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)

Experiments using the physical loading of purified recombinant p21 ras proteins into quiescent normal cells to analyze how the proteins stimulate DNA synthesis and morphological transformation are reviewed. The results indicate that oncogenic p21ras proteins rapidly activate a protein-kinase-C-dependent pathway and a protein-kinase-C-independent pathway. The activation of protein kinase C is absolutely required for p21ras to stimulate DNA synthesis but is not required for morphological transformation.
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PMID:Signal transduction by p21ras. 268 Oct 10

Antigen activation of murine T lymphocytes leads to phosphorylation of three subunits of the murine T cell antigen receptor (L.E. Samelson, M.D. Patel, A.M. Weissman, J.B. Harford, and R.D. Klausner. 1986. Cell 46:1083). Two kinases are activated in this process: protein kinase C which leads to phosphorylation of the gamma and, to a lesser extent, the epsilon subunits on serine residues and a tyrosine kinase which phosphorylates the p21 subunit (M.D. Patel, L.E. Samelson, and R.D. Klausner. 1987. J. Biol Chem. 262:5831). We sought to determine whether treatment of these cells with NaF could simulate any of these antigen-induced events. Indeed NaF treatment resulted in breakdown of polyphosphoinositides and production of phosphoinositols. This treatment also resulted in a rise in cytosolic free Ca2+. EGTA failed to block this rise suggesting that NaF liberated intracellular stores of Ca2+. Finally NaF treatment resulted in phosphorylation of the gamma and epsilon chains of the T cell receptor indistinguishable from the effects of phorbol esters. The NaF effect was potentiated by addition of A1Cl3 consistent with the view that the active moiety is A1F4-. The A1F4--induced phosphorylations were abolished in cells in which protein kinase C was depleted by prior treatment with phorbol myristate acetate. All of these observations are compatible with the interpretation that the A1F4- phosphorylation is mediated by protein kinase C. Antigen and anti-receptor antibody-induced receptor serine phosphorylation and phophatidylinositol turnover are blocked by raising intracellular levels of cyclic adenosine monophosphate. In contrast, A1F4--induced effects were insensitive to cyclic adenosine monophosphate.
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PMID:Aluminum fluoride induces phosphatidylinositol turnover, elevation of cytoplasmic free calcium, and phosphorylation of the T cell antigen receptor in murine T cells. 282 7

We have examined phosphatidylinositol turnover and C-kinase distribution in a flat cellular ras-resistant cell line (C11) derived from Kirsten murine sarcoma virus (Ki-MSV) transformed NIH/3T3 cells (DT). This cell type has been shown to express high levels of the p21 Ki-ras gene product yet is resistant to the transforming effects of this protein. Our data indicate that C11 cells have reduced levels of total C-kinase activity when compared to NIH/3T3 cells and do not retain the ability to phosphorylate the growth associated 80-kDa C-kinase substrate either in vivo or in vitro. Furthermore, whilst the steady state levels of diacylglycerol and the sum of inositol phosphates are elevated in DT cells, in C11 cells these levels are reduced to an amount equivalent to that seen in NIH/3T3 cells. These data indicate a correlation between a protein kinase C dependent pathway and resistance to transformation by ras.
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PMID:Reduced protein kinase C activity in a ras-resistant cell line derived from Ki-MSV transformed cells. 283 May 75

The c-Ha-ras oncogene has been implicated as a causative agent in the development of tumors in humans as well as mice. The molecular nature of the ras-induced tumorigenic process remains unclear, however. To address this question directly we have constructed a cell line which carries a zinc-inducible metallothionein-ras hybrid oncogene, transformant 212. Upon exposure to zinc for 24-48 hr, 212 cells assume a highly transformed morphology, concomitant with the induction of ras-expression. Natural killer cells constitute a subpopulation of lymphoid effector cells which have for a long time been hypothesized to be involved in the earliest stages of antitumor surveillance. Central to this hypothesis is the prediction that NK sensitivity arises during cellular transformation. By carrying out cytotoxicity assays against the 212 transformant, we showed that, indeed, increased sensitivity to NK-mediated lysis correlated with expression of the ras oncogene, which is consistent with the above hypothesis. We then addressed the question of the biochemical mechanism of ras-induced transformation. Owing to their similarity to G proteins, regulatory elements interposed between cell-surface receptors and their effector enzymes, it has been postulated that p21, the ras oncogene protein, mediates its transforming effects by constitutive activation of proliferative signal transduction pathways. We studied the effect of ras expression on the regulation of adenylate cyclase (A.C.), key enzyme of one such major pathway. We found that ras expression correlated with a dampening of responsiveness of A.C. to several stimuli, including hormones such as isoproterenol and other agents such as GMP-PNP, forskolin and fluoride-ion. Accumulation of cAMP as measured by RIA in intact cells, as basal or in response to stimulation of A.C. activity with forskolin, was also decreased (approximately 10-fold) with ras expression. Because the regulation of calcium, another important second messenger is dependent, in part, upon cAMP and GTP-binding proteins, we investigated the possible influence of ras expression on the intracellular concentration of calcium. Steady-state intracellular free Ca2+ concentration, as measured by fluorimetry, was indeed increased by approximately 50-125% in association with ras expression. Finally, we studied the possible influence of p21ras on protein kinase C (PKC), which is a key enzyme in the important signal transduction pathway of phosphatidylinositol lipid turnover. We assessed PKC activity directly, in a cell-free system, by measuring the ability of the enzyme to transfer radiolabelled phosphate from gamma-32P-ATP to histone, and exogenous substrate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The cell biology of ras-induced transformation: insights from studies utilizing an inducible hybrid oncogene system. 284 54

