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 microsomal protein having N-terminal amino acid sequence SDVLELTDEN, was initially described as a phosphatidyl inositol-specific phospholipase C alpha when its cDNA was cloned (Bennett et al., Nature, 334, 268, 1988). Later, this protein, with an estimated molecular mass of 54 to 60 kDa, was shown to lack the phospholipase activity and instead a protein disulfide oxidoreductase and a thiol protease activities were ascribed to it. Following evidences indicated that the protein in question is the carnitine medium/long chain acyltransferase (CPT) of microsomes that was recently purified as a approximately 54 kDa protein (Murthy and Bieber, Protein Exp. Purif. 3, 75, 1992). First, the N-terminal amino acids of the microsomal CPT showed 100% homology to the sequence described above. Second, during purification of this CPT, the oxidoreductase and the thiol protease activities of the microsomes became separated from the CPT and these other activities were not found in the approximately 900 fold enriched CPT preparations. Third, an antibody to this protein did not immunoprecipitate oxidoreductase of the solubilized microsomal extract but precipitated the CPT. This same protein has been studied by others as the ERp61 (endoplasmic reticulum protein), GRP58 (glucose regulated protein), and HIP-70 (hormone induced protein) but its function was not identified.
Mol Cell Biochem 1993 May 26
PMID:Carnitine medium/long chain acyltransferase of microsomes seems to be the previously cloned approximately 54 kDa protein of unknown function. 823 44

Internalization of TRH receptor (TRH-R) is dependent on sequences/structures in the receptor carboxyl-terminal tail. Here, we studied whether coupling to guanine nucleotide-binding protein (G-protein) and phospholipase-C (PLC) is involved in internalization. We constructed two mutant TRH-Rs: delta 218-263 TRH-R, in which most of the residues that form the putative third intracellular loop were deleted, and D71A TRH-R, in which an Asp in the putative second transmembrane helix was mutated to Ala; these TRH-Rs did not activate PLC when expressed transiently in COS-1 cells. In contrast to wild-type (WT) TRH-Rs, approximately 60% of which were internalized at steady state after binding methyl-HisTRH, only approximately 15% of delta 218-263 and D71A TRH-Rs were internalized. Thus, mutant TRH-Rs that do not activate PLC, most likely because they are uncoupled from G-proteins, are internalized to lesser extents than WT TRH-Rs. We also studied the effects of U73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino] hexyl]-1H-pyrrole-2,5-dione), an amino steroid that inhibits receptor-mediated activation of PLC. In COS-1 and AtT-20 cells transfected with WT TRH-Rs and in GH3 cells, U73122 virtually abolished TRH activation of PLC and partially reduced the fraction of WT TRH-Rs internalized. Thus, uncoupling WT TRH-Rs from PLC decreases internalization. We conclude that TRH-R coupling to G-protein and PLC increases the number of TRH-Rs internalized at steady state even though the primary signals for agonist-induced internalization are present in the receptor. These data support the idea that a quaternary complex of TRH/TRH-R/G protein/PLC is normally internalized.
Mol Endocrinol 1993 Sep
PMID:Decreased levels of internalized thyrotropin-releasing hormone receptors after uncoupling from guanine nucleotide-binding protein and phospholipase-C. 824 12

Previous studies have shown a close temporal relationship between lipid abnormalities and membrane dysfunction in ischemia and that phospholipase-inhibiting drugs limit such derangements. Amiodarone is a potent phospholipase inhibitor, but its potential or that of any other inhibitor to simultaneously attenuate lipid abnormalities and electrophysiological changes in the very early phase of ischemia has never been studied. We therefore investigated simultaneously such changes in early ischemia. In isolated porcine hearts perfused with or without pure amiodarone solutions, electrophysiologic changes before and during 20 min of LAD occlusion were recorded using unipolar electrodes and Franz contact electrode catheters, and full thickness myocardial biopsies obtained for lipid analyses. In untreated hearts (n = 5), occlusion of LAD resulted in the rapid onset of TQ depression/ST elevation within 1 min and plateauing at 10 min. There were mean increases of 33% and 50% in lysophosphatidylcholine and 33% and 70% in lysophosphatidylethanolamine levels at 5-7 min and 20 min of ischemia, respectively. Non-esterified fatty acid (NEFA) content did not change significantly during the first 5-7 min, but increased by 75% after 20 min of LAD occlusion. In treated hearts (n = 5) there was a 37% increase in sinus cycle length after amiodarone administration (503 +/- 85 vs 689 +/- 115 ms, P < 0.01) but no significant change in ventricular effective refractory period (202 +/- 22 vs 204 +/- 21 ms), action potential duration (215 +/- 11 vs 217 +/- 7 ms), or amplitude (31 +/- 6 vs 28 +/- 3 mV) was observed. Also, amiodarone treatment did not alter total phospholipid content, lysophospholipids and NEFA levels of non-ischemic hearts. However, there was significant attenuation (P < 0.01) of the onset of the TQ/ST shift and preservation of action potential amplitude (P < 0.02) during the first 5-7 min of LAD occlusion with concomitant suppression of the increase in both lysophospholipids (hydrolysis products of membrane phospholipids by endogenous phospholipases) and NEFA levels observed after 5-7 and 20 min of ischemia. The results suggest that amiodarone can delay the onset and limit the extent of electrophysiologic change in early myocardial ischemia in temporal association with suppression of myocardial phospholipase activities.
J Mol Cell Cardiol 1993 Sep
PMID:Phospholipase inhibition and the electrophysiology of acute ischemia: studies with amiodarone. 828 71

