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)

In dog thyroid cell primary cultures the prolonged presence (up to 4-6 days) of TSH induced down regulation of the isoenzyme I (PKA I) of cAMP-dependent protein kinases. In the simultaneous presence of TSH and EGF this down regulation of PKA I was maintained, although it was slightly smaller than in assays without EGF. In contrast, the simultaneous presence of TPA, totally inhibited the TSH induced down regulation of PKA I. These results partly explain the previously observed additivity of TSH and EGF, and the non-additivity of TSH and TPA actions on cell proliferation in these cells.
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PMID:Epidermal growth factor and phorbol ester actions on the TSH induced down regulation of the isoenzyme I (PKA I) of cyclic AMP-dependent protein kinases in dog thyroid cell primary cultures. 187 89

Transcription factor AP-1 is inducible by phorbol esters and thus could be considered to be one final target of the protein kinase C signal transduction pathway. AP-1 consists of the products of the fos and jun oncogenes, which associate as dimers to bind TPA-responsive promoter elements (TRE) efficiently. We show that AP-1 activity is modulated by an inhibitory protein (IP-1), present both in the nucleus and cytoplasm of several cell types. IP-1 specifically blocks DNA binding of AP-1 from nuclear extracts and of in vitro synthesized Fos/Jun proteins. It is a labile protein of 30-40 kd, which exerts its activity only in the nonphosphorylated form. Block of IP-1 function is obtained by PKA-mediated phosphorylation, possibly suggesting a cross talk mechanism at transcriptional level. Competition experiments with synthetic peptides suggest that IP-1 could interact with Fos and/or Jun leucine zippers. We speculate that IP-1 might act as a transcriptional antioncogene.
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PMID:IP-1: a dominant inhibitor of Fos/Jun whose activity is modulated by phosphorylation. 190 Apr 58

The Ras-related protein, Rap1B, has previously been shown to serve as a PKA substrate in vitro and to be phosphorylated by cAMP elevating agents in human platelets. We have purified a Rap1 protein that serves as a PKA substrate from human neutrophils, and we now identify this protein as Rap1A. A 23-kDa protein that co-migrated with recombinant Rap1A was phosphorylated in electroporated human neutrophils upon stimulation by cAMP in the presence of [gamma-32P]ATP. This protein could be immunoprecipitated by the Rap1A/B-specific antibody, R61. The 23-kDa phosphoprotein was monitored during the purification of Rap1 from neutrophil membrane extracts and was shown to copurify with Rap1 during the DEAE Sephacel, heptylamine Sepharose, and MonoQ chromatography steps utilized. The purified protein was phosphorylated to an extent of 1 mol phosphate/mol GTP gamma S bound. This protein was identified as Rap1A by: 1) amino acid sequence analysis; and 2) immunoblotting with a Rap1A-specific antibody. The amino acid phosphorylated on Rap1A by PKA was a serine residue. The site of phosphorylation was indicated by carboxypeptidase digestion and confirmed using a mutant recombinant Rap1A lacking the relevant serine (serine-180). Rap1A, not Rap1B, appears to be the major 23-kDa PKA substrate in human neutrophils. It is possible that Rap1A plays a role in human neutrophils in mediating the inhibitory effects of cAMP-elevating agents upon chemoattractant-stimulated cell activation.
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PMID:Rap1A is a substrate for cyclic AMP-dependent protein kinase in human neutrophils. 190 79

Using several novel in vitro culture systems, we have examined the tissue-specific regulation of the proglucagon-derived peptides, at the levels of proglucagon gene expression and pGdp synthesis and secretion. Our studies indicate that proglucagon gene expression in intenstine, hypothalamus and pancreas is under the regulatory control of protein kinase A- but not a protein kinase C-dependent pathway. PKA and PKC stimulate secretion of the intestinal pGdp's, whereas only PKA stimulates secretion of the hypothalamic peptides. Pancreatic glucagon secretion in response to PKA is subject to further modulation by prevailing glucose concentrations. This diversity in intracellular regulation of the pGdp's may account for some of the tissue-specific differences in synthesis and secretion of the pGdp's that we have observed in diabetes and during development.
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PMID:Proglucagon-derived peptides in the neuroendocrine system. 192 80

