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)

Cancer is a multi-step process, one of the latest events correspond to metastasis formation and dissemination, to date the major cause of deaths. The h-prune-nm23-H1 protein complex and its activation of PDE-cAMP activity have been shown to correlate with breast cancer progression and metastasis formation. Here, we describe the protein complex formation and its involvement in cell migration. By gene expression studies and protein-protein pull-down analyses coupled to mass spectrometry we have identified new genes and pathways along which the h-prune-nm23-H1 complex exerts its function. We review here h-prune binding to the glycogen synthase kinase (GSK-3beta) and identify a new h-prune protein partner, Gelsolin, an ATP severing protein acting in focal adhesions, in a MDA-435 breast cancer cellular model. The results presented here underline the importance of this protein complex leading to new translational studies involved into the inhibition of cell migration, thus enhancing the potential of using this knowledge to direct inhibition of metastases formation in humans.
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PMID:H-prune-nm23-H1 protein complex and correlation to pathways in cancer metastasis. 1710 19

cGMP-inhibited cAMP phosphodiesterase 3A (PDE3A) is expressed in mouse oocytes, and its function is indispensable for meiotic maturation as demonstrated by genetic ablation. Moreover, PDE3 activity is required for insulin/insulin-like growth factor-1 stimulation of Xenopus oocyte meiotic resumption. Here, we investigated the cAMP-dependent protein kinase B (PKB)/Akt regulation of PDE3A and its impact on oocyte maturation. Cell-free incubation of recombinant mouse PDE3A with PKB/Akt or cAMP-dependent protein kinase A catalytic subunits leads to phosphorylation of the PDE3A protein. Coexpression of PDE3A with constitutively activated PKB/Akt (Myr-Akt) increases PDE activity as well as its phosphorylation state. Injection of pde3a mRNA potentiates insulin-dependent maturation of Xenopus oocytes and rescues the phenotype of pde3(-/-) mouse oocytes. This effect is greatly decreased by mutation of any of the PDE3A serines 290-292 to alanine in both Xenopus and mouse. Microinjection of myr-Akt in mouse oocytes causes in vitro meiotic maturation and this effect requires PDE3A. Collectively, these data indicate that activation of PDE3A by PKB/Akt-mediated phosphorylation plays a role in the control of PDE3A activity in mammalian oocytes.
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PMID:Protein kinase B/Akt phosphorylation of PDE3A and its role in mammalian oocyte maturation. 1712 99

Major changes in the cAMP-dependent signal transduction pathway triggered by FSH take place during transition of rat Sertoli cells from proliferative to the quiescent/terminally differentiated state. Using Sertoli cell cultures isolated from 10-, 20-, and 30-day-old rats, we recorded a specific increase in PDE4 activity in both the soluble and particulate subcellular fractions of 20-day-old Sertoli cells, which also displayed the highest cAMP response to FSH and the highest FSH-induced increase in PDE4 activity in both subcellular compartments. RT-PCR and immunoblotting experiments showed that almost all the PDE4D isoforms, known as the main cAMP-regulated rolipram-sensitive PDE in Sertoli cells, were expressed throughout the early postpartum period, whereas only the short PDE4D isoforms (PDE4D1 and PDE4D2) were transcriptionally regulated by FSH. Unexpectedly, the immunoblot data also revealed that the soluble PDE4 activities were mainly related to the long PDE4D isoforms and that short PDE4D1 was predominantly particulate. The subcellular distribution and expression of PDE4D proteins were unaffected by the developmental status of the Sertoli cells. Only the expression of short PDE4D1 appeared to be upregulated by FSH and only in 20-day-old Sertoli cells, which suggests phenotype-dependent differential regulation of Pde4d1 mRNA translation. Resensitization of the cAMP response to FSH in 20-day-old Sertoli cells was also associated with the highest FSH-induced transient increase in both soluble and particulate PDE4 activities, which suggests developmental changes in the PKA-mediated upregulation of the catalytic activities of long PDE4D. Such alterations may be involved in the phenotype-dependent alterations in FSH receptor coupling with its associated G proteins in rat Sertoli cells.
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PMID:Expression of the cAMP-phosphodiesterase PDE4D isoforms and age-related changes in follicle-stimulating hormone-stimulated PDE4 activities in immature rat sertoli cells. 1721 91

