had no direct effect on IGF1 binding to cell surface receptors or on the S6 kinase activity of cell cytosols.
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PMID:Early effect of BCNU on rat astrocytes. Inhibition of S6 kinase activation by growth factors. 171 61

Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin protect density-inhibited murine Balb/c-3T3 fibroblasts against death by distinctive mechanisms. Determination of the cell survival-enhancing activity of growth factors by cell enumeration and neutral red uptake measurement gives equivalent results. PDGF displays a steep dose-response relationship in the 1-5 ng/ml range. The other factors display shallow log-linear relationships in the following ranges: EGF: 0.2-5 ng/ml; IGF-1: 2-80 ng/ml; and insulin: 57-4,500 ng/ml. Agonists that lead to the activation of protein kinase A, including forskolin, 8-bromoadenosine 3':5'-cyclic monophosphate (Br-cAMP) and N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (db-cAMP), markedly increase both short-term (5-h) and long-term (20-h) survival of cells. 2-Isobutyl-1-methylxanthine (IBMX) markedly enhances short-term survival, but its effect decays with time. The protein kinase C agonist 12-O-tetradecanoyl phorbol-13-acetate (TPA) has a moderate protective effect at concentrations of 16-32 nM, and 64 nM TPA is highly effective. The synthetic diaclglycerols 1,2-dioctanoylglycerol (DiC8) and 1-oleoyl-2-acetylglycerol (OAG) and the calcium ionophore ionomycin show low activity. Supplementation of EGF with a protein kinase A or C agonist results in a varying additive increase in short-term (5-h) cell survival and supplementation of EGF + insulin or PDGF + EGF + insulin increases further the already high level of protection given by the growth factor combinations. Combining a protein kinase A and a protein kinase C agonist in the absence of growth factors gives an approximately additive increase in cell survival. Results obtained with kinase, RNA, and protein synthesis inhibitors suggest that: 1) activated protein kinase C catalyzes one or more phosphorylation events in quiescent Balb/c-3T3 cells that lead to gene expression with the protein product(s) mediating protection of quiescent cells against death, and 2) phosphorylation events catalyzed by protein kinase A largely serve to protect cells by a mechanism not requiring de novo RNA and protein biosynthesis.
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PMID:Activation of signal transduction pathways protects quiescent Balb/c-3T3 fibroblasts against death due to serum deprivation. 171 93


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