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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endogenous and hormone-induced protein (polypeptide) phosphorylations were studied in isolated rat fat cells, in fat pads, and in subcellular fractions obtained from fat tissue under different physiological conditions. Insulin (25-100 muU/ml) increased the incorporation of 32P into two proteins: insulin-phosphorylated proteins (IPP 140 and IPP 50; similar to 140,000 and 50,000 daltons, respectively). Epinephrine (10(-7)-10(-6) M) increased the incorporation of 32P into another protein: epinephrine-phosphorylated protein (EPP 60-65; similar to 60,000-65,000 daltons). Endogenous IPP 140 phosphorylation in fat cells obtained from fasted and refed rats was similar to that of insulin in normal cells. Studies of insulin and epinephrine interactions showed that insulin increased IPP 140 phosphorylation even in the presence of epinephrine or lithium (25 mM times 10(-3) M). dibutyryl cyclic AMP (5 times 10(-4) M) markedly stimulated EPP 60-65 phosphorylation, but neither epinephrine (10(-7)-10(-6) M) nor dibutyryl cyclic AMP reproduced insulin's phosphorylation of APP 140. Lithium inhibited both endogenous and epinephrine-stimulate EPP 60-65 phosphorylation, but did not inhibit that induced by dibutyryl cyclic AMP. These findings suggest that insulin stimulated a specific, cyclic AMP independent protein kinase for IPP 140 phosphorylation. Cell-free extracts from insulin-treated fat tissue catalyzed the specific transfer of 32P from ATP to IPP 140 more rapidly than control extracts. No differences in the total receptor protein or total protein kinase activity using [gamma(-32P]ATP were noted between insulin-treated and control preparations. IPP 140 may be either (a) an insulin-sensitive protein kinase (phosphotransferase) or (b) a protein whose function is regulated by an insulin-sensitive protein kinase or phosphatase.
...
PMID:Actions of insulin, epinephrine, and dibutyryl cyclic adenosine 5'-monophosphate on fat cell protein phosphorylations. Cyclic adenosine 5'-monophosphate dependent and independent mechanisms. 16 23

The Ca2+-dependent regulation of contractile protein interactions in cardiac and vascular smooth muscle involves structurally related but distinct Ca2+ binding proteins. In vascular smooth muscle, Ca2+ binds to calmodulin, and Ca2+-calmodulin activates myosin light chain (MLC) kinase with ultimate stimulation of MLC phosphorylation and actin-myosin interactions. The largest class of inhibitors of vascular contractile protein interactions are the calmodulin antagonists which include certain Ca2+ entry blockers. Pharmacologically, some of these agents can be distinguished from pure Ca2+ entry blockers by being more effective vs. vasoconstrictor agents in vitro, less cardiac depressant, and more effective as platelet aggregation inhibitors. An even greater distinction from Ca2+ entry blockers is evident with another series of agents, isoquinolinesulfonamides, which directly inhibit protein kinase activity. Cardiac muscle myofibrillar regulation involves Ca2+ binding to troponin C (TnC). Some cardiotonics, such as Vardax and APP 201-533, increase the Ca2+ sensitivity of cardiac myofibrillar ATPase activity with a concomitant increase in Ca2+ binding to TnC. Several calmodulin antagonists, Ca2+ blockers, and structurally related agents differentially affect cardiac myofibrillar ATPase activity. Potency and efficacy of some of these stimulating agents is markedly greater than Vardax or APP 201-533. Mechanistically, all agents do not affect cardiac MLC phosphorylation, but directly enhance the Ca2+ sensitivity of ATPase activity. However, differential effects on basal and maximum ATPase activity by some agents suggest more complex or additional effects which are related to the type of agent as well as the species (dog vs. hamster). A major subcellular defect in congestive heart failure in various small animal models is a depressed maximum ATPase activity. Thus, a desired goal would be a pharmacological modulator which increases maximum ATPase activity, not necessarily Ca2+ sensitivity. In sum, it is possible to identify agents, Ca2+ binding protein modulators, which directly inhibit vascular smooth muscle and stimulate cardiac muscle contractile protein interactions. The potential advantages/disadvantages of this approach for vasodilator/cardiotonic drug development will have to await future development of novel compounds targeted specifically for these cellular regulatory processes.
...
PMID:Pharmacological modulation of cardiac and vascular contractile protein function. 243 41

