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 neurotrophic peptide PACAP (pituitary adenylate cyclase-activating polypeptide) elevates cAMP in PC12 cells. Forskolin and dibutyryl cAMP mimic PACAP's neuritogenic and cell morphological effects, suggesting that they are driven by cAMP. Comparison of microarray expression profiles after exposure of PC12 cells to either forskolin, dibutyryl cAMP, or PACAP revealed a small group of cAMP-dependent target genes. Neuritogenesis induced by all three agents is protein kinase A (PKA)-independent [not blocked by N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89)] and extracellular signal-regulated kinase (ERK)-dependent [blocked by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio) butadiene (U0126)], and therefore cAMP-dependent target genes potentially mediating neuritogenesis were selected for further analysis based on the pharmacological profile of their induction by PACAP (i.e., mimicking that of neuritogenesis). Small interfering RNA (siRNA) targeting one of these genes, Egr1, blocked PACAP-induced neuritogenesis, and siRNA targeting another, Vil2, blocked a component of the cell size increase elicited by PACAP. Neither siRNA blocked PACAP's PKA-dependent antiproliferative effects. PACAP signaling to neuritogenesis was also impaired by dominant-negative Rap1 expression but was not affected by inhibition of protein kinase C (PKC), indicating a G-protein-coupled receptor-mediated differentiation pathway distinct from the one activated by receptor tyrosine kinase ligands such as nerve growth factor (NGF), that involves both Rap1 and PKC. We have thus identified a cAMP-dependent, PKA-independent pathway proceeding through ERK that functions to up-regulate the transcription of two genes, Egr1 and Vil2, required for PACAP-dependent neuritogenesis and increased cell size, respectively. Dominant-negative Rap1 expression impairs both PACAP-induced neuritogenesis and Egr1 activation by PACAP, suggesting that cAMP elevation and ERK activation by PACAP are linked through Rap1.
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PMID:A cAMP-dependent, protein kinase A-independent signaling pathway mediating neuritogenesis through Egr1 in PC12 cells. 1836 3

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium and regulates parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of parathyroid hormone-related protein (PTHrP) and participate in the regulation of calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to stimulate PTHrP production by breast cancer cells. In this study, we confirmed that the CaR inhibits PTHrP production by MMECs but stimulates PTHrP production by Comma-D cells (immortalized murine mammary cells) and MCF-7 human breast cancer cells. We found that changes in intracellular cAMP, but not phospholipase C or MAPK signaling, correlated with the opposing effects of the CaR on PTHrP production. Pharmacologic stimulation of cAMP accumulation increased PTHrP production by normal and transformed breast cells. Inhibition of protein kinase A activity mimicked the effects of CaR activation on inhibiting PTHrP secretion by MMECs and blocked the effects of the CaR on stimulating PTHrP production in Comma-D and MCF-7 cells. We found that the CaR coupled to Galphai in MMECs but coupled to Galphas in Comma-D and MCF-7 cells. Thus, the opposing effects of the CaR on PTHrP production are because of alternate G-protein coupling of the receptor in normal versus transformed breast cells. Because PTHrP contributes to hypercalcemia and bone metastases, switching of G-protein usage by the CaR may contribute to the pathogenesis of breast cancer.
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PMID:Switching of G-protein usage by the calcium-sensing receptor reverses its effect on parathyroid hormone-related protein secretion in normal versus malignant breast cells. 1862 40

