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)

The 1.3-kilobase (kb) Pst I DNA fragment C (Pst I-C) of herpes simplex virus type 2 (HSV-2) morphological transforming region III (mtrIII; map unit 0.562-0.570) encodes part of the N-terminal half of the large subunit of ribonucleotide reductase (RR1; amino acid residues 71-502) and induces the neoplastic transformation of immortalized cell lines. To assess directly the role of these RR1 protein sequences in cell transformation, the Pst I-C fragment was cloned in an expression vector (p91023) containing an adenovirus-simian virus 40 promoter-enhancer to generate recombinant plasmid p9-C. Expression of a protein domain (approximately 65 kDa) was observed in p9-C-transfected COS-7 and Rat2 cells but not in those transfected with plasmid pHC-14 (Pst I-C in a promoterless vector). In Rat2 cells, p9-C induced highly transformed foci at an elevated frequency compared with that of pHC-14. Introduction of translation termination (TAG) condons within the RR1 coding sequence and within all three reading frames inactivated RR1 protein expression from p9-C and reduced its transforming activity to the level seen with the standard pHC-14 construct. Wild-type p9-C specified a protein kinase capable of autophosphorylation. Computer-assisted analysis further revealed significant similarity between regions of mtrIII-specific RR1 and amino acid patterns conserved within the proinsulin precursor family and DNA transposition proteins. These results identify a distinct domain of the HSV-2 RR1 protein involved in the induction of enhanced malignant transformation. In addition, the data indicate that the mtrIII DNA itself can induce basal-level transformation in the absence of protein expression.
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PMID:Enhanced malignant transformation induced by expression of a distinct protein domain of ribonucleotide reductase large subunit from herpes simplex virus type 2. 165 64

Rat liver microsomes contain type-1 S6 phosphatase (acting on the serine residues phosphorylated by protein kinase A) and type-1 phosphorylase phosphatase activities. The main aim of this study has been to characterize the microsomal S6 phosphatase activity and to compare its properties with those of the phosphorylase phosphatase activity in the same microsomal preparation. The specific activities of both microsomal S6 phosphatase and phosphorylase phosphatase were 1.6- to 1.7-fold higher in the smooth endoplasmic reticulum than in the rough sarcoplasmic reticulum. Both phosphatase activities were inhibited to a similar extent by MgCl2 (10 mM) and NaF (22 mM), were completely suppressed by glycerophosphate (80 mM) and ZnCl2(10 mM), and were stimulated by MnCl2(1 mM). When analyzed by gel filtration on Sephadex G-100 superfine, both phosphatase activities eluted as broad peaks, stretching from the void volume to 45-60 kDa. The microsomal S6 phosphatase and phosphorylase phosphatase activities also displayed the following distinct characteristics: (a) Mn2+ stimulated the S6 phosphatase activity 2.9-fold more than the phosphorylase phosphatase activity, (b) limited trypsin digestion of microsomal preparations increased the phosphorylase phosphatase activity by 1.5- to 2-fold, but decreased the S6 phosphatase activity by 50%, (c) a synthetic peptide analog of S6 (S6229-239) (200 microM), which did not act as a substrate for the microsomal S6 phosphatase and did not affect its activity, inhibited the microsomal phosphorylase phosphatase activity by about 50%, and (d) the elution profile of the phosphorylase phosphatase activity was markedly broader than that of the S6 phosphatase activity. A series of in vivo studies showed that streptozotocin-diabetes and insulin replacement therapy as well as ip injection of insulin or vanadate, which modified the microsomal S6 phosphatase activity, had no statistically significant effects on the microsomal phosphorylase phosphatase activity. Taken together, these results suggest that the microsomal S6 phosphatase and phosphorylase phosphatase activities are due to two distinct enzyme populations.
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PMID:A comparative study of the microsomal S6 phosphatase and phosphorylase phosphatase activities in rat liver. 165 55