Neoplastic mouse lung epithelial cells express greatly diminished activity, protein, and mRNA for the type I isozyme of cAMP-dependent protein kinase (PKA I). To address the mechanism of this decrease, the turnover rate of PKA subunit mRNA was examined. Northern blot analysis of PKA mRNAs from transcriptionally inhibited cells indicated that these messages exhibit different stabilities and that they are more stable in neoplastic E9 cells than in normal C10 cells. This suggests that the mechanism of decreased PKA I mRNA in E9 cells resides at the level of transcription. To examine whether this was due to an altered responsiveness to agents which regulate PKA transcription, PKA levels were experimentally manipulated in C10 and E9 cells by long-term treatment with forskolin or 8-chloro-cAMP. PKA activity and the concentration of RI (regulatory subunit of PKA I) and C (catalytic subunit) are coordinately regulated in both cell lines, but this does not reflect the changes in PKA I subunit mRNAs. RI alpha mRNA is specifically induced by forskolin in normal C10 cells, but not in E9 cells. C alpha mRNA is forskolin-inducible in E9 cells, but this enhanced level of expression does not approach that found constitutively in C10 cells. Thus, while C10 and E9 undergo similar changes in PKA I protein subunits following these treatments, a differential modulation of their PKA I mRNA occurs. These cell-specific mRNA responses to cAMP-mediated induction suggest that the mechanism of the decreased constitutive concentration of PKA I in E9 cells involves altered regulation of PKA I mRNAs.
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PMID:Altered regulation of mRNA levels encoding the type I isozyme of cAMP-dependent protein kinase in neoplastic mouse lung epithelial cells. 193 70

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) enhanced the phosphorylation of identical cytosolic 65 kDa protein (P65 or l-plastin) and 74 kDa protein (P74) at serine residues in human peripheral blood mononuclear cells (PBMC). The isoelectric points of P65 and P74 were 5.6 and 4.7 to 5.0, respectively. The phosphorylation of these proteins increased with a few minutes and reached maximal levels of approximately 3 times the unstimulated levels by 10 minutes. The phosphorylation of P65 and P74 was extensively enhanced by a potent protein kinase C (PKC) activator, PMA. However, there was no translocation of PKC from cytosol to membrane in PBMC that was stimulated with either TNF or IL-1, which suggests that PKC does not participate in TNF or IL-1 signal transduction. cAMP dependent protein (PKA) activators, forskolin and PGE2, failed to increase the phosphorylation, which is in agreement with the data showing that neither TNF nor IL-1 increased cAMP levels in PBMC. These results suggest that induction of phosphorylation of P65 and P74 by TNF and IL-1 is not mediated by PKC and PKA but may be mediated by another protein kinase and result in overlapping of biological activities between TNF and IL-1.
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PMID:Enhanced phosphorylation of 65 and 74 kDa proteins by tumor necrosis factor and interleukin-1 in human peripheral blood mononuclear cells. 196 46

In Dictyostelium, cAMP functions as an extracellular regulatory molecule that controls aggregation, expression of a number of classes of genes, and cellular differentiation by binding to cell-surface receptors that activate intracellular signal transduction pathways. To investigate possible roles for intracellular cAMP, we have overexpressed the wild-type mouse type-I regulatory subunit (RI) of cAMP-dependent protein C (PKA) in Dictyostelium cells, as well as mutant forms of the subunit that are altered in their ability to bind cAMP. We show that overexpression of a mutated RI, which lacks both cAMP-binding sites and presumably forms a complex with the endogenous Dictyostelium catalytic subunit that cannot be activated by cAMP, results in cells that do not aggregate or express sets of genes that are normally induced in the multicellular stages. Transformations that express the mutant subunit at low levels show no observable phenotype. We show that these cells can respond to pulses of cAMP and activate cAMP receptor/G protein-mediated processes, including the activation of adenylate and guanylate cyclases and the induction of a class of genes known to be regulated through the receptor-mediated pathways; however, the cells do show an altered pattern of expression of other genes normally active during the preaggregation/interphase and aggregation stages. Of interest is a substantial overexpression of the developmentally regulated PDE mRNA. Cell lines carrying constructs encoding the wild-type subunit or mutant subunits lacking one of the two binding sites show no visual phenotype. The results suggest that PKA-mediated functions, presumably controlled by increases in intracellular cAMP, are essential for Dictyostelium aggregation.
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PMID:A role for cAMP-dependent protein kinase A in early Dictyostelium development. 196 13