A-kinase Anchoring Proteins (AKAPs) define an expanding group of scaffold proteins that display a signature binding site for the RI/RII subunit of protein kinase A. AKAP5 and AKAP12 are multivalent (with respect to protein kinases and phosphatases) and display the ability to associate with the prototypic member of G protein-coupled receptors, the beta(2)-adrenergic receptor. We probed the relative abundance, subcellular distribution and localization of AKAP5 and AKAP12 in human embryonic kidney HEK293 and epidermoid carcinoma A431 cells. HEK293 cells are relatively rich in AKAP5 (found mostly in association with the cell membrane); whereas A431 cells are rich in AKAP12 (found distributed both in the cytoplasm and in association with the cell membrane). In biochemical analysis of subcellular fractions and in whole-cell imaging, the membrane localization of AKAP5 was decreased in response to treating cells with the beta-adrenergic agonist isoproterenol, whereas membrane association of AKAP12 was increased initially in response to agonist treatment. These data demonstrate quantitatively a clearly different pattern of AKAP-receptor association for AKAP5 versus AKAP12. AKAP5 remains associated with its G-protein-coupled receptor, at the cell membrane, docked with the receptor during agonist-induced internalization and later receptor recycling after agonist wash-out. AKAP12-receptor docking, in contrast, is dynamic, driven by agonist stimulation (accounting for movement of AKAP12 from the cytoplasm to the cell membrane). AKAP12 then is internalized with the beta(2)-adrenergic receptor, but segregates away from the G-protein-coupled receptor upon recycling of the internalized receptor to the cell membrane. Thus these homologous, AKAPs that dock G-protein-coupled receptors have markedly different patterns of trafficking, docking, and re-distribution.
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PMID:G-protein-coupled receptor-associated A-kinase anchoring proteins AKAP5 and AKAP12: differential trafficking and distribution. 1895 Jul 3

G-protein-coupled receptors (GPCRs), one of the most versatile groups of cell surface receptors, can recognize specific ligands from neural, hormonal, and paracrine organs and regulate cell growth, proliferation, and differentiation. Gpr48/LGR4 is a recently identified orphan GPCR with unknown functions. To reveal the functions of Gpr48 in vivo, we generated Gpr48-/- mice and found that Gpr48-/- fetuses displayed transient anemia during midgestation and abnormal definitive erythropoiesis. The dramatic decrease of definitive erythroid precursors (Ter119pos population) in Gpr48-/- fetal liver at E13.5 was confirmed by histological analysis and blood smear assays. Real-time PCR analyses showed that in Gpr48-/- mice both adult hemoglobin alpha and beta chains were decreased while embryonic hemoglobin chains (zeta, betaH1, and epsilony) were increased, providing another evidence for the impairment of definitive erythropoiesis. Furthermore, proliferation was suppressed in Gpr48-/- fetal liver with decreased c-Myc and cyclin D1 expression, whereas apoptosis was unaffected. ATF4, a key transcription factor in erythropoiesis, was down-regulated in Gpr48-/- fetal livers during midgestation stage through the cAMP-PKA-CREB pathway, suggesting that Gpr48 regulated definitive erythropoiesis through ATF4-mediated definitive erythropoiesis.
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PMID:Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. 1895 81

In molluscs, the neurotransmitter serotonin (5-HT) has been linked to a variety of biological roles including gamete maturation and spawning. The possible involvement of 5-HT in abalone gamete release was demonstrated by a dose-dependent increase in Haliotis rubra gonad contractile bioactivity following 5-HT stimulation. Physiological functions associated with 5-HT, are mediated through binding to 5-HT receptors. A cDNA encoding a putative 5-HT receptor consisting of 359 amino acids was isolated from the tropical abalone H. asinina, termed 5-HT(1 ha). The 5-HT(1 ha) shares G-protein-coupled receptor motifs with metazoan 5-HT receptors, including predicted transmembrane domains, active sites for protein kinase action, and N-linked glycosylation sites. However, the third intracellular loop of 5-HT(1 ha) is relatively short, and only six transmembrane domains are predicted, implying a truncated receptor. Phylogenetic analysis with known 5-HT receptor genes suggests that 5-HT(1 ha) belongs to the type 1 5-HT receptor family. Expression analysis by RT-PCR showed that 5-HT(1 ha) mRNA was present in all tissues examined, including the neural ganglia and gonad tissues. Immunocytochemistry revealed the presence of 5-HT(1 ha) specifically within the soma of neuronal cells located in the outer cortex of both cerebral and pleuropedal ganglia. In ovarian and testicular tissues, 5-HT(1 ha) immunoreactivity was observed in epithelial cells of the outer capsule and connective tissue of the trabeculae to which the gamete follicles adhere. Whether this receptor transcript is translated to a functional protein needs to be verified, but if so, it could play a role in reproduction.
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PMID:Molecular characterization and analysis of a truncated serotonin receptor gene expressed in neural and reproductive tissues of abalone. 1921 54