Protein phosphatase-1 (PP-1) and -2A (PP-2A), two regulatory subunits of PP-1, the glycogen-binding subunit G and inhibitor-2 (I-2), kinase FA, and casein kinase II (CK-II) were investigated in skeletal muscle of diabetic rats 2 days after streptozotocin injection. FA and CK-II activate PP-1 in vitro and might be involved in the activation of PP-1 by insulin. Following muscle fractionation we found that (1) diabetes decreased both basal and trypsin-stimulated PP-1 activities; the decrease was more significant in the glycogen-bound and microsomal fractions than in the cytosol (cytosolic PP-1 decreased as specific activity but not as activity/g of muscle); also PP-2A was lower in diabetic cytosols; (2) less G was immunoprecipitated from diabetic glycogen-bound fractions compared to controls, while I-2 was not significantly changed; (3) diabetes decreased also FA (assayed as PP-1 activator) and CK-II (assayed using a synthetic peptide as substrate); (4) diabetes did not have any effect on phosphorylase (a + b) activity in the glycogen-bound fraction. Altogether the data show that acute diabetes decreased PP-1, one of its regulatory subunits and two potentially physiological regulators of PP-1, in addition to PP-2A. This may indicate that insulin is responsible for the long-term regulation of the same enzymes that are also under acute insulin control.
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PMID:Protein phosphatase-1 and -2A, kinase FA, and casein kinase II in skeletal muscle of streptozotocin diabetic rats. 165 59

Immunoaffinity-purified insulin receptors were used to analyse and compare the serine/threonine sites phosphorylated on the insulin receptor in vitro (isolated receptor) with the insulin-stimulated phosphorylation in vivo (intact cells in culture). In vivo, insulin-stimulation resulted in the appearance of three phosphoserine-containing phosphopeptides and a distinct phosphothreonine peptide (threonine 1348). In vitro, similar phosphoserine peptides were observed but the phosphothreonine peptide was absent. These results indicate that multiple serine sites are phosphorylated in vivo and in vitro and that an additional protein kinase mediates insulin-stimulated insulin receptor threonine phosphorylation in vivo.
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PMID:Insulin-stimulated serine/threonine phosphorylation of the insulin receptor: paucity of threonine 1348 phosphorylation in vitro indicates the involvement of more than one serine/threonine kinase in vivo. 165 5

Okadaic acid, a potent inhibitor of Type 1 and Type 2A protein phosphatases, was used to investigate the mechanism of insulin action on membrane-bound low Km cAMP phosphodiesterase in rat adipocytes. Upon incubation of cells with 1 microM okadaic acid for 20 min, phosphodiesterase was stimulated 3.7- to 3.9-fold. This stimulation was larger than that elicited by insulin (2.5- to 3.0-fold). Although okadaic acid enhanced the effect of insulin, the maximum effects of the two agents were not additive. When cells were pretreated with 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), the level of phosphodiesterase stimulation by okadaic acid was rendered smaller, similar to that attained by insulin. In cells that had been treated with 2 mM KCN, okadaic acid (like insulin) failed to stimulate phosphodiesterase, suggesting that ATP was essential. Also, as reported previously, the effect of insulin on phosphodiesterase was reversed upon exposure of hormone-treated cells to KCN. This deactivation of previously-stimulated phosphodiesterase was blocked by okadaic acid, but not by insulin. The above KCN experiments were carried out with cells in which A-kinase activity was minimized by pretreatment with H-7. Okadaic acid mildly stimulated basal glucose transport and, at the same time, strongly inhibited the action of insulin thereon. It is suggested that insulin may stimulate phosphodiesterase by promoting its phosphorylation and that the hormonal effect may be reversed by a protein phosphatase which is sensitive to okadaic acid. The hypothetical protein kinase thought to be involved in the insulin-dependent stimulation of phosphodiesterase appears to be more H-7-resistant than A-kinase.
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PMID:Effects of okadaic acid on insulin-sensitive cAMP phosphodiesterase in rat adipocytes. Evidence that insulin may stimulate the enzyme by phosphorylation. 165 32

