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)

Using the sequence homology approach for cloning related genes within the G-protein-coupled receptor gene family, we have cloned the gene for the rat beta 1-adrenergic receptor (beta 1-AR). The rat beta 1-adrenergic receptor gene was isolated from a lambda EMBL3 rat genomic DNA library using the hamster beta 2-adrenergic receptor (beta 2-AR) coding sequence as a probe under low stringency hybridization conditions. The rat beta 1-AR gene encodes a protein of 466 amino acids that contains one consensus site for N-linked glycosylation (Asn-15) and three consensus sites for cAMP-dependent protein kinase phosphorylation (Ser-296, Ser-301, and Ser-401). The encoded rat beta 1-AR is 98 and 91% similar at the amino acid level with the human beta 1-AR in the transmembrane domains and in the overall sequence, respectively. Genomic Southern blot and gene dosage analyses indicate that the rat beta 1-AR gene is a single copy gene. The tissue distribution of the rat beta 1-AR mRNA was highest in the pineal gland with other brain regions and peripheral tissues, including the heart, expressing the mRNA at moderate levels. The bacteriophage clone containing the rat beta 1-AR gene with its natural promoter was co-transfected with the selectable marker (pRSVneo) conferring neomycin resistance into beta 1-AR-deficient mouse L cells. Analyses of the selected transfectant demonstrates efficient expression of the beta 1-AR gene and functional receptor. 125I-Labeled iodocyanopindolol bound transfectant membranes with an affinity of KD = 24 pm; the beta 1-AR-selective antagonist ICI 89,406 displaced iodocyanopindolol binding with a Ki approximately 140 times lower than that for the beta 2-AR-selective antagonist ICI 118,551. In addition, in the transfectant cell line, adenylylcyclase was stimulated by beta-adrenergic receptor agonists with the rank order of potency of isoproterenol greater than norepinephrine = epinephrine, consistent with properties expected of the beta 1-AR subtype.
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PMID:Molecular cloning and expression of the rat beta 1-adrenergic receptor gene. 169 99

The N-formyl peptide chemoattractant receptor (fMLF-R) is a cell-surface, G-protein-coupled glycoprotein that mediates the directed locomotion of neutrophils upon binding N-formylated peptides. The fMLF-R is encoded primarily by a 1.6-kb mRNA in differentiated HL-60 and U937 cells, although larger less abundant transcripts are present. To study the origin of different fMLF-R transcripts, the genetic linkage of chemotactic receptor genes, and the regulation of fMLF-R gene expression, we determined the copy number, chromosomal location, structural organization, and 5'-flanking sequence of the human fMLF-R gene. BamHI restriction fragments derived from a human fMLF-R genomic cosmid clone were isolated, subcloned, and sequenced. These data indicate that the fMLF-R structural gene is approximately 7.5 kb in length and is comprised of two exons separated by an approximately 5.0-kb intron. The first exon encodes 66 bp of the 5'-untranslated sequence, while exon 2 encodes the coding and 3'-untranslated sequences. The genomic organization of the fMLF-R gene is similar to that of the adrenergic beta-1 and beta-2 G-protein-coupled receptor genes in that the coding sequence is contained in a single exon. The different 3'-untranslated sequences observed in fMLF-R cDNA clones are contiguous in the genomic structure, thereby indicating that these clones are derived in part by alternative polyadenylation. Southern blot analysis using human X hamster somatic cell hybrids and in situ hybridization indicated that the h-fMLF-R gene is located on chromosome 19q13.3. Primer extension experiments using dbcAMP-differentiated U937 RNA indicated a single transcriptional initiation site. Sequence analysis 5' of the transcriptional initiation site indicated possible cis-acting motifs that may regulate fMLF-R gene expression. These included AP-1 and CK-2 consensus sequences that bind nuclear factors of the Fos/Jun family and NF-GMb, respectively.
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PMID:Structure, 5'-flanking sequence, and chromosome location of the human N-formyl peptide receptor gene. A single-copy gene comprised of two exons on chromosome 19q.13.3 that yields two distinct transcripts by alternative polyadenylation. 768 42