Ovulation is an essential physiological process in sexual reproduction; however, the underlying cellular mechanisms are poorly understood. We have previously shown that OAMB, a Drosophila G-protein-coupled receptor for octopamine (the insect counterpart of mammalian norepinephrine), is required for ovulation induced upon mating. OAMB is expressed in the nervous and reproductive systems and has two isoforms (OAMB-AS and OAMB-K3) with distinct capacities to increase intracellular Ca2+ or intracellular Ca2+ and cAMP in vitro. Here, we investigated tissue specificity and intracellular signals required for OAMB's function in ovulation. Restricted OAMB expression in the adult oviduct epithelium, but not the nervous system, reinstated ovulation in oamb mutant females, in which either OAMB isoform was sufficient for the rescue. Consistently, strong immunoreactivities for both isoforms were observed in the wild-type oviduct epithelium. To delineate the cellular mechanism by which OAMB regulates ovulation, we explored protein kinases functionally interacting with OAMB by employing a new GAL4 driver with restricted expression in the oviduct epithelium. Conditional inhibition of Ca2+/Calmodulin-dependent protein kinase II (CaMKII), but not protein kinase A or C, in the oviduct epithelium inhibited ovulation. Moreover, constitutively active CaMKII, but not protein kinase A, expressed only in the adult oviduct epithelium fully rescued the oamb female's phenotype, demonstrating CaMKII as a major downstream molecule conveying the OAMB's ovulation signal. This is consistent with the ability of both OAMB isoforms, whose common intracellular signal in vitro is Ca2+, to reinstate ovulation in oamb females. These observations reveal the critical roles of the oviduct epithelium and its cellular components OAMB and CaMKII in ovulation. It is conceivable that the OAMB-mediated cellular activities stimulated upon mating are crucial for secretory activities suitable for egg transfer from the ovary to the uterus.
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PMID:The octopamine receptor OAMB mediates ovulation via Ca2+/calmodulin-dependent protein kinase II in the Drosophila oviduct epithelium. 1926 50

The serine-protease urokinase (uPA) and its specific membrane receptor uPAR controls matrix degradation through the conversion of plasminogen into plasmin and play a crucial role in a number of biological processes including local fibrinolysis, inflammation, angiogenesis, matrix remodelling during wound healing, tumor invasion and metastasis. Most of the cellular responses modulated by the uPA/uPAR system, including migration, cellular adhesion, differentiation, proliferation and apoptosis require transmembrane signaling, which is mediated by direct contacts of uPAR with a variety of extracellular proteins and membrane receptors, such as integrins, EGF receptor, high molecular weight kininogen, caveolin and the G-protein-coupled receptor FPRL1. As a result of these interactions, uPAR activates intracellular signalling molecules such as tyrosine- and serine-protein kinases, Src, focal adhesion kinase (FAK), Rac, extracellular-signal-regulated kinase (ERK)/mitogen- activated protein kinase (MAPK) and JAK/STAT, being part of a large "signalosome" interacting with several molecules on both the outside and inside of the cell. This review is focused on the biochemistry of the pathways affected by uPAR and its partners.
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PMID:The urokinase receptor as an entertainer of signal transduction. 1927 72

