Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyroglutamyl peptidase II (EC 3.4.19.-), a membrane-bound metalloproteinase, is a highly specific TRH-degrading enzyme. Exposure of Y-79 human retinoblastoma cells to 12-0-tetradecanoyl phorbol 13-acetate (TPA) decreased the activity of this enzyme in a time- and concentration-dependent manner (IC50 5 x 10(-9) M). After 15 min of TPA treatment, only 10% of pyroglutamyl peptidase II activity remained. TPA treatment did not affect the activity of the cytosolic enzyme pyroglutamyl peptidase I (EC 3.4.19.3) or the membrane-bound enzyme dipeptidyl peptidase IV (EC 3.4.19.3). Pretreatment of the cells with the protein kinase C inhibitors H-7 or sphingosine prevented the inactivation of pyroglutamyl peptidase II by TPA. The time course of the TPA-mediated effect paralleled the time course of translocation and activation of protein kinase C in this cell line. Immunoblot analysis demonstrated that inactivation of pyroglutamyl peptidase II was not due to dissociation or internalization of this enzyme molecule. Incubation of TPA-activated Y-79 cell membranes with gamma-[32P]-ATP followed by immunoprecipitation revealed a time-dependent phosphorylation of a 48 kilodalton subunit of pyroglutamyl peptidase II. These studies indicate that the phorbol ester effect is mediated by protein kinase C, and reveal a mechanism of potentiation of the action of TRH at its target sites.
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PMID:Rapid inactivation and phosphorylation of pyroglutamyl peptidase II in Y-79 human retinoblastoma cells after exposure to phorbol ester. 197 29

Phorbol esters, acting via activation of the protein kinase C family of protein serine/threonine kinases, are able to exert profound effects on various cellular functions. In this study, we used the EL4 thymoma cell line to study the potential role of "downstream" protein serine/threonine kinases in cellular responses to phorbol esters. In wild-type EL4 cells, addition of phorbol ester caused a rapid activation of kinase activity toward RRLSSLRA (S6P). This increased activity was maintained for at least 15 min but diminished to control levels by 60 min. Activation of a myelin basic protein (MBP) kinase was also seen in response to phorbol ester. In a variant EL4 cell line in which phorbol ester does not induce interleukin 2 transcription, phorbol ester failed to activate either the S6P kinase or MBP kinase. Partial purification of the activated S6P and MBP kinases from wild-type cells showed that they represent separate enzymes that are distinct from protein kinase C. Although the variant cells had reduced levels of protein kinase C as compared with the wild-type cells, the amount of membrane-bound enzyme increased in response to phorbol 12-myristate 13-acetate in both wild-type and variant cells. Treatment of intact cells with phorbol ester resulted in phosphorylation of some of the same protein substrates in both cell lines. Okadaic acid, a phosphatase inhibitor, increased S6P and MBP kinase activities in both wild-type and variant cells. Thus, phorbol ester failed to activate the S6P and MBP kinases in the variant cells even though these cells express activatable protein kinase C, S6P kinase, and MBP kinase. Two protein kinase inhibitors, staurosporine and H-7, inhibited the activity of all three kinases in vitro, while a peptide inhibitor (PKC 19-31) showed specificity for protein kinase C. In summary, these results suggest that activation of messenger-independent protein kinases may be critical for certain protein kinase C-dependent responses.
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PMID:Activation of messenger-independent protein kinases in wild-type and phorbol ester-resistant EL4 thymoma cells. 198 54

In an effort to characterize serotonergic receptor activation in rat stomach fundus, the potential role of protein kinases, more specifically protein kinase C (PKC), in serotonin-induced contraction of rat stomach fundus was examined. Staurosporine, a potent, but nonselective, inhibitor of protein kinases, attenuated basal, membrane-bound PKC activity in rat stomach fundus (IC50 = 10 nM). Although staurosporine (3-100 nM) produced a concentration-dependent inhibition of contractions elicited by serotonin (which does not increase phosphatidylinositol hydrolysis in the fundus), carbamylcholine (an agent stimulating phosphatidylinositol hydrolysis), and phorbol 12,13-dibutyrate (PDBu; a phosphatidylinositol-independent activator of PKC translocation), it was a more potent inhibitor of contractions produced by serotonin and PDBu than by carbamylcholine. Potassium chloride-induced contractions were attenuated minimally by staurosporine. These results raised the possibility that serotonin might exert an effect on protein kinase activity by a phosphatidylinositol-independent mechanism. Focusing on PKC, serotonin's ability to translocate PKC from cytosol to membrane in rat fundus was examined. Concentrations of serotonin (0.1-10 microM) which maximally contracted rat fundus did not translocate PKC. However, PDBu (10 nM-1 microM) and carbamylcholine (0.1-10 microM) significantly increased membrane-bound PKC activity. These results: 1) demonstrate that translocation of PKC occurred in rat stomach fundus in response to some, but not all, contractile agonists; 2) are consistent with the possibility that contraction of rat stomach fundus by carbamylcholine and PDBu may be related to increased membrane-bound PKC activity; and 3) indicate that serotonin-induced contraction, although potently blocked by staurosporine, did not result from PKC translocation in the rat stomach fundus.
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PMID:Protein kinase C translocation in rat stomach fundus: effects of serotonin, carbamylcholine and phorbol dibutyrate. 198 50

