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 efficiency of efflux of rapidly labeled poly(A)-containing mRNA from isolated rat liver nuclei was found to be modulated by insulin and epidermal growth factor (EGF) in a biphasic but opposite way. At physiological concentrations (10 pM insulin and 1 pM EGF), maximal stimulation of the transport rate by insulin (to 137%) and maximal inhibition by EGF (to 69%) were obtained; at higher concentrations (greater than 100 pM and greater than 10 pM, respectively), the amount of poly(A)-containing mRNA released into the postnuclear supernatant was nearly identical with the level found in untreated nuclei (= 100%). Using mRNA entrapped into closed nuclear envelope (NE) vesicles as a model system, it was found that the modulation of nuclear efflux of mRNA by the two growth factors occurs at the level of translocation through the nuclear pore. The NE nucleoside-triphosphatase (NTPase) activity, which is thought to mediate nucleocytoplasmic transport of at least some mRNAs, responded to insulin and EGF in the same manner as the mRNA transport rate. The increase in NTPase activity caused by insulin and the decrease in NTPase activity caused by EGF were found to be due to changes of the maximal catalytic rate; the Michaelis constant of the enzyme remained almost constant. Investigating the effect of the two growth factors on transport of specific mRNAs, poly(A)-containing actin mRNA was found to display the same alteration in efflux rate as rapidly labeled, total poly(A)-containing mRNA. In contrast, efflux of histone H4 mRNA, which lacks a 3'-poly(A) sequence, decreased in response to insulin and reached minimum levels at the same concentration at which maximum levels of actin mRNA transport rate were obtained. Studying the mechanism of action of insulin and EGF on NE mRNA translocation system, insulin was found to cause an enhancement of NE-associated phosphoprotein phosphatase activity, resulting in a dephosphorylation of the NE poly(A) binding site (= mRNA carrier) and, hence, in a decrease in its affinity to poly(A) [the poly(A) binding affinity of the poly(A)-recognizing mRNA carrier within the envelope is increased after phosphorylation]. EGF, on the other hand, stimulated the protein kinase, which phosphorylates the carrier, and, hence increased the NE poly(A) binding affinity. Because the stage of phosphorylation of the mRNA carrier (which is coupled with the NTPase within the intact NE structure) is inversely correlated with the activity of the NTPase, an enhancement of poly(A)-containing mRNA transport rate by insulin and an inhibition by EGF are observed.
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PMID:Differential effect of insulin and epidermal growth factor on the mRNA translocation system and transport of specific poly(A+) mRNA and poly(A-) mRNA in isolated nuclei. 197 Sep 36

Activity of crude histidine decarboxylases (HisDC) from the hypothalamus and the lungs, was markedly reduced by incubating with ATP.Mg, cAMP and cAMP-dependent protein kinase A, whereas activity of the crude glandular stomach enzyme changed only slightly under equal condition. The omission of one of these components failed to reduce HisDC activity by as much as the complete system. Addition of bovine heart (type II) or rat cerebellum protein kinase A (types I and II) inhibitor to the assay prevented enzyme inactivation; moreover, protein kinase A inhibitors permitted moderate activation under phosphorylating and control conditions. Cytosolic hypothalamus HisDC activity was elevated 2-2.2-fold by incubating the cytosol for 15 min in the presence of MnCl2, a known stimulator of phosphoprotein phosphatase; this was prevented when 20 mM NaF, a common inhibitor of phosphoprotein phosphatase, was added to the cytosol. The apparent Km of ATP.Mg-treated hypothalamus HisDC for histidine was elevated 5-10-fold compared to controls, whereas the Vmax was approximately the same. Under this condition, the Km was calculated as high as 0.5-2.2 mM (depending on phosphorylating conditions), while controls had a Km of 0.1-0.3 mM (depending on the initial phosphorylating states). Addition of rabbit muscle (type I), bovine heart (type II) or rat cerebellum (types I and II) inhibitor of protein kinase A, to the phosphorylating mixture, abolished the difference in Km between control and ATP.Mg-treated HisDC. Moreover, rat cerebellum protein kinase A inhibitors increased Vmax to above the control level; while 20 mM NaF (inhibitor of phosphoprotein phosphatase) decreased Vmax to approximately one half of that of the controls. These data indicate that HisDC activity in the hypothalamus and the lungs, but not in the stomach, is affected in oppositely by protein kinase A and phosphoprotein phosphatases.
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PMID:Possible regulation of hypothalamus and lung histidine decarboxylase activity by cAMP-dependent protein kinase. 201 19

