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)

Somatic cell homologs to the Xenopus laevis S6 protein kinases (referred to collectively as pp90rsk) have recently been identified and partially characterized. Here we examine alterations in pp90rsk phosphorylation and S6 phosphotransferase activity in response to regulators of multiple signal transduction systems: purified growth factors, phorbol ester, changes in cyclic AMP (cAMP) levels, and sodium vanadate. All reagents tested increased pp90rsk serine and threonine phosphorylation, but only those agents that regulate cell proliferation and sodium vanadate activated its S6 kinase activity. In addition to the cAMP-stimulated phosphorylation of pp90rsk, a simple correlation between the extent of growth-regulated pp90rsk phosphorylation and S6 phosphotransferase activity was not observed. Quantitative phosphorylation of pp90rsk continued to increase after its S6 kinase activity began its return towards basal levels. However, a close correlation between the appearance and disappearance of a slow-mobility form of phosphorylated pp90rsk (by electrophoresis) and pp90rsk activity was observed. In addition, pp90rsk was regulated by both protein kinase C-independent and -dependent signaling mechanisms. The extent of protein kinase C participation, however, varied depending on which growth factor receptor was activated. Furthermore, growth factor-specific differences in the temporal regulation of pp90rsk S6 phosphotransferase activity were also observed. These results support the notion that the complex regulation of the rsk gene product constitutes one of the primary responses of animal cells to mitogenic signals.
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PMID:Regulation of pp90rsk phosphorylation and S6 phosphotransferase activity in Swiss 3T3 cells by growth factor-, phorbol ester-, and cyclic AMP-mediated signal transduction. 184 64

Ligation of interleukin 2 (IL2) is known to regulate both protein tyrosine and serine/threonine phosphorylation. A family of leukocyte transmembrane proteins whose cytoplasmic domain exhibits intrinsic protein tyrosine phosphatase activity is collectively called CD45 and is identified by a set of common cell surface epitopes. Although CD45 is known to be a phosphoprotein, it is not known how phosphorylation specifically regulates its function. We therefore identified a cell line, the IL4-dependent line CTLL-2.4, in which CD45 could be phosphorylated in response to addition of IL2. These cells are a variant of an IL2-dependent murine cell line which were selected for long-term growth on IL4 but which retain the ability to proliferate on exposure to IL2. Incubation of CTLL-2.4 in low serum concentrations followed by stimulation with IL2 caused a three- to fivefold increase in the phosphorylation of CD45 in a time- and concentration-dependent manner. CD45 in non-stimulated cells contained one major tryptic phosphopeptide, whereas, after exposure of the cells to IL2, two new phosphopeptides were present in CD45. The pattern of IL2-induced phosphorylation was different from that found following addition of phorbol 12-myristate 13-acetate (PMA) to the cells. Although IL2 induced rapid and potent tyrosine phosphorylation in CTLL-2.4 cells, all of the basal and cytokine-activated phosphorylation of CD45 occurred on serine residues. The IL2-stimulated phosphorylation caused no change in the amount of cell surface CD45 and no alteration of its catalytic activity using an artificial tyrosine phosphorylated substrate-RCM-lysozyme. We speculate that the increase in phosphorylation of CD45 may modify its association with potential substrates. The differences in the phosphorylation patterns induced by IL2 and PMA further suggest that more than one kinase can use CD45 as substrate and that IL2 activates a protein serine/threonine kinase different from protein kinase C.
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PMID:Interleukin 2 stimulates serine phosphorylation of CD45 in CTLL-2.4 cells. 185 Mar 60

Activation of the EGF receptor tyrosine kinase by ligand indirectly activates a series of other cellular enzymes, including protein kinase C. To test the hypothesis that phosphorylation of the EGF receptor by protein kinase C provides an intracellular negative feedback loop to attenuate EGF receptor signaling, we used scanning EM to follow the characteristic EGF-induced retraction of lamellipodia and concomitant cell shape changes. Wild type and mutant EGF receptors were expressed in receptor-deficient NR6 cells. The mutant receptors were prepared by truncation at C' terminal residue 973 (c'973) to provide resistance to ligand-induced down regulation that strongly attenuates receptor signaling and by replacement of threonine 654 (T654) with alanine (A654) to remove the site of phosphorylation by protein kinase C. Cells expressing WT and c'973 EGF receptors demonstrated characteristic lamellipodial retraction after exposure to EGF, with the non-down regulating c'973 EGF receptors responding more rapidly. Exposure of cells to TPA blocked this response. Replacement of T654 by alanine resulted in EGF receptors that were resistant to TPA. Cells expressing the A654 mutation underwent more rapid and more extensive morphologic changes than cells with the corresponding T654 EGF receptor. In cells expressing T654 EGF receptors, down regulation of protein kinase C resulted in more rapid and extensive EGF-induced changes similar to those seen in cells expressing A654 EGF receptors. These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling.
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PMID:A negative feedback loop attenuates EGF-induced morphological changes. 186 Aug 84