Increases in cytoplasmic [Ca2+] caused by receptor activation are thought to stimulate the redistribution of loosely associated protein kinase C (PKC) to a tightly membrane-bound form that is activated by diacylglycerol. The precise role of Ca2(+)-dependent redistribution of PKC in the activation of this enzyme has not been critically assessed. We examined the relationship between PKC redistribution and substrate phosphorylation by comparing the kinetics and the Ca2+ dependence of the two events. Using immunoblotting with specific PKC antibodies, we find that 1321N1 cells express the alpha form of PKC, approximately 10-20% of which is membrane-associated in unstimulated cells. This fraction is increased to 60% in response to muscarinic receptor stimulation. Agonist-induced redistribution of PKC is rapid and transient, peaking at 30 s and returning to control levels by 2-5 min. Stimulation of muscarinic receptors also rapidly increases phosphorylation of both an endogenous 80-kDa protein and the peptide substrate, VRKRTLRRL. However, unlike the time course of PKC redistribution, PKC-mediated phosphorylation of these substrates is sustained for up to 30 min. To compare the Ca2+ dependence of PKC redistribution and substrate phosphorylation, we buffered muscarinic receptor-induced increases in cytoplasmic [Ca2+] with the divalent cation chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Under these conditions, redistribution of PKC and phosphorylation of the exogenous peptide substrate are inhibited by about 80%. In contrast, muscarinic receptor-stimulated phosphorylation of the 80-kDa protein occurs even when increases in cytoplasmic [Ca2+] are prevented. Taken together, these data demonstrate that the redistribution of PKC does not correlate in extent or duration with phosphorylation of PKC substrates.
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PMID:Dissociation of protein kinase C redistribution from the phosphorylation of its substrates. 202 58

Acute forebrain ischemia reduced protein kinase C (PKC) activity in the adult rat cortex, striatum and hippocampus by 60-70% after 20 min ischemia episodes, followed by 48 h of recirculation. Ischemia of 1 min, followed by recirculation, produced a less pronounced but significant decrease in PKC activity. The ischemia-induced decrease of PKC affected both the soluble and the membrane-bound kinase. Alterations of PKC predate neuronal death following ischemia.
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PMID:Reduction of protein kinase C activity in the adult rat brain following transient forebrain ischemia. 202 20

A transmembrane precursor to human macrophage colony-stimulating factor (M-CSF, CSF-1) is stably expressed at the cell surface where it is slowly and inefficiently cleaved to yield a soluble form of the growth factor. Incubation in the presence of phorbol ester resulted in rapid cleavage of the plasma membrane-bound precursor and release of soluble CSF-1. Within 60 min after phorbol treatment the quantity of growth factor recovered in the medium was more than 30-fold greater than that observed in the absence of the agent. The growth factor released in the presence of phorbol was biologically active and exhibited the same electrophoretic mobility as that obtained in the absence of the drug. Phorbol ester-accelerated processing of the cell surface CSF-1 precursor was abrogated by long-term exposure to phorbol, but was not inhibited by pretreatment with cycloheximide or incubation in serum-free medium. These results suggest that the enhanced post-translational processing of the CSF-1 precursor resulted from activation of a pre-existing cellular protease via a mechanism involving phorbol ester-mediated stimulation of protein kinase C.
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PMID:Proteolytic processing of a plasma membrane-bound precursor to human macrophage colony-stimulating factor (CSF-1) is accelerated by phorbol ester. 203 Sep 12