Certain forms of cardiac failure appear to be associated with a decrease in the Ca++ sensitivity of the contractile structures, possibly due to troponin I phosphorylation. Interference of cardiotonic drugs with myofibrillar Ca++ activation instead of enhancement of Ca++ influx may therefore provide a more causal therapeutic concept in the treatment of cardiac insufficiency. APP 201-533 (3-Amino-6-methyl-5-phenyl-2(1H)-pyridinone) (the structure of which is shown below) is a novel cardiotonic agent acting neither via beta adrenoceptor stimulation nor inhibition of Na+/K+ ATPase. In the 100 microM concentration range, it increases the Ca++ sensitivity and the Ca++ affinity of functionally isolated cardiac contractile structures. This coincides with an inhibitory effect on the cAMP-dependent protein kinase from rat liver. A possible relation with the regulation of troponin I phosphorylation is discussed.
...
PMID:Myofibrillar Ca++ activation and heart failure--Ca++ sensitization by the cardiotonic agent APP 201-533. 281 53

A significant fraction of the beta-amyloid precursor protein is proteolytically processed to yield large secreted forms (sAPP). These proteins have pleiotropic effects which potentially involve control of gene expression. We have investigated the influence of sAPP on the class of transcription factors which bind kappa B enhancer sequences. Transcription dependent on a kappa B element was enhanced by sAPP in several cell lines, as measured by expression of a transfected chloramphenicol acetyltransferase reporter gene. Secreted APP also induced an increase in kappa B DNA-binding activity in hippocampal neurons treated with sAPP. Both effects were mimicked by an analog of cyclic GMP and inhibited by an antagonist of cyclic GMP-dependent protein kinase. Such activation of kappa B-dependent transcription was correlated in two ways with the ability of sAPP to protect neuronal cells against calcium-mediated damage: (1) tumor necrosis factor beta also protected against calcium-mediated insults and induced kappa B-dependent transcription; (2) antisense oligonucleotide-mediated reduction of an endogenous inhibitor of NF-kappa B activated kappa B-binding activity and attenuated calcium-mediated toxicity in both a neuronal cell line and in primary neurons. These findings suggest that a kappa B-binding transcription factor can act as a coordinator of neuroprotective gene expression in response to cytokines.
...
PMID:Induction of neuroprotective kappa B-dependent transcription by secreted forms of the Alzheimer's beta-amyloid precursor. 884 19

The beta-amyloid precursor protein undergoes a physiological cleavage by alpha-secretase that leads to the release of a secreted C-terminally truncated fragment called APP alpha and likely concomitantly reduces the formation of the amyloidogenic A beta peptide. Here we demonstrate that APP alpha secretion is increased by the protein kinase A (PKA) effectors 8-bromo cyclic AMP and forskolin in human embryonic kidney cells (HK293), and that this can be prevented by a proteasome inhibitor. Furthermore, we establish that PKA effectors but not protein kinase C agonists increase the chymotrypsin-like activity and phosphorylation state of the proteasome in vitro and in vivo in HK293 cells. Altogether, this report demonstrates that the alpha-secretase pathway is under the control of PKA in human cells and that the proteasome likely contributes, either directly or through yet unknown intermediates, to the PKA-stimulated APP alpha secretion in human cells.
...
PMID:Protein kinase A phosphorylation of the proteasome: a contribution to the alpha-secretase pathway in human cells. 893 98

The effect of the secretory form of amyloid precursor protein (sAPP) on synaptic transmission was examined by using developing neuromuscular synapses in Xenopus cell cultures. The frequency of spontaneous postsynaptic currents (SSCs) was reduced by the addition of sAPP, whereas the amplitude of impulse-evoked postsynaptic currents (ESCs) was increased by sAPP. These opposing effects on spontaneous versus evoked release were separated by using the specific domain of APP. The C-terminal fragment of sAPP (CAPP) only reduced SSC frequency and did not affect ESCs. By contrast, the N-terminal fragment of sAPP (NAPP) did not affect SSC frequency but did increase ESC amplitude. The reduction of SSC frequency by sAPP appears to be mediated by activation of potassium channels through a cGMP-dependent pathway, whereas the increase of ESC amplitude is mediated by a different pathway involving activation of protein kinase(s). These results suggest the potential role of sAPP as a modulator of synaptic activity by two specific domains.
...
PMID:Novel domain-specific actions of amyloid precursor protein on developing synapses. 980 77

To examine the regulation of amyloid secretion in more detail, Abeta sandwich ELISAs with high sensitivity and specificity were developed. Using this technique, we measured Abeta secreted from COS7 cells transiently transfected with APP C100 in the presence of LiCl, a potent glycogen synthase kinase (GSK)-3beta inhibitor. We found that both Abetax-40 and Abetax-42 secretion were reduced by LiCl treatment in a dose-dependent manner. Diminished amyloid secretion was associated with GSK-3beta activity. These results suggest that GSK-3beta might function as a possible mediator for regulating both amyloid deposition and tau pathology in Alzheimer's disease (AD), and that lithium should be re-evaluated as a candidate reagent for preventing AD pathology.
...
PMID:Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. 1187 57