Seabuckthorn fatty acids were extracted by crushing and centrifuging from china seabuckthorn fruit. We detected cyclic nucleotides concentration in serum of different stages in aged rats (from 16 to 21 months), cyclic nucleotides concentration, PKA activity and PDE activity in hepatic tissue in aged rats by seabuckthorn fatty acids. Our data showed that the serum cAMP concentration decreased, accompany with the cGMP concentration increased and the imbalance of the cAMP/cGMP ratio in aged process. This kind of change equally in the hepatic tissue, the cAMP concentration decreased, PKA activity also decreased, but no change of the cAMP particularity PDE activity. And the SBFAs raised serum cAMP level in different stages, and raised the cAMP concentration and PKA activity of hepatic tissue, but did not effect the cAMP particularity PDE activity. Our study demonstrated that it is imbalance of the cAMP/cGMP ratio in aged process. SBFAs enhanced the cAMP/PKA pathway, regulated cAMP/cGMP ratio in aged rats.
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PMID:Enhanced cAMP/PKA pathway by seabuckthorn fatty acids in aged rats. 1738 85

The activity, expression and function of phosphodiesterase 4 (PDE 4) were investigated in the HMG human gingiva-derived malignant melanoma cell line. A specific PDE4 inhibitor, rolipram, inhibited PDE activity in homogenates of HMG cells, and PDE4B and 4D mRNAs were detected by RT-PCR in RNA from HMG cells. Two specific PDE4 inhibitors, rolipram and Ro-20-1724, and an adenylate cyclase activator, forskolin, increased intracellular cAMP in HMG cells. Cell growth induced by rolipram, Ro-20-1724, and forskolin was inhibited by the H-89 protein kinase A (PKA) inhibitor. However, in contrast to effects of H-89, two other PKA inhibitors, KT5720 and PKI, did not inhibit rolipram-induced cell growth. A cAMP analogue that selectively activates Epac, 8-pCPT-2'-O-Me-cAMP, also promoted the growth of HMG cells. These findings suggested that PDE4, PDE4B and/or 4D regulate cell growth through cAMP targets in the HMG malignant melanoma cell line. There have been no previous studies of positive regulation of cell growth by PDE4 inhibition, suggesting that it may be possible to target PDE4 in therapy for human malignant melanoma.
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PMID:A role for cyclic nucleotide phosphodiesterase 4 in regulation of the growth of human malignant melanoma cells. 1739 56

By activating two distinct classes of effector enzymes, namely Protein Kinases A [PKA] or Exchange Proteins Activated by cAMP [EPAC], the ubiquitous second messenger cAMP selectively coordinates numerous events simultaneously in virtually all cells. Studies focused on dissecting the manner by which cAMP simultaneously regulates multiple cellular events have shown that cAMP activates its effectors non-uniformly in cells and that this localized cAMP-mediated signalling is made possible, at least in part, by anchoring of cAMP effectors to selected subcellular structures. In the work described here, we report that HEK293T cells ["293T"] contain several PKA- and EPAC1-based signalling complexes. Interestingly, our data do not identify signalling complexes in which both PKA and EPAC are each present but rather are consistent with the idea that these two effectors operate in distinct complexes in these cells. Similarly, we report that while individual PKA- or EPAC-containing complexes can contain either phosphodiesterase 3B, [PDE3B] or phosphodiesterase 4D [PDE4D], they do not contain both these phosphodiesterases. Indeed, although PDE4D enzymes were identified in both PKA- and EPAC-based complexes, PDE3B was largely identified in EPAC-based complexes. Using a combination of approaches, we identified that integration of PDE3B into EPAC-based complexes occurred through its amino terminal fragment [PDE3B(AT)]. Consistent with the idea that integration of PDE3B within EPAC-based complexes was dynamic and regulated PDE3 inhibitor-mediated effects on cellular functions, expression of PDE3B(AT) competed with endogenous PDE3B for integration into EPAC-based complexes and antagonized PDE3 inhibitor-based cell adhesion. Our data support the concept that cells can contain several non-overlapping PKA- and EPAC-based signalling complexes and that these complexes may also represent sites within cells were the effects of family-selective PDE inhibitors could be integrated to affect cell functions, including adhesion.
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PMID:Numerous distinct PKA-, or EPAC-based, signalling complexes allow selective phosphodiesterase 3 and phosphodiesterase 4 coordination of cell adhesion. 1788 39