The v-erbA oncogene of avian erythroblastosis virus (AEV) encodes a ligand-independent mutated version of the chicken c-erbA alpha-encoded thyroid hormone receptor. The v-erbA gene product, a 75-kD gag/v-erbA fusion protein, is phosphorylated on Ser-16/17 of its v-erbA-encoded domain, and phosphorylation at this site is increased in vivo after activation of either the PKA or PKC signal transduction pathways. To test the hypothesis that phosphorylation of Ser-16/17 regulates gag/v-erbA protein function, mutant proteins in which Ser-16/17 had been changed to alanine or threonine residues were analyzed for their ability to inhibit erythroid differentiation of ts v-erbB or ts v-sea-transformed erythroblasts at nonpermissive temperature. Conversion of Ser-16/17 into alanine, although not affecting nuclear localization or DNA binding of the gag/erbA protein, prevented phosphorylation of the v-erbA-encoded domain of the protein both in unstimulated cells or after stimulation by PKA and PKC activators. The nonphosphorylatable AA-gag/v-erbA protein proved unable to inhibit temperature-induced differentiation of ts v-erbB and ts v-sea-transformed erythroblasts and to block expression of the erythrocyte-specific genes band 3 and carbonic anhydrase II. Back mutation of these alanine residues to serine resulted in the recovery of both normal phosphorylation levels and wild-type biological activity. In contrast, substitution of Ser-16/17 for threonine, which preserved phosphorylation in unstimulated cells but not PKA- and PKC-enhanced phosphorylation, resulted in a partially active gag/v-erbA protein. These results, together with the fact that the protein kinase inhibitor H7 resulted in both a dose-dependent inhibition of gag/v-erbA protein phosphorylation and the induction of terminal differentiation of AEV-transformed erythroblasts show that phosphorylation of gag/v-erbA protein is required for full biological activity. These results support the hypothesis that phosphorylation of the gag/v-erbA protein is important for transcriptional repression of at least some of its target genes in erythroid cells.
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PMID:Phosphorylation of the v-erbA protein is required for its function as an oncogene. 197 40

Exposure of rat thyroid cells for 1 week to a temperature-sensitive variant of Kirsten murine sarcoma virus (KiMSV) Ras inactivated the thyroglobulin promoter (pTg). Cellular dedifferentiation was paralleled by the loss of the thyroid-specific trans-acting factor, TgTF1, which binds to pTg. When Ras was denatured by shifting cells to 39 degrees C, TgTF1 binding and pTg function recovered rapidly without the synthesis of new protein. TgTF1 could be reactivated in vitro by treating nuclear extracts with protein kinase A. After 4 weeks of exposure to the oncogene, denaturation of Ras no longer restored TgTF1 binding or reactivated pTg. Incubation of nuclear extracts with protein kinase A likewise did not reactivate TgTF1. Cells chronically exposed to Ras did, however, yield differentiated clones after treatment with 5-azacytidine. We suggest that Ras induces dedifferentiation in two sequential steps: (1) Ras reduces PKA activity; TgTF1 (or an auxiliary protein) becomes dephosphorylated, and binding to pTg is abolished. (2) The effects of Ras become imprinted by methylation, possibly of the TgTF1 gene.
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PMID:Reversible inhibition of a thyroid-specific trans-acting factor by Ras. 198 5

We investigated the influence of the thyroid hormone status on the levels of protein kinases C (PKC) and A (PKA) in the soluble fraction of rat liver. The immunodetectable PKC level in hypothyroid liver was elevated 7.7-fold, whereas the phorbol-ester binding capacity and the immunodetectable alpha-PKC level were increased 2.4- and 2.6-fold, respectively. Conversely, in hypothyroid livers the abundance of the regulatory type I and the catalytic subunits of PKA were lowered to 42% of the euthyroid level as determined by immunoblotting and by measuring the substrate specific phosphorylation rate of PKA. These changes in the PKC and PKA levels were reversible upon treatment with 0.5 microgram T4/100 g body weight for 2-21 days. The thyroid state dependent alterations in hepatic PKC and PKA levels may be responsible for the known changes in the response of hepatocytes to other hormonal stimuli in hypothyroidism.
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PMID:Effect of hypothyroidism and thyroid hormone replacement on the level of protein kinase C and protein kinase A in rat liver. 203 57


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