Pituitary Adenylate Cyclase Activating Peptide (PACAP) strongly induces proliferation of the rat pancreatic carcinoma cell line AR4-2J via interaction with the G-protein coupled type 1 PACAP/VIP (PVI) receptor. RT-PCR analysis revealed that this mitogenic effect of PACAP is preceded by a rapid and transient increase of transcription of the protooncogene c-fos and to a lesser extent of c-jun. Transcriptional activation is abolished by a specific PACAP antagonist and by inhibitors of PKC and PKA. In parallel to c-fos/c-jun induction, PACAP rapidly activates the heterodimeric transcription factor AP-1, as shown by electrophoretic mobility shift assay. These findings demonstrate that signal transduction of a growth-stimulating G-protein-coupled receptor involves the c-fos/c-jun/AP-1 cascade, a pathway mainly linked to classical growth factor receptor tyrosine kinases.
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PMID:PACAP stimulates transcription of c-Fos and c-Jun and activates the AP-1 transcription factor in rat pancreatic carcinoma cells. 866 Mar 19

5-HT activates the peristaltic reflex and is the neurotransmitter of a subset of myenteric interneurons. Hyperpolarizing afterpotential (AH)/type 2 neurons respond to 5-HT with a long-lived depolarization that is caused by the inhibition of a Ca(2+)-activated K+ conductance (gKCa). This effect is mediated by a G-protein-coupled receptor, 5-HT1P. 5-HT1P agonists specifically activate G alpha o, the immunoreactivity of which was found to be highly abundant and membrane-associated in almost all enteric neurons. Responses of hyperpolarizing AH/type 2 neurons to 5-HT were inhibited by intracellular injection of GDP beta S or anti-G alpha o Fab fragments but were potentiated and prolonged by intracellular GTP gamma S. Responses to 5-HT were antagonized by pertussis toxin, downregulation of protein kinase C (PKC) and inhibitors of phosphatidylcholine phospholipase C (PC-PLC), PKC (including pseudosubstrate peptides, chelerythrine, and the alpha/beta isoform-specific inhibitor Go 6976), protein kinase A (PKA), and adenylate cyclase. Responses to 5-HT were mimicked by activators of PKC, and 5-HT induced a concentration-dependent increase in the membrane-associated PKC activity in isolated myenteric ganglia. Immunocytochemical studies suggested that the most abundant isoforms of PKC in enteric neurons are alpha and delta. These data suggest that signal transduction of the 5-HT1P-mediated slow response to 5-HT involves activation of PC-PLC by G alpha o to liberate diacylglycerol, which stimulates PKC (most likely alpha). PKC probably activates adenylate cyclase, which through cAMP, activates PKA. Activation of both PKA and PKC lead to closure of gKCa.
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PMID:Mediation by protein kinases C and A of Go-linked slow responses of enteric neurons to 5-HT. 899 56

The extracellular signal-regulated protein kinase (ERK) and Jun N-terminal kinase (JNK) signalling cascades transduce signals from the cell cytoplasm to the nucleus, where they regulate gene expression. The activation of ERK1 by lysophosphatidic acid (LPA) and endothelin 1 (Et-1) was compared in Rat-1 cells. Both stimulated DNA synthesis to a similar degree but, in contrast with LPA, Et-1 did not stimulate sustained ERK1 activation, a signal that is thought to be important for the proliferation of fibroblasts. Et-1, but not LPA, was able to activate JNK1; pharmacological analysis revealed that the same EtA receptor mediates DNA synthesis, ERK1 and JNK1 activation. However, activation of JNK1 required higher concentrations of Et-1 than was required for stimulation of ERK1 or DNA synthesis. Signalling to ERK1 and JNK1 was partly inhibited by pertussis toxin, suggesting that both pathways are regulated in part by Gi or G0 proteins. Activation of JNK1 by Et-1 lagged behind ERK1 activation but was not dependent on it because PD98059, an inhibitor of mitogen-activated protein kinase (or ERK) kinase, was without effect on JNK1 activation. In contrast with recent studies, activation of protein kinase C (PKC) or Ca2+ fluxes inhibited activation of JNK1 but not ERK1; furthermore inhibition of PKC or sequestration of Ca2+ potentiated JNK1 activation by Et-1 but not by anisomycin, and again had little effect on ERK1 activation. These results demonstrate that the same G-protein-coupled receptor can activate both the ERK and JNK signal pathways but the two kinase cascades seem to be separate, parallel pathways that are differentially regulated by PKC and Ca2+. The results are discussed in terms of the role of ERK and JNK in proliferative signalling.
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PMID:Differential regulation of extracellular signal-regulated protein kinase 1 and Jun N-terminal kinase 1 by Ca2+ and protein kinase C in endothelin-stimulated Rat-1 cells. 903 68