In a study that was reported from this laboratory, the mitogenic potency of an apparent mol wt (appMr) of 15,000 precursor form of human insulin-like growth factor-II (hIGF-II) was shown to be greater than that of completely processed hIGF-II for human fetal-derived fibroblasts, and both were more potent than rIGF-I. Since it is generally acknowledged that the stimulation of cell replication by the IGFs is mediated by IGF-I receptors, we undertook to determine whether differences between the receptors' affinity for the two Mr forms of hIGF-II and recombinant IGF-I (rIGF-I) or between its efficiency to couple specific growth factor occupancy to the activation of protein kinase could explain the greater replicating potential of appMr 15,000 hIGF-II. Equilibrium dissociation, i.e. Kd, and inhibition, i.e. Ki, constants were determined by measuring the ability of rIGF-I, hIGF-II, appMr 15,000 hIGF-II, insulin, and the antireceptor monoclonal antibody alpha IR-3 to compete with 125I-labeled rIGF-I and hIGF-II for binding to purified preparations of IGF-I receptors prepared from an enriched source of fetal membrane, i.e. human term placenta. The results of these experiments established that 1) hIGF-II and appMr 15,000 hIGF-II bind to the IGF-I receptor with the same affinity as rIGF-I, e.g. with Kd and Ki values between 0.03-0.07 nM; 2) the total binding capacity, i.e. Ro, for IGF-I binding was not statistically different from the Ro calculated for IGF-II binding; and 3) the statistical analysis of 12 data sets from the competitive binding experiments for goodness of fit indicated that a 1-site model for IGF-I and -II binding was a better fit of the data than a 2-site model. Measurements of the stimulation of IGF-I receptor autophosphorylation at low ligand concentrations established that appMr 15,000 hIGF-II and hIGF-II were more effective than rIGF-I in coupling receptor occupancy to the activation of its protein kinase. At saturating ligand concentrations, the 3 had similar potencies. The original preparation of appMr 15,000 hIGF-II contains a mixture of forms with acidic isoelectric points (pIs) and was more potent than Mr 7,500 IGF-II in stimulating receptor autophosphorylation. These results are consistent with the relative potencies of this preparation, hIGF-II, and rIGF-I in stimulating the replication of 12-week-old fetal dermal fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Binding specificities and transducing function of the different molecular weight forms of insulin-like growth factor-II (IGF-II) on IGF-I receptors. 165 23

The pathways depicted in Figure 1 summarize the data discussed in this article. In neurons, the binding of insulin and IGF-I to their respective receptors triggers autophosphorylation of the receptor beta-subunits. IGF-II binds to both neuronal insulin and IGF-I receptors and can stimulate autophosphorylation of either receptor type. In addition to enhancing insulin and IGF-I receptor autophosphorylation, all 3 peptides stimulate the tyrosine phosphorylation of a 70 kDa protein with a similar time course and dose response to receptor phosphorylation. The identity of pp70 is unknown, although the close temporal relationship between pp70 phosphorylation and neurite outgrowth suggests a potential role for this protein. Subsequent to these very early events, two neuronal serine kinases are activated by insulin. One has S6 kinase activity and may represent either the pp90rsk or pp70 class of S6 kinases. Since S6 kinases are activated by direct phosphorylation rather than by second messengers, it is likely that a neuronal S6 kinase kinase exists. The activation of S6 kinase is likely to mediate insulin's effects on neuronal protein synthesis or other growth-related processes. The second serine kinase that is activated by insulin is PKC epsilon. This enzyme is largely restricted to the nervous system, so this signalling pathway may be neuronal-specific. The mechanism of activation of PKC epsilon is unknown, although preliminary data suggests that enhanced phosphorylation of the enzyme is involved. Studies are currently underway to investigate the potential role of diacylglycerol, a potential second messenger generated from either phosphotidylinositol or phosphotidylcholine hydrolysis, in the activation of PKC epsilon by insulin.
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PMID:Regulation of protein phosphorylation by insulin and insulin-like growth factors in cultured fetal neurons. 166 64

Spontaneous S6 phosphatase activities dephosphorylating Ser(P)-235 and Ser(P)-236 of the ribosomal protein S6 were measured and compared in microsomes and cytosol of rat liver. The substrate used, small (40S) ribosomal subunits 32P-labelled in vitro by protein kinase A, contained phosphorylated S6 (mainly in the diphosphorylated form) and some minor phosphorylated species. The microsomal and cytosolic S6 phosphatase activities displayed a number of distinct properties. The microsomal activity, representing ca 20% of the S6 phosphatase activity in the post-mitochondrial supernatant, was mainly due to a type-1 phosphatase and dephosphorylated only S6. The remaining post-mitochondrial S6 phosphatase activity, which was fully recovered in the cytosol, and appeared to result from a combination of type-1 (43%) and type 2 (57%) phosphatases, acted on S6 as well as on the minor phosphorylated species. The microsomal activity was 50% inhibited by MgCl2 (10 mM) and was stimulated at least 4.3 fold by MnCl2 (1 mM), while the cytosolic activity was inhibited only 18% by Mg2+ (10 mM) and was increased 2.2 fold by Mn2+ (1 mM). The microsomal activity was increased 10% (P less than 0.06) by lower doses of insulin (25 U/Kg) and 14% (P less than 0.05) by vanadate, but was not significantly (P greater than 0.10) affected by larger doses of insulin (100 U/kg), hepatectomy or cycloheximide. By comparison the cytosolic S6 phosphatase activity was unresponsive to insulin and vanadate, but was decreased 14% and 17% (P less than 0.05) by hepatectomy and cycloheximide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A comparative study of microsomal and cytosolic S6 phosphatase activities in rat liver. 166 99