Two Dictyostelium discoideum protein kinase(PK)-encoding cDNAs (Dd PK1 and Dd PK2) have been isolated by hybridization with an oligodeoxyribonucleotide derived from a highly conserved region of eukaryotic PKs. The two nucleotide (nt) sequences encode new putative serine/threonine-specific PKs. Dd PK1 is a partial cDNA covering the entire catalytic domain. The derived amino acid (aa) sequence is about 30% identical to both cAMP-dependent protein kinase (cAPK) and protein kinase C. The Dd PK2 sequence was extended through the isolation of a genomic fragment encoding a complete putative protein. A single intron is present, as deduced from sequence comparison with the cDNA. The catalytic domain appears more closely related to the catalytic subunit of cAPK (54% sequence identity). However, our nt sequence potentially codes for a much larger protein (648 vs. about 350 aa for most cAPKs) with a N-terminal half containing long homopolymers of threonines, glutamines and asparagines. Similar repeats occur at the C terminus of Dd PK1, Dd PK1 is expressed in vegetatively growing cells and during development. Dd PK1 RNA decreases after 6 h of starvation to re-accumulate once the cells have aggregated. Dd PK2 transcripts, present at a low amount in growing cells, rise upon starvation. A switch to a shorter form of transcripts occurs between 3 and 6 h into development.
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PMID:Isolation of two genes encoding putative protein kinases regulated during Dictyostelium discoideum development. 186 10

The increase in the intracellular concentration of Ca2+ in A431 cells induced by the calcium ionophore A23187 leads to phosphorylation of epidermal growth factor (EGF) receptors at serine and/or threonine residues. This process is accompanied by the decrease in the level of EGF receptor autophosphorylation at tyrosine residues. Preincubation of cells in a A23187-containing medium in the presence of phorbol-12-myristoyl-13-acetate leads to a further decrease of the phosphotyrosine content in EGF receptors. At increased intracellular concentrations of Ca2+ preincubation of A431 cells with the protein kinase C inhibitor H-7 has no effect on the degree of EGF receptor autophosphorylation. Down-regulation of cellular protein kinase C does not change the A23187-induced effect either. The data obtained suggest that the decreased autophosphorylation of EGF receptors induced by Ca2+ is not due to the activation of cellular protein kinase C.
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PMID:[Autophosphorylation of EGF receptors in the A431 cell line with an increased intracellular concentration of Ca(2+) ions]. 187 50

This report shows that N-acylation of the protein kinase C (PKC) substrate Arg-Lys-Arg-Thr-Leu-Arg-Arg-Leu (RKRTLRRL) provides it with a potent inhibitory activity against PKC. N-myristoyl-RKRTLRRL inhibited Ca2(+)- and phosphatidylserine (PS)-dependent histone phosphorylation catalyzed by PKC with a 50% inhibitory concentration (IC50) of 5 microM, whereas neither RKRTLRRL nor myristic acid inhibited PKC-catalyzed histone phosphorylation at concentrations as high as 50 microM. A fully active, Ca2(+)- and PS-independent catalytic fragment of PKC can be generated by limited proteolysis. N-myristoyl-RKRTLRRL inhibited histone phosphorylation catalyzed by the catalytic fragment of PKC (IC50 = 80 microM), but neither myristic acid nor the nonmyristylated peptide inhibited the activity of the catalytic fragment at concentrations up to and including 200 microM. The Km app and Vmax app for N-myristoyl-RKRTLRRL were similar to those of RKRTLRRL. Thus, N-myristylation provided the octapeptide with an inhibitory activity against PKC but had only minor effects on its Km app and Vmax app. Kinetic analysis provided evidence that the peptide inhibited PKC noncompetitively with respect to ATP. Previously, we reported that the protein kinase inhibitor H7 partially reverses Adriamycin resistance in the multidrug resistant (MDR) murine fibrosarcoma line UV-2237M-ADRR. In this report, we show that N-myristoyl-RKRTLRRL also partially reverses Adriamycin resistance in UV-2237M-ADRR cells. These results suggest that potent and selective cell permeable PKC inhibitors may be designed by N-acylating small PKC peptide substrates.
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PMID:A novel N-myristylated synthetic octapeptide inhibits protein kinase C activity and partially reverses murine fibrosarcoma cell resistance to adriamycin. 187