The Serratia liquefaciens phospholipase (PhlA) is secreted to the medium from its natural host. Here we present results which indicate that, when cloned and expressed in Escherichia coli, secretion can be mediated by a putative host-encoded pathway, expression of which is controlled by FlhD (formerly FlbB), the master regulator of the flagellar/chemotaxis regulon. In the absence of this secretion pathway, the synthesized phospholipase accumulates inside the host cell where it forms a complex with the PhlB protein. PhlB, which is encoded from the promoter distal gene of the phospholipase operon, inhibits the phospholipase activity of PhlA. Formation of this enzymatically inactive PhlA/PhlB complex is required for maintenance of cell viability.
Mol Microbiol 1993 Apr
PMID:Secretion of Serratia liquefaciens phospholipase from Escherichia coli. 831 77

The highly homologous bovine and porcine pancreatic phospholipase A2 (85% amino acid residue identity) show a large conformational difference in the loop from residue 59 to 71. In bovine phospholipase A2 residues 59 to 66 adopt an alpha-helix conformation, while residues 67 to 71 are in a surface loop. Residues 59 to 66 in the porcine enzyme have a random coil conformation, and residues 67 to 71 form a short 3(10)-helix. It has been suggested that most probably this conformational difference is caused by the substitution Val63 (bovine) to Phe63 (porcine) in the otherwise invariant loop 59 to 70. To test this hypothesis, a mutant porcine phospholipase A2 was constructed in which residue Phe63 was replaced by a Val. The activity of this F63V mutant towards aggregated substrates was about half the activity of wild-type porcine phospholipase A2, but significantly different from that of the bovine enzyme. The affinity for zwitterionic interfaces was found to be intermediate between porcine and bovine phospholipase. The mutation did not have any effect on the stability of the enzyme towards denaturation by guanidine.HCl. The F63V mutant was crystallized in space group P2(1)2(1)2(1) with cell dimensions a = 79.88 A, b = 65.23 A, c = 52.62 A, with two molecules per asymmetric unit. Its three-dimensional structure was solved by molecular replacement methods, and refined to a crystallographic R-factor of 17.6% for all data between 10 and 2.2 A resolution. In one molecule the 58 to 71 loop is in very weak density, suggesting a high degree of disorder or flexibility. The conformation of the same loop in the other molecule could be determined unambiguously. It shows a conformation which resembles more that of bovine phospholipase A2 than that of porcine phospholipase. It is concluded that indeed the single F63V substitution causes a dramatic conformational change.
J Mol Biol 1993 Aug 05
PMID:Crystal structure of a porcine pancreatic phospholipase A2 mutant. A large conformational change caused by the F63V point mutation. 835 74

The effect of aspirin (0.45 mg/100 g body wt, orally for 60 days) on mitochondrial lipids induced by isoproterenol (200 mg/Kg body wt, Sc for 2 days) was studied in rats. In isoproterenol treated rats, marked increases in cholesterol, free fatty acids, triglycerides and lipid peroxides in heart mitochondria were observed. The phospholipid level was lowered with a significant increase in the activity of phospholipase. The activity of Na+K(+)-ATPase registered a decrease and the activity of Ca(2+)-ATPase increased in isoproterenol treatment. Aspirin treatment is found to counteract the effect of isoproterenol on lipid and lipid peroxide formation and associated enzyme changes in heart mitochondria.
Biochem Mol Biol Int 1993 Apr
PMID:Effect of aspirin on mitochondrial lipids in experimental myocardial infarction in rats. 838 35