We have examined the activity and intracellular compartmentalization of protein kinase C (PKC) following activation of human B lymphocytes by anti-human leukocyte antigen (HLA) class II antibodies. 12-O-Tetradecanoylphorbol 13-acetate (TPA) treatment increased membrane-associated PKC (between five and nine times greater than the control value) and decreased cytosolic PKC (between 70% and 100% of the control value). In contrast, anti-class II antibodies induce an activation of PKC which results either in an increase of cytosolic activity or membrane-bound activity without redistribution of cytosolic PKC. The effect of TPA and HLA class II molecules on total PKC activity was comparable: when TPA induced an increase of total PKC activity so did HLA class II molecules and when TPA did not, HLA class II molecules did not. Measurement on SDS PAGE of histone phosphorylation confirmed the above results of PKC activity. Taken together, our results suggest that PKC might be implicated in HLA class II-induced B lymphocyte activation.
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PMID:Signal transduction in B lymphocytes. 205 84

The involvement of protein kinase C (PKC) in regulation of cellular properties related to tumor cell invasiveness was tested in a murine methylcholanthrene-induced fibrosarcoma tumor cell model. A metastatic clone (IE7) derived from the T10 fibrosarcoma was found to possess 30 and 90% more cytosolic and membrane-bound PKC, respectively, compared with the IC9 metastatic clone. Intravenous injection of IE7 but not IC9 cells resulted in lung tumor formation. Long-term (3 months) treatment of IE7 cells with 500 ng/ml phorbol 12,13-dibutyrate (PDB) resulted in a 4-fold reduction in total PKC activity and increase in the tumor cell metastatic ability. Short-term (2h) PDB treatment induced cytosol-to-membrane PKC translocation and decreased the IE7 cells' ability to form hematogenous metastases. Treatment of IC9 cells with PDB did not render them metastatic. To test the possible involvement of distinct PKC isoenzymes in the determination of metastatic properties, we stained the cells with appropriate anti-PKC antibodies followed by FACS analysis. IC9 and IE7 cells exhibited similar levels of fluorescent intensity when stained with either anti-PKC alpha or anti-PKC beta antibodies. The relative proportion of PKC alpha and PKC beta was not changed following short-term PDB treatment of cells, but the intensity of staining was reduced 1.5- to 2-fold following long-term PDB treatment of both cell types. The results indicate that phorbol ester-induced alterations in PKC levels and subcellular distribution affect the metastatic ability of tumor cells and suggest that tumor promoting agents that promote induction of primary tumors may also affect tumor spread by regulating hematogenous metastases formation.
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PMID:Effect of protein kinase C activating tumor promoters on metastases formation by fibrosarcoma cells. 206 Oct

Incubation of isolated rat adipocytes with insulin, vasopressin, or oxytocin increased plasma membrane-bound protein kinase C (PKC) activity by 100-400%. PKC activity was assayed by a procedure that is virtually background-free, thus permitting assay of protein kinase activity in highly diluted samples of solubilized membranes. Hormone-dependent increases in PKC activity were limited to plasma membranes. Stimulation of the kinase was half-maximal with 70 pM insulin, and the hormone effect was rapid. Oxytocin and vasopressin produced effects on PKC similar to insulin, but the magnitude of the vasopressin stimulation exhibited seasonal variations. Treatment of cells with phorbol 12-myristate 13-acetate (PMA) resulted in a loss of PKC activity from the cytosol and a gain in plasma membrane activity, indicative of translocation of the enzyme. With activity measurements it was not possible to determine if insulin stimulated a translocation of the kinase. However, Western blot analysis of plasma membranes with polyclonal antibodies directed against PKC suggest that at least some of the insulin-stimulated PKC activity resulted from enzyme translocation.
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PMID:Insulin, oxytocin, and vasopressin stimulate protein kinase C activity in adipocyte plasma membranes. 210 94

The potent protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) and staurosporine, significantly enhanced concanavalin A (Con A)-induced cap formation in polymorphonuclear leukocytes (PMNs) from C57BL/6 mice after pretreatment for 30 min at concentrations of 10 microM and 1 nM, respectively. However, neither 10 microM of N-(2-aminoethyl)-5-isoquinolinesulfonamide dihydrochloride (H-9) nor N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride (HA1004), which inhibit cyclic nucleotide-dependent protein kinases more effectively than other kinases, affected the capping. Meanwhile, treatment of PMNs with Con A induced the translocation of PKC from the cytosol to the membrane fraction within 5 min, which is considered to be important for the activation of this enzyme. When cells were pretreated with H-7 or staurosporine for 30 min at the concentrations that enhanced the capping, both the cytosolic and the membrane-bound PKC activity was inhibited during the further incubation with Con A. These results suggest that PKC may play an important role in the regulation of Con A-induced cap formation in PMNs.
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PMID:Protein kinase C inhibitors enhance concanavalin A cap formation in polymorphonuclear leukocytes. 210 14


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