A cDNA encoding a G-protein-coupled receptor was cloned from the central nervous system of the pond snail Lymnaea stagnalis. The predicted amino acid sequence of this cDNA most closely resembles the Drosophila tyramine/octopamine receptor, the Locusta tyramine receptor, and an octopamine receptor (Lym oa1) that we recently cloned from Lymnaea. After stable expression of the cDNA in HEK293 cells, we found that [3H]rauwolscine binds with high affinity to the receptor (KD = 6.2.10(-9) M). Octopamine appears to be the most potent naturally occurring agonist to displace the [3H]rauwolscine binding (Ki = 3.0.10(-7) M). Therefore, the receptor is considered to be an octopamine receptor and is consequently designated Lym oa2. The novel receptor shares little pharmacological resemblance with Lym oa1, indicating that the two receptors represent different octopamine receptor subfamilies. Octopaminergic stimulation of Lym oa2 does not induce changes in intracellular concentrations of cAMP or inositol phosphates. However, electrophysiological experiments indicate that octopamine is able to activate a voltage-independent Cl- current in HEK293 cells stably expressing Lym oa2. Although opening of this chloride channel most probably does not require the activation of either protein kinase A or C, it can be blocked by inhibition of protein phosphorylation.
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PMID:Cloning and expression of a complementary DNA encoding a molluscan octopamine receptor that couples to chloride channels in HEK293 cells. 904 34

A broad array of stressors induce ACTH release from the anterior pituitary, with consequent stimulation of the adrenal cortex and release of glucocorticoids critical for survival of the animal. ACTH stimulates adrenocortical gene expression in vivo and inhibits adrenocortical cell proliferation. Binding of ACTH to its G-protein-coupled receptor stimulates the production of cAMP and activation of the protein kinase A pathway. The stress-activated protein kinases (SAPKs) (or c-Jun N-terminal kinases) and the extracellular signal-regulated kinases (ERKs) are members of the mitogen-activated protein kinase family of serine/threonine kinases, which have recently been implicated in G-protein-coupled receptor intracellular signaling. The SAPKs are preferentially induced by osmotic stress and UV light, whereas the ERKs are preferentially induced by growth factors and proliferative signals in cultured cells. In these studies, ACTH stimulated SAPK activity 3-4-fold both in the adrenal cortex in vivo and in the Y1 adrenocortical cell line. 12-O-Tetradecanoylphorbol-13-acetate but not cAMP induced SAPK activity in Y1 cells. The isoquinolinesulfonamide inhibitors H-8 and H-89 blocked ACTH induction of SAPK activity at protein kinase C inhibitory doses but not at protein kinase A inhibitory doses. The calcium chelating agent EGTA inhibited ACTH-induced SAPK activity and the calcium ionophore A23187 induced SAPK activity 3-fold. In contrast with the induction of SAPK by ACTH, ERK activity was inhibited in the adrenal cortex in vivo and in Y1 adrenal cells. Together these findings suggest that ACTH induces SAPK activity through a PKC and Ca+2-dependent pathway. The induction of SAPK and inhibition of ERK by ACTH in vivo may preferentially regulate target genes involved in the adrenocortical stress responses in the whole animal.
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PMID:Adrenocorticotropin induction of stress-activated protein kinase in the adrenal cortex in vivo. 924 78