The PDE4 (phosphodiesterase-4) enzyme family consists of a distinct array of N-terminal splice variant isoforms arising from four subfamily genes (4A, 4B, 4C and 4D). These all hydrolyse specifically the intracellular second messenger cAMP. Although identical in catalytic function, each isoform appears to serve a non-superfluous regulatory role. For example, a beta-arrestin-sequestered subpopulation of the PDE4D5 isoform specifically regulates the phosphorylation of the beta(2)-AR (beta(2)-adrenergic receptor) by PKA (protein kinase A; also called cAMP-dependent protein kinase). This was elucidated by the use of novel technologies, including dominant-negative approaches, siRNA (small interfering RNA) knockdown and spot-immobilized peptide array analyses. Functional phenotypes uncovered using these methodologies have shown that beta-arrestin-sequestered PDE4D5 shapes the spatial cAMP gradient around the membrane-bound beta(2)-AR, regulating its phosphorylation by PKA and its ability to activate ERK (extracellular-signal-regulated kinase) through G(i) in cardiomyocytes and HEK-293 (human embryonic kidney)-B2 cells. This approach has provided the very first identification of a non-redundant and specific role for a PDE isoform. The fact that phenotypes can be uncovered by displacing PDE4 isoforms from specific anchor sites using dominant-negative constructs and cell-permeable peptides points to novel means for developing therapeutics aimed at disrupting specifically sequestered PDE isoforms and even specifically sequestered subpopulations of individual isoforms.
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PMID:cAMP-specific phosphodiesterase-4D5 (PDE4D5) provides a paradigm for understanding the unique non-redundant roles that PDE4 isoforms play in shaping compartmentalized cAMP cell signalling. 1795 50

Agents expected to increase intracellular cAMP levels were tested on the diffusional water permeability (P(dw)) of isolated rabbit conjunctival epithelia given recent indications of the apical expression of AQP5, a water channel homologue regulated by cAMP in other cell systems. For these experiments, segments of conjunctivae were mounted between Ussing-type hemichambers under short-circuit conditions. Unidirectional water fluxes (J(dw)) were measured by adding (3)H(2)O to one hemichamber and sampling from the other, while the electrical parameters (I(sc) and R(t)) were recorded simultaneously. J(dw) were determined under control conditions and after the introduction of forskolin, dibutyryl-cAMP, rolipram and IBMX. All agents reduced J(dw), with rolipram and IBMX the most effective inhibitors (~28% reduction), while simultaneously evoking stimulations of the I(sc); suggesting that cAMP regulates ionic transport and P(dw) independently. This observation was consistent with the elimination of the IBMX-elicited I(sc) stimulations by the PKA inhibitor, H89, and the ineffectiveness of the sulfonamide in preventing the J(dw) reductions produced by the xanthine. Data from mannitol fluxes and Arrhenius plots indicated that the IBMX-elicited P(dw) reduction occurred at the level of water-transporting channels, but the specific moiety was not identified. Instead it was observed that lipophiles commonly used in other systems to uncouple cellular communication precluded the effects of IBMX on J(dw), but the mechanism for these results was not directly linked to gap-junction blockade in the conjunctiva, as assessed by the transepithelial electrical parameters. Putatively, agents such as heptanol, by also fluidizing the bilayer, may have changed the conformation of a water channel in a manner preventing down-regulation by IBMX. Nevertheless, this study uncovered an apparently unique response to cAMP elevation exhibited by the conjunctiva, namely that P(dw) declines via an H89-insensitive pathway under conditions whereby PKA-dependent electrolyte transport might be over stimulated due to excessive cAMP levels (e.g., PDE inhibition).
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PMID:IBMX-elicited inhibition of water permeability in the isolated rabbit conjunctival epithelium. 1823 93

