Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyroglutamyl peptidase II (EC 3.4.19.-), a highly specific membrane-bound TRH-degrading enzyme, is inactivated in Y-79 human retinoblastoma cells by exposure to 12-O-tetradecanoyl phorbol-13-acetate (TPA) in a biphasic manner. We have previously demonstrated a rapid decrease in pyroglutamyl peptidase II activity to 10% of the control level within 15 min, which returns to 70% of the control level by 1 h. This decrease results from enzyme phosphorylation by TPA-activated protein kinase-C. We now report a second phase of inactivation after longer exposure of cells to TPA. After 1 h, enzymatic activity slowly and progressively declined. By 7 h, only 15% of control activity remained. Cotreatment of cells with H-7, a protein kinase-C inhibitor, prevented this second phase of inactivation. Immunoblot experiments demonstrated a reduction in the amount of pyroglutamyl peptidase II in Y-79 membranes after long term exposure to TPA. Y-79 cells were labeled with [35S]methionine, and pyroglutamyl peptidase II was immunoprecipitated. A decreased incorporation of [35S]methionine paralleled the decrease in enzyme activity. These studies demonstrate that the second phase of inactivation after exposure to TPA is due to an inhibition of enzyme synthesis.
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PMID:Inhibition of pyroglutamyl peptidase II synthesis by phorbol ester in the Y-79 retinoblastoma cell. 167 74

In the adenohypophysis, thyrotrophin-releasing hormone (TRH) is inactivated by pyroglutamyl peptidase II (PPII), a TRH-specific ectoenzyme localized in lactotrophs. TRH slowly downregulates surface PPII activity in adenohypophyseal cell cultures. Protein kinase C (PKC) activation mimics this effect. We tested the hypothesis that other hypothalamic factors controlling prolactin secretion could also regulate PPII activity in adenohypophyseal cell cultures. Incubation for 16 h with pituitary adenylate cyclase activator peptide 38 (PACAP; 10(-6) M) decreased PPII activity. Bromocryptine (10(-8) M), a D2 dopamine receptor agonist, or somatostatin (10(-6) M) stimulated enzyme activity and blocked the inhibitory effect of [3-Me-His2]-TRH, a TRH receptor agonist. Bromocryptine and somatostatin actions were suppressed by preincubation with pertussis toxin (400 ng ml(-1)). Because these hypophysiotropic factors transduce some of their effects using the cAMP pathway, we analysed its role on PPII regulation. Cholera toxin (400 ng ml(-1)) inhibited PPII activity. Forskolin (10(-6) M) caused a time-dependent decrease in PPII activity, with maximal inhibition at 12-16 h treatment; ED50 was 10(-7) M. 3-isobutyl-1-methylxanthine or dibutiryl cAMP, caused a dose-dependent inhibition of PPII activity. These data suggest that increased cAMP down-regulates PPII activity. The effect of PACAP was blocked by preincubation with H89 (10(-6) M), a protein kinase A inhibitor, suggesting that the cAMP pathway mediates some of the effects of PACAP. Maximal effects of forskolin and 12-O-tetradecanoylphorbol 13-acetate were additive. PPII activity, therefore, is independently regulated by the cAMP and PKC pathways. Because most treatments inhibited PPII mRNA levels similarly to PPII activity, an important level of control of PPII activity by these factors may be at the mRNA level. We suggest that PPII is subject to 'homologous' and 'heterologous' regulation by elements of the multifactorial system that controls prolactin secretion.
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PMID:Multiple hypothalamic factors regulate pyroglutamyl peptidase II in cultures of adenohypophyseal cells: role of the cAMP pathway. 957 8

Released thyrotropin-releasing hormone (TRH) is inactivated by a narrow specificity ectopeptidase, pyroglutamyl aminopeptidase II (PPII), present in brain and lactotrophs. Various hypothalamic/paracrine factors, including TRH, slowly (in hours) regulate the activity of PPII on the surface of adenohypophyseal cells. TRH-induced down-regulation was mimicked by protein kinase C (PKC) activation but was not affected by inhibition of PKC. Adenylate cyclase activation can also down-regulate PPII. The purpose of this study was to identify elements of the transduction pathway used by TRH to regulate PPII activity. In primary cultures of female adenohypophyseal cells, activation of the stimulatory G protein or adenylate cyclase produced an effect additive to that of TRH; inhibition of protein kinase A activity did not interfere with TRH action. However, regulation of PPII activity by TRH was inhibited by a phospholipase C beta inhibitor or chelation of intracellular calcium. L-type calcium channels (LCC) agonists mimicked TRH action and their effect was not additive with that of TRH. Antagonists of LCC channels and inhibitors of calmodulin or calcium/calmodulin-dependent protein kinase blocked TRH action. Therefore, TRH-induced calcium entry through L-type calcium channels and the activity of calcium/calmodulin-dependent protein kinase are required for TRH effect on PPII activity in primary cultures of adenohypophyseal cells. This pathway may coregulate PPII and prolactin biosynthesis in response to TRH.
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PMID:Thyrotropin-releasing hormone-induced down-regulation of pyroglutamyl aminopeptidase II activity involves L-type calcium channels and cam kinase activities in cultures of adenohypophyseal cells. 1199 17