The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The intracellular signaling pathways that mediate clozapine action remain unknown. A potential candidate is the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) cascade that links G-protein-coupled receptor and ErbB growth factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. Here, we examined how clozapine differentially modulated phosphorylation of the MAPK isoforms, ERK1/ERK2 in primary murine prefrontal cortical neurons compared to the typical antipsychotic drug haloperidol. While clozapine and haloperidol acutely decreased cortical pERK1 activation, only clozapine but not haloperidol stimulated pERK1 and pERK2 with continued drug exposure. This delayed ERK increase however, did not occur via the canonical dopamine D(2)-Gi/o-PKA or serotonin 5HT(2A)-Gq-phospholipase-C-linked signaling pathways. Rather, epidermal growth factor (EGF) receptor signaling mediated clozapine-induced ERK activation, given dose-dependent reduction of pERK1 and pERK2 stimulation with the EGF receptor inhibitor, AG1478. Immunocytochemical studies indicated that clozapine treatment increased EGF receptor (Tyr1068) phosphorylation. In vivo mouse treatment studies supported the in vitro findings with initial blockade, subsequent activation, and normalization of the cortical ERK response over 24 h. Furthermore, in vivo clozapine-induced ERK activation was significantly reduced by AG1478. This is the first report that clozapine action on prefrontal cortical neurons involves the EGF signaling system. Since EGF receptor signaling has not been previously linked to antipsychotic drug action, our findings may implicate the EGF system as a molecular substrate in treatment-resistant schizophrenia.
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PMID:Clozapine-induced ERK1 and ERK2 signaling in prefrontal cortex is mediated by the EGF receptor. 1927 91

Extracellular acidification inhibited formyl-Met-Leu-Phe- or C5a-induced superoxide anion (O(2)(-)) production in differentiated HL-60 neutrophil-like cells and human neutrophils. A cAMP-increasing agonist, prostaglandin E(1), also inhibited the formyl peptide-induced O(2)(-) production. The inhibitory action on the O(2)(-) production by extracellular acidic pH was associated with cAMP accumulation and partly attenuated by H89, a protein kinase A inhibitor. A significant amount of mRNAs for T-cell death-associated gene 8 (TDAG8) and other proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1)-family receptors is expressed in these cells. These results suggest that cAMP/protein kinase A, possibly through proton-sensing G-protein-coupled receptors, may be involved in extracellular acidic pH-induced inhibition of O(2)(-) production.
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PMID:Inhibition of superoxide anion production by extracellular acidification in neutrophils. 1953 99

Increasing evidence is demonstrating that drugs affecting dopamine levels in the brain induce cytoskeletal modifications. These evolving changes may impact neuronal synaptic plasticity as cytoskeletal constituents are involved in the maintenance of dendritic processes, and any alterations in their stability could influence major cellular compartments of neurons, such as dendrites, spines and synapses. Here, we describe a molecular chain of events that links dopamine D1 receptor activation to hyperphosphorylation of the microtubule-associated protein tau, which is normally involved in microtubules stabilization. We show, in SK-N-MC cells and rat striatal sections, that phosphorylation of tau at serines 199-202 and 214 appears to be mediated through activation of calcium-dependent intracellular mechanism, subsequent to D1 receptor-induced cAMP-dependent protein kinase A (PKA). We demonstrate, using pharmacological tools, that PKA activation causes increase of calcium levels, leading to cyclin-dependent kinase 5 activation by calpain proteolysis of p35 to p25 and glycogen synthase kinase 3beta activation by its phosphorylation at tyrosine 216. The D2 receptor agonism or lowering cAMP levels has no effect in our experimental settings. Moreover, we do not observe any association between phosphorylated tau and cellular damage. These data unravel novel mechanisms of tau hyperphosphorylation during G-protein-coupled receptor activation and are the first to show that stimulation of D1 receptors could have a profound influence on the neuronal cytoskeletal constituent tau.
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PMID:Dopamine D1 receptor activation induces tau phosphorylation via cdk5 and GSK3 signaling pathways. 1959 49


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