The enhanced phosphorylations via cAMP, Ca2+ mobilization, and diacyl glycerol formation via the activation of the respective kinases is now classical. The decreased phosphorylation via inhibition of adenylate cyclase via the alpha adrenergic receptor is also becoming understood. What the insulin studies on the control of glycogen synthesis have taught us is that the rate limiting enzyme glycogen synthase is regulated by multiple covalent phosphorylation in an elegant but complex manner. The overall pattern of dephosphorylation is influenced by effecting both phosphatase and kinase activities in a set of interrelated mechanisms. In the presence of glucose, in muscle, fat, and liver under physiological conditions G-6-P acts as a signal to stimulate the phosphatase. An additional stimulation could occur via a novel insulin phosphatase stimulatory mediator. The phosphatase is also stimulated by at least three covalent mechanisms involving altered phosphorylation state. In one there is a decreased phosphorylation of the phosphatase inhibitor 1 potentially related to decreased cAMP-dependent protein kinase activity. In the second, there is decreased phosphorylation of the deinhibitor also potentially related to decreased cAMP-dependent protein kinase phosphorylation. In the third, an increased activity of casein kinase 2 could activate the ATP-Mg dependent phosphatase by an increased phosphorylation of phosphatase inhibitor 2 (modulatory subunit). In the liver, allosteric control of the phosphatase by G-6-P and nucleotides is of great importance. Insulin also stimulates the phosphatase in long-term experiments via increased protein synthesis. It is clear that future work will be required to determine which species of the various classes of phosphatases are regulated in short-term and long-term regulation by insulin. In terms of kinases, the effects of insulin to inactivate and desensitize the cAMP-dependent protein kinase are established. The molecular mechanisms of this effect remain to be worked out. The enhanced activity of MAP and S-6 kinase would appear to be part of a cascade of reactions perhaps originating in the autophosphorylation and activation of the insulin receptor tyrosine kinase. The mechanism of the short-term activation of casein kinase 2 remains to be elucidated. A cAMP-dependent protein kinase inhibitory mediator, which also inhibits adenylate cyclase is an important element in the regulation of kinase and adenylate cyclase activity by insulin. Its physiological significance must be established in the future, in terms of its control of glycogen synthase activation by insulin. Clearly this kinase inhibitor as well as the phosphatase stimulator are potential regulators of glycogen synthase activity by insulin.
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PMID:Insulin and the stimulation of glycogen synthesis. The road from glycogen structure to glycogen synthase to cyclic AMP-dependent protein kinase to insulin mediators. 215 10

Goat cauda-epididymal intact sperm ecto [32P] proteins phosphorylated in presence of exogenous [gamma-32P]ATP by an endogenous ecto-cyclic AMP-independent protein kinase (CIK), have been found to lose 32P when the labelled cells are incubated at 37 degrees C in a modified Ringer's solution. Analysis of the 32P-labelled products of the turnover of the ecto-phosphoproteins show that 32Pi rather than 32P-labelled peptides, is released from the cell-surface phosphoproteins indicating that the turnover of the ecto-phosphoproteins is mediated by an endogenous sperm outer-surface phosphoprotein phosphatase (ecto-PPase). The ecto-PPase is not a non-specific phosphatase since unlabelled p-nitrophenyl phosphate, beta-glycerophosphate or ATP at a relatively high concentration (1 mM each) has no appreciable effect on the dephosphorylation of the cell-surface proteins. The intact-sperm ecto-proteins phosphorylated and then dephosphorylated by the endogenous ecto-CIK and PPase respectively, undergo rephosphorylation by the cell-surface CIK. The data are consistent with the view that sperm external surface possesses a novel coupled-ecto-CIK and PPase enzyme system that regulates the phosphorylated states of the intact-sperm ecto-proteins by a cyclic mechanism of protein phosphorylation and dephosphorylation.
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PMID:Occurrence of a coupled-enzyme system on the intact-sperm outer surface that phosphorylates and dephosphorylates ecto-proteins. 216 95

