Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mutation in the gene IRA1 (formerly called PPD1) was originally characterized as a deficiency of a phosphoprotein phosphatase. The IRA1 gene has been cloned and sequenced. A large open reading frame (8,817 base pairs) which can encode a protein of 2,938 amino acids was found. Northern (RNA) blot analysis detected a message of about 10 kilobases, and nuclease S1 protection demonstrated mRNA start points at 97 and 98 base pairs upstream from the putative initiator ATG codon. Disruption of the IRA1 gene resulted in sensitivity to nitrogen starvation and heat shock. Diploids homozygous for the disrupted IRA1 gene were deficient in sporulation. Disruption of the IRA1 gene suppressed the lethality of the cdc25 mutation but did not suppress the lethality of either the ras1 ras2 or the cyr1 mutations. Deficiency of the phosphoprotein phosphatase was not reproducible in the disruption mutant of the IRA1 gene. Moreover, the ira1 mutant showed an increased level of cyclic AMP. Our results suggest that the IRA1 protein inhibits the function of the RAS proteins in a fashion antagonistic to the function of the CDC25 protein in the RAS-cyclic AMP pathway in Saccharomyces cerevisiae.
Mol Cell Biol 1989 Feb
PMID:IRA1, an inhibitory regulator of the RAS-cyclic AMP pathway in Saccharomyces cerevisiae. 254 Apr 26

Ca2+-calmodulin-dependent protein phosphatase activity is found in cytoskeletons of Y-1 mouse adrenal and bovine fasciculata cells. The activity is inhibited by three inhibitors of calmodulin (trifluoperazine, W-7 and pimozide) with EC50 in the low micromolar range. Protein phosphatase activity is inhibited by vanadate, fluoride, Zn2+ and pyrophosphate, stimulated by Mn2+ and found to be tightly bound to the cytoskeleton. Substrates for endogenous phosphatase activity were defined by one- and two-dimensional polyacrylamide gels. Phosphatase activity was seen with proteins that are substrates for both cyclic AMP-dependent and cyclic AMP-independent kinase enzymes. One specific Ca2+-calmodulin-dependent phosphatase, namely calcineurin, was purified to near homogeneity from cytoskeletons of Y-1 cells. The enzyme was found to be a heterodimer (MW 61,000 and 16,000) and the smaller subunit was shown to cross-react with antibodies raised against calcineurin from bovine brain. The purified enzyme catalyzes dephosphorylation of proteins (phosphorylase kinase and casein), phosphoamino acids (tyr greater than thre greater than ser) and a synthetic substrate (p-nitrophenyl phosphate). In addition, a new application of membrane transfer was devised by which the purified enzyme was incubated with a Western blot of cytoskeleton following incubation with [32P]ATP. This method defined four specific substrates of the enzyme (MW 150,000, 55,000, 35,000 and 30,000). Anti-calcineurin revealed that only a single Ca2+-calmodulin-dependent phosphatase is found in adrenal cell cytoskeleton.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1989 May
PMID:Isolation and characterisation of calcineurin from adrenal cell cytoskeleton: identification of substrates for Ca2+-calmodulin-dependent phosphatase activity. 254 40

Fractionation of rabbit skeletal muscle cytosol on Aminohexyl-Sepharose has resulted in the identification of a latent ATP, Mg-dependent protein phosphatase whose catalytic subunit is in the active conformation, but is inhibited by the presence of more than one modulator unit. The partially purified enzyme is converted to an inactive, kinase FA-dependent form upon incubation at 30 degrees C unless modulator-specific polyclonal antibodies are added to the preparation. The immunoglobulins also relieve the inhibition which is responsible for the low basal phosphatase activity of the enzyme, and they counteract all of the heat-stable inhibitor activity present in the preparation. Addition of free catalytic subunit abolishes the inhibition of the latent enzyme in a dose-dependent way, but cannot prevent the inactivation process. The inactivated phosphatase and the original latent enzyme exhibit the same apparent Mr in sucrose density-gradient centrifugation (70,000) and in gel filtration (110,000).
Mol Cell Biochem 1989 May 04
PMID:Identification and partial characterization of a latent ATP, Mg-dependent protein phosphatase in rabbit skeletal muscle cytosol. 254 91