The relationship between the phospholipase-stimulating and immunosuppressive properties of cyclosporin A (CsA) has been investigated in vitro. At concentrations of 0.025 microM and upwards, CsA caused dose-related inhibition of both mitogen- and alloantigen-stimulated uptake of tritiated thymidine by human mononuclear leukocytes (MNL), which was associated with a time- and dose-related enhancement of the generation of lysophosphatidylcholine (LPC), arachidonic acid, and prostaglandin E2 from mitogen-stimulated cells. Arachidonate alone, at concentrations of up to 20 microM, did not affect lymphocyte activation, whereas cyclooxygenase and 5'-lipoxygenase inhibitors failed to protect the cells against the antiproliferative effects of CsA. However, LPC caused dose-related inhibition of MNL proliferation. Moreover, coincubation of MNL with alpha-tocopherol, a lysophospholipid-complexing agent, or with lysophospholipase protected the cells against CsA, as well as against LPC. The Na+,K(+)-ATPase activity of mitogen-activated lymphocytes was also inhibited by CsA, whereas inclusion of alpha-tocopherol or lysophospholipase protected this enzyme. Excessive production of lysophospholipids and consequent inhibition of Na+,K(+)-ATPase during CsA treatment of mitogen- or antigen-activated lymphocytes is a possible biochemical mechanism of the immunosuppressive activity of this agent.
Mol Pharmacol 1993 Sep
PMID:Lysophospholipid-mediated inhibition of Na+,K(+)-adenosine triphosphatase is a possible mechanism of immunosuppressive activity of cyclosporin A. 839 20

Treatment of intact Rat-1 fibroblasts with epidermal growth factor (EGF) leads to rapid activation of cellular ras-encoded proteins. By using the bacterial toxin streptolysin O to permeabilize these cells, it was shown that the low basal rate at which guanine nucleotides bind to, and dissociate from, ras-encoded protein in quiescent fibroblasts was greatly accelerated by EGF treatment. Nucleotide binding to other proteins was not affected. Stimulation of nucleotide exchange on ras-encoded protein required tyrosine kinase but not phospholipase activity. EGF had no effect on total GTPase-activating protein activity. Regulation of ras-encoded protein in Rat-1 fibroblasts is therefore mediated by stimulation, either directly or indirectly, of ras-encoded protein-specific guanine nucleotide exchange factors by the EGF receptor tyrosine kinase.
Mol Cell Biol 1993 Mar
PMID:Epidermal growth factor regulates the exchange rate of guanine nucleotides on p21ras in fibroblasts. 844 21

alpha 1-Adrenoceptors in most tissues couple with the heterotrimeric GTP-binding protein Gq, the alpha subunit of which activates the beta-isoforms of phospholipase C. However, in heart (and in liver) alpha 1-adrenoceptors have been reported to couple to a high molecular weight GTP-binding protein. Gh, which functions both as a type II transglutaminase and as a receptor coupling protein. Gh activates a phospholipase isoform distinct from phospholipase C-beta. Here we report that isolation and culture of neonatal cardiomyocytes decreased the expression of Gh without reducing the content of Gq or Gi. Gh was readily detected in extracts from intact neonatal and adult heart tissues. The expression of Gh thus appears to be a feature of intact cardiac tissue.
J Mol Cell Cardiol 1995 Oct
PMID:Isolation of neonatal cardiomyocytes reduces the expression of the GTP-binding protein, Gh. 857 53

Fibroblast growth factor receptor (FGFR) activation leads to receptor autophosphorylation and increased tyrosine phosphorylation of several intra cellular proteins. We have previously shown that autophosphorylated tyrosine 766 in FGFR1 serves as a binding site for one of the SH2 domains of phospholipase Cy and couples FGFR1 to phosphatidylinositol hydrolysis in several cell types. In this report, we describe the identification of six additional autophosphorylation sites (Y-463, Y-583, Y-585, Y-653, Y-654 and Y-730) on FGFR1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of FGFR1 and is therefore essential for FGFR1-mediated biological responses. In contrast, autophosphorylation of the remaining four tyrosines is dispensable for FGFR1-mediated mitogen-activated protein kinase activation and mitogenic signaling in L-6 cells as well as neuronal differentiation of PC12 cells. Interestingly, both the wild-type and a mutant FGFR1 (FGFR1-4F) are able to phosphorylate Shc and an unidentified Grb2-associated phosphoprotein of 90 kDa (pp90). Binding of the Grb2/Sos complex to phosphorylated Shc and pp90 may therefore be the key link between FGFR1 and the Ras signaling pathway, mito-genesis, and neuronal differentiation.
Mol Cell Biol 1996 Mar
PMID:Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. 862 1


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