Rolipram, a specific inhibitor of the phosphodiesterase IV (PDE IV), has recently been shown to exert neuroprotective effects in an Alzheimer transgenic mouse model and in hypoxic-ischemic damage in the rat brain. It activates the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway and it inhibits inflammation. We tested the neuroprotective effects of the specific PDE IV inhibitor rolipram in C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that rolipram administered at 1.25 mg/kg or 2.5 mg/kg doses significantly attenuated MPTP-induced dopamine depletion in the striatum, and reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra. There was a bell-shaped dose effect with greater efficacy at the 1.25 mg/kg dose than 2.5 mg/kg and a higher dose of rolipram, 5 mg/kg, had no protective effect and even increased the mortality of animals when co-administered with MPTP. Rolipram did not interact with MPTP in its absorption into the brain and in its metabolism to 1-methyl-4-phenylpyridinium (MPP(+)). Our data show a neuroprotective effect of the PDE IV specific inhibitor rolipram against dopaminergic neuron degeneration, suggesting that PDE IV inhibitors might be a potential treatment for Parkinson's disease.
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PMID:Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV. 1832 79

6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)quinolinone (cilostazol), a phosphodiesterase type 3 (PDE III) inhibitor, activates cAMP-dependent protein kinase A (PKA). The cAMP/PKA pathway potentiates the opening of mitochondrial Ca(2+)-activated K(+) (mitoK(Ca)) channels and confers cardioprotection. Although cilostazol has been reported to directly activate sarcolemmal large-conductance Ca(2+)-activated K(+) channels, it remains unclear whether cilostazol modulates the opening of mitoK(Ca) channels. Therefore, we tested the possibility that cilostazol opens mitoK(Ca) channels and protects hearts against ischemia/reperfusion injury. Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoK(Ca) channel activity. Infarct size in the isolated perfused rabbit hearts subjected to 30-min global ischemia and 120-min reperfusion was determined by triphenyltetrazolium chloride staining. Cilostazol (1, 3, 10, and 30 microM) oxidized flavoprotein in a concentration-dependent manner. The oxidative effect of cilostazol (10 microM) was antagonized by the mitoK(Ca) channel blocker paxilline (2 microM). Activation of PKA by 8-bromoadenosine 3'5'-cyclic monophosphate (0.5 mM) potentiated the cilostazol-induced flavoprotein oxidation. Treatment with cilostazol (10 microM) for 10 min before ischemia significantly reduced the infarct size from 67.2 +/- 1.3 (control) to 33.6 +/- 5.3% (p < 0.05). This infarct size-limiting effect of cilostazol was abolished by paxilline (60.3 +/- 4.9%) but not by the PKA inhibitor (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylic acid hexyl ester (KT5720) (200 nM, 40.5 +/- 3.5%). On the other hand, another PDE III inhibitor, milrinone (10 microM), neither oxidized flavoprotein nor reduced infarct size. Our results suggest that cilostazol exerts a cardioprotective effect via direct activation of mitoK(Ca) channels.
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PMID:6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)quinolinone (cilostazol), a phosphodiesterase type 3 inhibitor, reduces infarct size via activation of mitochondrial Ca2+-activated K+ channels in rabbit hearts. 1838 26


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