The phenolic antioxidant 2,6-bis(1,1-dimethyl ethyl)-4-methylphenol (BHT) evokes a transient phosphorylation of two platelet proteins of Mr 20,000 and 47,000 that are well-known substrates of protein kinase C (PKC) and, similarly to phorbol esters, a slight but persistent phosphorylation of a protein of Mr 26,000. These effects are observed both in the presence and in the absence of extracellular calcium, but are abolished in the presence of the protein kinase C inhibitor staurosporine. The phosphorylation of the 47 kDa protein takes place mostly at the serine and, to a lesser extent, at threonine residues. BHT induces an increased binding of tritiated phorbol dibutyrate to platelets indicating a PKC translocation from cytosol to plasma membrane. Addition of BHT (20 microM) a few min prior to thrombin causes inhibition of both agonist-evoked protein phosphorylation and increase in the Ca2+ concentration, the latter inhibition being counteracted by staurosporine. The inhibitory effect lasts for several minutes even after removal of BHT from the cellular suspending medium. Similar results are obtained with nordihydroguaiaretic acid, whereas 2- and 3-tert-butyl-4-methoxyphenol (BHA) produce only slight effects. BHT activates the protein kinase C purified from pig brain in a concentration-dependent manner (up to 200 microM), whereas it does not affect the activity of other purified protein kinases such as type 1 and 2 casein kinases, type II A, II B and III tyrosine protein kinases from rat spleen and the catalytic subunit of cyclic AMP-dependent protein kinase. It is concluded that, similarly to diacylglycerols and phorbol esters, these phenolic antioxidants activate the protein kinase C, which in turn desensitizes platelets towards subsequent phospholipase C activation.
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PMID:The antioxidant butylated hydroxytoluene stimulates platelet protein kinase C and inhibits subsequent protein phosphorylation induced by thrombin. 188 50

The c-raf-1 protooncogene encodes a p72-74 serine/threonine-specific kinase that has been implicated in growth factor-mediated signal transduction and malignant transformation. Here, we compared the effects of Ha-c-ras and v-src oncogenes on the regulation of p72-74 RAF-1 kinase in NIH3T3 cells. In both serum-starved and platelet-derived growth factor-treated v-src-transformed cells, the RAF-1 kinase was constitutively activated, displaying characteristic retarded mobility in electrophoretic gels and elevated activity in in vitro kinase assays. In contrast, the RAF-1 protein from quiescent ras-transformed cells did not exhibit constitutively shifted gel mobility or elevated kinase activity but did respond normally with regard to platelet-derived growth factor- and phorbol myristate acetate-induced changes in p72-74 RAF-1 phosphorylation and kinase activity. 3T3 cells transformed by ras, however, contained elevated levels of p72-74 RAF-1 protein (as determined by immunoblotting), suggesting an indirect influence on this kinase. Quantitative differences in the levels and subcellular distribution of immunodetectable protein kinase C enzymes did not account for the differences between src- and ras-transformed 3T3 cells with regard to regulation of the RAF kinase. These findings in serum-deprived 3T3 cells demonstrate that expression of a ras oncogene can be insufficient for full activation of the p72-74 RAF-1 kinase, implying necessity for an additional growth factor-mediated stimulus.
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PMID:Differential regulation of the p72-74 RAF-1 kinase in 3T3 fibroblasts expressing ras or src oncogenes. 188 99

Phosphorylation events are major regulatory mechanisms of signal transduction pathways that control cell growth and differentiation. We analyzed the potential contribution of serine/threonine specific protein phosphatases to the regulation of the c-fos gene, a proto-oncogene that is involved in the regulation of cell growth and differentiation. By use of okadaic acid, an inhibitor of protein phosphatases 1 and 2A, we present evidence that expression of the c-fos gene is regulated by serine/threonine specific protein phosphatases. This control is exerted on the transcriptional as well as the post-transcriptional level. The results suggest that dephosphorylation of regulatory phosphoproteins is an important mechanism for the down-regulation of c-fos promoter activity and the rapid degradation of c-fos mRNA. Examination of two protein kinase pathways that are known to regulate c-fos expression indicated that okadaic acid acted synergistically with protein kinase C, but not with protein kinase A. Since inhibition of serine/threonine specific phosphatases increases proto-oncogene expression, these experiments further strengthen the view that certain protein phosphatases may act as negative regulators of cell growth.
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PMID:Transcriptional and post-transcriptional regulation of c-fos expression by the tumor promoter okadaic acid. 190 2

MCH (melanin concentrating hormone) is a heptadecapeptide, Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val, which stimulates melanosome (melanin granule) aggregation to a perinuclear position within teleost fish integumental melanocytes, resulting in lightening of the skin. The mechanisms of action of MCH are unknown. Drugs that affect the diacylglycerol/inositol triphosphate pathway were used to investigate the possible roles of this pathway in the mechanisms of action of MCH on Synbranchus marmoratus (teleost) melanocytes. The shift of the dose-response curve to MCH in the presence of various concentrations of 4-bromophenacyl bromide and neomycin sulphate, phospholipase C inhibitors, suggests that phospholipase C is stimulated after MCH receptor activation. Low concentrations (10(-9) to 10(-8) M) of the phorbol ester TPA exhibited MCH-like activity, eliciting a dose-dependent melanosome aggregation. Higher doses, however, displaced to the right the dose-response curve to MCH, as did the protein kinase C inhibitors, dibucaine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). These results support the assumption that protein kinase C mediates the pigment aggregating activity of MCH. Both MCH and norepinephrine lightening actions were abolished by beta-glycerophosphate, a phosphatase inhibitor, suggesting that a protein dephosphorylation occurs during melanosome aggregation, and is, therefore, a common event triggered by MCH and norepinephrine, although both agonists act through separate receptors and exhibit different transduction mechanisms.
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PMID:Protein-kinase C mediates MCH signal transduction in teleost, synbranchus marmoratus, melanocytes. 194 11


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