A protein inhibitor of HMG-CoA reductase phosphatase activity from rat liver was purified to homogeneity. The protein was purified 4,000-fold with an overall yield of 4%. The purified protein had a molecular mass of 31 kDa. This spontaneously active protein is thermostable and acid-resistant. The protein inhibitor is phosphorylated by glycogen synthase kinase-3 and cAMP-dependent protein kinase without change in its inhibitory activity. The inhibition caused by this inhibitor on phosphatases 1 and 2A is similar to that of inhibitor-2 from rabbit skeletal muscle using hydroxymethylglutaryl-CoA reductase as substrate. The regulation properties of this inhibitor towards phosphatase 1 together with another protein inhibitor of phosphatase 2A in cholesterol metabolism are discussed.
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PMID:Purification and characterization of a protein inhibitor from rat liver that inhibits type 1 protein phosphatase when 3-hydroxy-3-methylglutaryl CoA reductase is the substrate. 216 23

Multifunctional protein kinase (MFPK) phosphorylates ATP-citrate lyase on peptide B on two sites, BT and BS, on threonine and serine, respectively, inhibitor 2 on a threonyl residue, and glycogen synthase at sites 2 and 3. The phosphorylation sites BT and BS of ATP-citrate lyase are dependent on prior phosphorylation at site A whereas site A phosphorylation is decreased by prior phosphorylation at sites BT and BS. To study the MFPK recognition sites and the site-site interactions, the amino acid sequences of ATP-citrate lyase peptide B and inhibitor 2 were determined and compared to each other and to glycogen synthase sites 3-5. The sequence of the tryptic peptide containing the two phosphorylation sites of peptide B is -Phe-Leu-Leu-Asn-Ala-Ser-Gly-Ser-Thr-Ser-Thr(P)-Pro-Ala-Pro-Ser(P)-Arg-, and the sequence of the MFPK phosphorylation site of inhibitor 2 is -Ile-Asp-Glu-Pro-Ser-Thr(P)-Pro-Tyr-. This inhibitor 2 site is identical with the site phosphorylated by glycogen synthase kinase 3/FA. These results suggest that at least some of the sites phosphorylated by MFPK (BT of ATP-citrate lyase, Thr 72 of inhibitor 2, and sites 3b and 4 of glycogen synthase) contain a Ser/Thr flanked by a carboxyl-terminal proline. However, as MFPK did not phosphorylate a series of peptides containing the -X-Thr/Ser-Pro-X- sequence, this minimum consensus sequence is not sufficient for phosphorylation by MFPK.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sequence of sites on ATP-citrate lyase and phosphatase inhibitor 2 phosphorylated by multifunctional protein kinase (a glycogen synthase kinase 3 like kinase). 217 22

Studies of in vitro models demonstrate that a forward motility protein (FMP) is required for the initiation of forward motility in the immature epididymal spermatozoa. FMP is a heat-stable glycoprotein derived from epididymal plasma. During the epididymal maturation of spermatozoa in vivo, there is a marked increase of intrasperm pH and level of cyclic adenosine monophosphate (cAMP). Several studies suggest that exogenous FMP in concert with elevated intrasperm pH and level of cAMP initiates flagellar motility during the epididymal transit of sperm. cAMP activates sperm cytosolic cAMP-dependent protein kinases, which in turn phosphorylate multiple intrasperm phosphoproteins that may regulate flagellar motility. Exogenous calcium ion activates intact sperm motility, although it inhibits motility of demembranated cells on reactivation. Occurrence of cAMP-dependent type I and II protein kinases, a novel cAMP-independent protein kinase, and a phosphoprotein phosphatase has been demonstrated on the external surface of spermatozoa. The sperm surface has a coupled-enzyme system: ecto-cAMP-independent protein kinase and phosphoprotein phosphatase that regulate the phosphorylation and dephosphorylation of endogenous sperm ectophosphoproteins. The specific activities of these ecto-enzymes increase markedly during forward progression, suggesting that they may have a role in regulating flagellar motility.
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PMID:Biochemical parameters of initiation and regulation of sperm motility. 219 32