Tg2576 mice overexpress a mutant form of human amyloid precursor protein with the Swedish mutation (APP(Sw)), resulting in high beta-amyloid (Abeta) levels in the brain. Despite this, amyloid plaques do not develop until 12 months of age, and there is no neuronal loss in mice as old as 16 months. Gene expression profiles in the hippocampus and cerebellum of 6-month-old APP(Sw) mice were compared with age-matched controls. The expression of transthyretin, a protein shown to sequester Abeta and prevent amyloid fibril formation in vitro, and several genes in the insulin-signaling pathway, e.g., insulin-like growth factor-2, were increased selectively in the hippocampus of APP(Sw) mice. Concomitant activation of the insulin-like growth factor-1 receptor, Akt, and extracellular signal-regulated protein kinase 1 and 2 as well as increased phosphorylation of Bad also were unique to the hippocampus of APP(Sw) mice. In addition, the increased expression of transthyretin and insulin-like growth factor-2 and the increased phosphorylation of Bad in hippocampal neurons were maintained in 12-month-old APP(Sw) mice when compared with age-matched controls. These results suggest that the slow progression and lack of full-fledged Alzheimer's disease pathology in the hippocampal neurons of APP(Sw) mice result from the genetic reprogramming of neural cells to cope with increased levels of Abeta.
...
PMID:Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. 1219 59

Based on the critical role of actin in the maintenance of synaptic function, we examined whether expression of familial beta-amyloid precursor protein APP-V642I (IAPP) or mutant presenilin-1 L286V (mPS1) affects actin polymerization in rat septal neuronal cells. Expression of either IAPP or mPS1 but not wild-type amyloid precursor protein or presenilin-1induced formation of actin stress fibers in SN1 cells, a septal neuronal cell line. Treatment with beta-amyloid (Abeta) peptide also caused formation of actin stress fibers in SN1 cells and primary cultured hippocampal neurons. Treatment with a gamma-secretase inhibitor completely blocked formation of actin stress fibers, indicating that overproduction of Abeta peptide induces actin stress fibers. Because activation of the p38 mitogen-activated protein kinase (p38MAPK)-mitogen-associated protein kinase-associated protein kinase (MAPKAPK)-2-heat-shock protein 27 signaling pathway mediates actin polymerization, we explored whether Abeta peptide activates p38MAPK and MAPKAPK-2. Expression of IAPP or mPS1 induced activation of p38MAPK and MAPKAPK-2. Treatment with a p38MAPK inhibitor completely inhibited formation of actin stress fibers mediated by Abeta peptide, IAPP or mPS1. Moreover, treatment with a gamma-secretase inhibitor completely blocked activation of p38MAPK and MAPKAPK-2. In summary, our data suggest that overproduction of Abeta peptide induces formation of actin stress fibers through activation of the p38MAPK signaling pathway in septal neuronal cells.
...
PMID:beta-Amyloid peptide induces formation of actin stress fibers through p38 mitogen-activated protein kinase. 1242 54

A large body of evidence supports a major role for the serotonin 5-HT(4) receptor in learning and memory and it is suggested that 5-HT(4) agonists may be beneficial for memory disorders such as Alzheimer's disease (AD). The 5-HT(4) receptors are members of the G protein-coupled receptor superfamily and are positively coupled to adenylyl cyclase. In this communication we show that a neuronal isoform of the human 5-HT(4) receptor, h5-HT(4(g)) regulates the metabolism of the amyloid precursor protein (APP695). This process is observed in Chinese hamster ovary (CHO) cells stably coexpressing the neuronal h5-HT(4(g)) receptor isoform as well as the human APP695. The 5-HT(4) agonists strongly stimulate the release of the non-amyloidogenic soluble amyloid precursor protein sAPPalpha as detected by immunoblot. Prucalopride was more potent than serotonin (5-HT) with regard to enhanced of sAPPalpha secretion. This process was blocked by a selective 5-HT(4) antagonist, GR113808. Furthermore, 5-HT(4) ligands enhance sAPPalpha secretion via cAMP-dependent and PKA-independent signalling pathways indicating there are alternative pathways by which the h5-HT(4) receptor via cAMP regulates APP metabolism. Because the alpha-cleavage event may preclude the formation of amyloidogenic peptides, and secreted sAPPalpha has putative neuroprotective and enhancing-memory properties, our present data suggest the 5-HT(4) receptor as a novel target for the treatment of AD.
...
PMID:The serotonin 5-HT4 receptor and the amyloid precursor protein processing. 1254 73


1 2 3 4 5 6 7 8 9 10 Next >>

---