Lutropin (LH) receptors in rat granulosa cells are expressed by activation of cAMP-dependent protein kinase in response to follitropin (FSH). In the present study, 12-O-tetradecanoylphorbol 13-acetate (TPA) could cause a dose-dependent expression of LH receptors in the presence of insulin, but not in the absence of insulin, as measured by binding of 125I-deglycosylated human choriogonadotropin (DGhCG). The synergistic action of TPA with insulin was achieved at 1 nM and 10 mIU/ml, respectively. The receptor expression induced by this synergistic action was accompanied by cAMP accumulation which was detected after a lag time of 6 h following exposure to TPA. However, a synthetic diacylglycerol and non-protein kinase C activating phorbol derivatives did not mimic the effect of TPA on the receptor expression. In addition, insulin modulated the inhibitory effect of TPA in FSH-induced LH receptor expression, indicating a peculiar action of insulin in the receptor expression. Indomethacin treatment led to a dose-dependent inhibition in the receptor expression in the cells treated with TPA plus insulin more than that in the cells with FSH plus insulin, suggesting that the synergistic action was dependent upon cyclooxygenase and/or phospholipase A2 activity. It was shown by Scatchard analysis of LH receptors and kinetic studies of hCG-stimulated cAMP formation that the synergistic action of TPA with insulin led to expression of functional LH receptors coupled with the adenylate cyclase system in cultured granulosa cells.
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PMID:Tumor-promoting phorbol ester acts synergistically with insulin to induce lutropin receptor expression in rat granulosa cells. 166 32

Maturation-activated protein-serine/threonine kinases were investigated in the high-speed supernatant fractions from sea-star oocytes harvested at the time of germinal vesicle breakdown. One of the major stimulated protein kinases able to phosphorylate acetyl-CoA carboxylase in these extracts was found to co-purify with a 44 kDa myelin basic protein kinase (p44mpk) that is activated with a similar time course during oocyte maturation. Purified sea-star oocyte p44mpk phosphorylated acetyl-CoA carboxylase (purified from rat liver) predominantly on serine and to a small extent on threonine. Furthermore, the phosphorylation of acetyl-CoA carboxylase occurred principally on a tryptic phosphopeptide which displayed electrophoretic and chromatographic properties very similar to those of the peptide that has previously been shown to undergo increased phosphorylation in response to insulin in rat adipocytes [Brownsey & Denton (1982) Biochem. J. 202, 77-86]. The acetyl-CoA carboxylase was phosphorylated at a similar rate and to a similar extent by casein kinase II, which was also purified from maturing sea-star oocytes. Although casein kinase II was also activated approximately 3-fold near the time of nuclear envelope breakdown, it was responsible for only a minor component of the total enhanced acetyl-CoA carboxylase kinase activity measured in the soluble extracts from maturing oocytes. Acetyl-CoA carboxylase was a relatively poor substrate for the major S6 peptide kinase activity that was also stimulated during resumption of meiosis in the oocytes. The properties of the p44mpk are reminiscent of those of a microtubule-associated protein 2 (MAP-2) kinase that is activated in response to insulin and other mitogens in mammalian cells [Ray & Sturgill (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 3753-3757; Hoshi, Nishida & Sakai (1988) J. Biol. Chem. 263, 5396-5401]. It is intriguing that several of the mammalian protein kinases that are acutely activated after mitogenic prompting of quiescent mouse fibroblasts (i.e. G0 to G1 transition), such as MAP-2 kinase, casein kinase II and S6 kinase II, have counterparts that are activated during M-phase in maturing sea star oocytes.
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PMID:Identification of a major maturation-activated acetyl-CoA carboxylase kinase in sea star oocytes as p44mpk. 167 14


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