We purified glucocorticoid receptors quickly but very partially using DEAE-resin. [3H]-Triamcinolone acetonide-labeled and non-activated receptors in the quickly purified fraction were found to be separated into two fractions (P-2 and P-3) by hydroxyapatite column chromatography. The P-2 receptor was the main component, and the ratio of P-2/P-3 was around 2. The molecular weights of the two receptors were calculated to be the same, 242,000: Rs = 6.2 nm and s20,w = 9.0. Treatment of the receptor with catalytic subunits of phosphoprotein phosphatase 2A1 reduced the P-2/P-3 ratio from 2 to 0.5, while treatment with catalytic subunits of cAMP-dependent protein kinase and ATP increased it to 2.5. The isolated P-3 receptor could be converted into the P-2 type by the kinase treatment. Tungstate, a phosphatase inhibitor, stabilized the P-2 receptor, and the P-2/P-3 ratio was larger than 3 when the DEAE-fraction was prepared in the presence of tungstate. However, the tungstate effect was not very strong, and the P-2 type tended to change into the P-3. [3H]-Triamcinolone acetonide-labeled and non-activated receptors were purified very highly by using an affinity gel; the procedure required more than 10 h. Only the P-3 form was observed in the preparation of highly purified receptors. Hormone-free receptors were affected by neither the phosphatase nor the kinase. The results indicate that the hormone binding makes the receptor sensitive to phosphatase. The reversibly dephosphorylated receptor is more stable than the non-dephosphorylated one, and can be activated.
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PMID:Phosphorylated and dephosphorylated types of non-activated glucocorticoid receptor. 222 27

Attention has focused on the regulation of the eucaryotic cell division cycle since the protein kinase p34cdc2 was identified as a key enzyme in mitotic induction. The level of this kinase remains constant throughout the cell cycle but its activity alters, particularly before M phase. Although the factors regulating cdc2 activity are still unknown, there is increasing evidence that it is influenced by p34cdc2 dephosphorylation. Protein phosphatase inhibitor-2 (I2) is a specific inhibitor of phosphatase type-1, which with type-2A is one of the two principal Ser(P) and Thr(P) phosphatases. Here we show that the level of I2, assayed by immunofluorescence staining, activity measurements, western immunoblotting and metabolic labelling, oscillates during the cell cycle in rat fibroblasts, peaking at S phase and mitosis. Moreover, when we inhibited I2 in vivo by microinjection of anti-I2 antibodies in S-phase cells, the pseudo-mitotic cellular response to injected p34cdc2 was restored, indicating that I2 might have a role in the modulation of p34cdc2 activity.
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PMID:Cell cycle oscillation of phosphatase inhibitor-2 in rat fibroblasts coincident with p34cdc2 restriction. 240 14

A protein kinase and an acidic phosphoprotein phosphatase were purified from Tetrahymena pyriformis which phosphorylate and dephosphorylate the purified ornithine decarboxylase (ODC) of this microorganism. The protein kinase and the phosphoprotein phosphatase are copurified with ODC and can be separated in three distinct peaks only by a hydrophobic column of phenyl-Sepharose. The purified kinase is not dependent on cAMP, requires Mg2+ for its catalytic activity and has a molecule mass of 45 kDa. Incubation of [32P]ODC with the purified phosphoprotein phosphatase results in a complete loss of 32P and its catalytic activity. Phosphorylation of the inactive phosphatase-treated ODC by endogenous kinase or rat liver casein kinase-2 results in 100 or 40% reactivation of the initial untreated ODC activity, respectively.
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PMID:Interconversion of Tetrahymena pyriformis ornithine decarboxylase from inactive to active form by phosphorylation. 250 Jan 53


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