Gonadotropin-releasing hormone (GnRH) is a decapeptide that regulates reproductive function via binding to the GnRH receptor, which is a G-protein-coupled receptor (GPCR). For several members of this family, the C-terminal domain of intracellular loop III is important in ligand-mediated coupling to G-proteins; mutations in that region can lead to constitutive activity. A specific alanine residue is involved in certain GPCRs, the equivalent of which is Ala-261 in the GnRH receptor. Mutation of this residue to Leu, Ile, Lys, Glu or Phe in the human GnRH receptor did not result in constitutive activity and instead led to complete uncoupling of the receptor (failure to support GnRH-stimulated inositol phosphate production). When this residue was mutated to Gly, Pro, Ser or Val, inositol phosphate production was still supported. All the mutants retained the ability to bind ligand, and the affinity for ligand, where measured, was unchanged. These results show that Ala-261 cannot be involved in ligand binding but is critical for coupling of the receptor to its cognate G-protein. Coupling is also dependent on the size of the residue in position 261. When the amino acid side chain has a molecular mass of less than 40 Da efficient coupling is still possible, but when its molecular mass exceeds 50 Da the receptor is uncoupled. Internalization studies on the Ala261-->Lys mutant showed a marked decrease in receptor internalization compared with the wild type, indicating that coupling is necessary for effective receptor internalization in the GnRH receptor system. Activation of protein kinase C (with PMA), but not protein kinase A (with forskolin) markedly increased the internalization of the mutant receptor while having a small effect on the wild-type receptor.
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PMID:Alanine-261 in intracellular loop III of the human gonadotropin-releasing hormone receptor is crucial for G-protein coupling and receptor internalization. 956 Mar 19

The mu-opioid receptor mediates the analgesic and addictive properties of morphine. Despite the clinical importance of this G-protein-coupled receptor and many years of pharmacological research, few intracellular signaling mechanisms triggered by morphine and other mu-opioid agonists have been described. We report that mu-opioid agonists stimulate three different effectors of a phosphoinositide 3-kinase (PI3K)-dependent signaling cascade. By using a cell line stably transfected with the mu-opioid receptor cDNA, we show that the specific agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) stimulates the activity of Akt, a serine/threonine protein kinase implicated in protecting neurons from apoptosis. Activation of Akt by DAMGO correlates with its phosphorylation at serine 473. The selective PI3K inhibitors wortmannin and LY294002 blocked phosphorylation of this site, previously shown to be necessary for Akt enzymatic activity. DAMGO also stimulates the phosphorylation of two other downstream effectors of PI3K, the p70 S6 kinase and the repressors of mRNA translation, 4E-BP1 and 4E-BP2. Upon mu-opioid receptor stimulation, p70 S6 kinase is activated and phosphorylated at threonine 389 and at threonine 421/serine 424. Phosphorylation of p70 S6 kinase and 4E-BP1 is also repressed by PI3K inhibitors as well as by rapamycin, the selective inhibitor of FRAP/mTOR. Consistent with these findings, DAMGO-stimulated phosphorylation of 4E-BP1 impairs its ability to bind the translation initiation factor eIF-4E. These results demonstrate that the mu-opioid receptor activates signaling pathways associated with neuronal survival and translational control, two processes implicated in neuronal development and synaptic plasticity.
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PMID:mu-Opioid receptor activates signaling pathways implicated in cell survival and translational control. 972 92

The aim of these studies was to examine the involvement of tyrosine phosphorylation in the signal transduction pathways and secretory events that are promoted by receptor agonists acting on rat parotid acinar cells. Fluid secretion by parotid acinar cells is initiated by the binding of neurotransmitters to GTP(G)-protein-coupled receptors that are linked to phospholipase C, which hydrolyzes phosphatidlyinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate. Although growth factors produce large changes in tyrosine phosphorylation of multiple proteins involved in proliferation and other cellular processes, tyrosine phosphorylation is not considered to be a general phenomenon of G-protein-coupled receptor activation. However, our results shown that carbachol (a muscarinic acetylcholine receptor agonist), and ligands to other phospholipase C-linked receptors, promoted a rapid increase in the tyrosine phosphorylation of protein kinase Cdelta (PKCdelta), a member of the PKC family of proteins. Phorbol 12-myristate 13-acetate, which binds to the site on PKCdelta to which the endogenous activator sn-1,2-diacylglycerol binds, also increased the tyrosine phosphorylation of PKCdelta. Genistein and staurosporine, two protein kinase inhibitors, blocked the tyrosine phosphorylation of this protein. Thus, PKCdelta becomes tyrosine phosphorylated in response to receptor activation, and this event appears to involve both diacylglycerol production and protein tyrosine kinase activity. This may contribute to early physiological events, including alterations in fluid secretion, that are initiated by neurotransmitters acting on the parotid salivary gland.
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PMID:Involvement of protein kinases and phosphatases in tyrosine phosphorylation of PKCdelta in rat parotid acinar cells exposed to secretory stimuli. 982 17


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