Alloxan diabetes induced in white rats by intraperitoneal injection of alloxan-monohydrate (15 mg/100 g body weight) was used to study changes in the glycogen phosphorylase a and b, phosphoprotein phosphatases and hexokinase activities under insulin deficiency conditions. Among the enzymes studied, an increase in muscle phosphorylase a activity as well as the a/b ratio have been obtained. In diabetic muscle phosphoprotein phosphatases and hexokinase activities were diminished. AMP increased the liver glycogen phosphorylase activity twice in diabetic rats whereas in normal animals the enzyme was less sensitive to this effector. The changes in liver hexokinase activity at diabetes were not connected and correlated with the altered phosphorylase and protein phosphatase activities. The logical chain of probable molecular events taking place in muscle glycogen metabolism under the conditions of insulin deficiency is offered.
Mol Cell Biochem 1989 Oct 31
PMID:Changes in the activity of enzymes, participating in glycogen metabolism of alloxan diabetic rats. 255 79

(1) The effects of norepinephrine on protein phosphorylation in isolated rat cardiac ventricular myocytes were determined by autoradiography on 32P-labelled proteins separated by electrophoresis; (2) In cells from young adult rats (6 months old) there was a marked increase due to norepinephrine (10(-8) to 10(-4) M) in the incorporation of 32P into proteins identified on the grounds of molecular weight as troponin I and C-protein: in cells from senescent rats (24 months old) this increase was much attenuated. (3) Age-associated decrements in protein phosphorylation were much diminished when maximally effective concentrations of the adenylate cyclase-activator forskolin and the cyclic AMP analog 8(4-chlorophenylthio) cyclic AMP were used instead of norepinephrine. Moreover, age-associated differences were abolished if the phosphodiesterase inhibitor isobutylmethylxanthine was present in addition to norepinephrine, or alone. (4) Study of the rates of dephosphorylation of troponin I, as initiated with the beta-adrenergic antagonist propranolol, showed no change in half-time as a function of age: this indicates no change in protein phosphatase activity. (5) These results suggest that there is less active net formation of cyclic-AMP in senescent heart cells in response to the neurotransmitter norepinephrine, giving a lesser activation of c-AMP-dependent protein kinase and less phosphorylation of these target proteins.
J Mol Cell Cardiol 1989 Dec
PMID:Decrease with senescence in the norepinephrine-induced phosphorylation of myofilament proteins in isolated rat cardiac myocytes. 256 Nov 60

Inhibitor-1 following phosphorylation by protein kinase A inhibits phosphoprotein phosphatase-1. We have found that in the rat heart inhibitor-1 is present only in the cytosolic fraction and that its phosphorylation in ventricular slices was increased by isoproterenol but not by isoproterenol and propranolol together. Cardiac microsomal phosphoprotein phosphatase activity, with added phosphorylase a as the substrate, was inhibited 33% by phosphorylated inhibitor-1. Phosphorylated inhibitor-1 decreased the dephosphorylation by exogenous phosphoprotein phosphatase-1 of phospholamban present in the sarcoplasmic reticulum membranes. These results suggest an interaction of cytoplasmic inhibitor-1 with either cytoplasmic or membrane-bound phosphoprotein phosphatase-1 with a subsequent effect on the level of phosphorylated phospholamban and the probable involvement of this interaction in the cardiac response to beta-adrenergic hormones.
Mol Cell Endocrinol 1988 Jan
PMID:A regulation of the level of phosphorylated phospholamban by inhibitor-1 in rat heart preparations in vitro. 283 40

Canine cardiac sarcoplasmic reticulum is phosphorylated by adenosine 3',5'-monophosphate (cAMP)-dependent and by calcium.calmodulin-dependent protein kinases on a 27,000 proteolipid, called phospholamban. Both types of phosphorylation are associated with an increase in the initial rates of Ca2+ transport by SR vesicles which reflects an increased turnover of elementary steps of the calcium ATPase reaction sequence. The stimulatory effects of the protein kinases on the calcium pump may be reversed by an endogenous protein phosphatase, which can dephosphorylate both the cAMP-dependent and the calcium.calmodulin-dependent sites on phospholamban. Thus, the calcium pump in cardiac sarcoplasmic reticulum appears to be under reversible regulation mediated by protein kinases and protein phosphatases.
Mol Cell Biochem
PMID:The role of protein kinases and protein phosphatases in the regulation of cardiac sarcoplasmic reticulum function. 284 12

Adrenocorticotropin (ACTH) acts via protein kinase A and the putative phosphorylation of a regulatory protein(s). We have examined a role in this process for inhibitor-1 which, following phosphorylation by protein kinase A, inhibits a phosphoprotein phosphatase activity. In the tissues we have examined inhibitor-1 was found primarily in the cytosol (90%) with the rest in the mitochondrial pellet. The highest concentration was in the adrenal cortex. Using adrenal cortex slices, the stimulation of steroidogenesis by ACTH and dibutyryl cAMP is paralleled by a corresponding increase in the phosphorylation of inhibitor-1 and this is not affected by inhibitors of protein synthesis which inhibit the steroidogenic response. The increase in the phosphorylation of inhibitor-1 occurs in the cytosol, while that in the mitochondrial pellet is not affected. Exogenous phosphorylated inhibitor-1, however, was found to inhibit phosphoprotein phosphatase activity in the mitochondrial pellet. The results suggest that the ACTH-induced increase in phosphorylated inhibitor-1 in the cytosol can affect susceptible phosphoprotein phosphatase activity both in the cytosol and the mitochondrial pellet and, hence, the level of phosphorylation of regulatory protein(s) involved in steroidogenesis.
Mol Cell Endocrinol 1988 Nov
PMID:The stimulation by adrenocorticotropin of the phosphorylation of adrenal inhibitor-1: a possible role in steroidogenesis. 285 Sep 49

The Mr = 33,000 catalytic fragment of rabbit skeletal muscle type 1 protein phosphatase was digested with trypsin after reduction and alkylation. The resulting peptides were isolated, subjected to automated Edman degradation, and their sequences compared to the deduced peptide sequence of the bovine type 2A protein phosphatase cDNA. Of 10 tryptic peptides from the type 1 phosphatase that were sequenced, nine showed a high degree of homology with the type 2A phosphatase. This provides the first direct sequence comparison suggesting that the type 1 and type 2 protein phosphatases, distinguished functionally by their substrate specificities and sensitivity to inhibitors, make up part of a family of closely related gene products with similar structures.
Mol Endocrinol 1987 Oct
PMID:Sequence homologies between type 1 and type 2A protein phosphatases. 285

This article summarizes some of our knowledge concerning intracellular protein phosphorylation pathways in nerve cells. It also summarizes, very briefly, recent direct experimental evidence involving intracellular injection of protein kinases, protein kinase inhibitors, and substrates, indicating that protein phosphorylation mediates the actions of a variety of neurotransmitters on their target cells. Finally, it summarizes in somewhat greater detail the results of studies of three different types of substrate proteins that appear to regulate different types of biological responses in nerve cells: synapsin I, a substrate protein present in virtually all nerve terminals, which appears to regulate neurotransmitter release from those nerve terminals; the acetylcholine receptor, the phosphorylation of which regulates its rate of desensitization in the presence of acetylcholine; and DARPP-32, the phosphorylation of which converts it into a very potent phosphoprotein phosphatase inhibitor that may be involved in the regulation by the neuromodulator dopamine of the effects of the neurotransmitter glutamate. The identification and characterization of additional neuronal phosphoproteins can be expected to lead to the clarification of numerous additional molecular mechanisms by which signal transduction is carried out in nerve cells.
Mol Neurobiol
PMID:Neuronal phosphoproteins. Mediators of signal transduction. 290 93


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