Novel p21 phosphorylation was found in cells expressing high levels of this product of c-H- and c-K-ras genes. Phorbol 12,13-dibutyrate, a protein kinase C (PKC) activator, and permeable c-AMP derivatives, which activate protein kinase A (PKA), stimulated phosphorylation of K-ras(4B) p21 in 416B cells 3 to 5 fold. By tryptic peptide mapping, it was found that both PKC and PKA phosphorylated in vitro the K-ras p21 at the same site as was found in p21 from cells labeled with [32P]orthophosphate in vivo. A common site of H-ras p21 was also phosphorylated by both PKC and PKA, although phosphopeptides of H-ras p21 were distinct from those of K-ras p21. The construction of a mutant by site-directed mutagenesis allowed the identification of serine-177 as the phosphorylation site of H-ras p21. This novel phosphorylation site lies in the hypervariable region, which links the globular catalytic domain of p21 to the membrane-anchoring site at the C-terminus, a location suggesting that this phosphorylation plays a role in modulating transmembrane signaling.
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PMID:Novel phosphorylation of c-ras p21 by protein kinases. 284 44

We have purified to near homogeneity a Mr 22,000 GTP-binding protein from human platelet membranes and identified it as the smg-21 gene product (smg p21), having the same putative effector domain as the ras gene products, which we have purified to near homogeneity from bovine brain membranes and characterized. This purified human platelet smg p21 was phosphorylated by cyclic AMP-dependent protein kinase. About one mol of phosphate was maximally incorporated into one mol of the protein. Only serine residue was phosphorylated. Both the guanosine 5'-(3-O-thio)-triphosphate (GTP gamma S)-bound and GDP-bound forms were phosphorylated with the same reaction velocity. The phosphorylation of smg p21 affected neither its GTP gamma S-binding nor GTPase activity. Human platelet smg p21 was not phosphorylated by protein kinase C. A Mr 24,000 GTP-binding protein partially purified from human platelet membranes was not phosphorylated by cyclic AMP-dependent protein kinase or protein kinase C.
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PMID:Phosphorylation by cyclic AMP-dependent protein kinase of a human platelet Mr 22,000 GTP-binding protein (smg p21) having the same putative effector domain as the ras gene products. 284 42

Genes involved in the transduction of signals required for normal cell proliferation commonly appear to be subverted in the neoplastic process. One such group is the highly conserved family of ras genes, which have been detected as transforming genes in a wide variety of naturally occurring tumours. By analogy with other known G proteins, the p21 proteins encoded by ras genes may act as regulatory proteins in the transduction of signals that lead to DNA synthesis. A major pathway involved in the DNA synthesis induced by growth factors is mediated by phosphatidylinositol turnover: cleavage of phosphoinositides by phospholipase C produces 1,2-diacylglycerol, and inositol phosphates. The former acts as an essential cofactor for protein kinase C (ref. 4), and inositol-(1,4,5)-triphosphate mobilizes Ca2+ from non-mitochondrial intracellular stores. We demonstrate a reproducible increase in 1,2-diacylglycerol, in the absence of a detectable increase in inositol phosphates, in transformed cells containing Ha-ras oncogenes and with different membrane targeting signals for the ras p21 protein. These findings suggest that a source other than phosphoinositides exists for the generation of 1,2-diacylglycerol and that the Ha-ras oncogene specifically activates this novel pathway for 1,2-diacylglycerol production.
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PMID:Novel source of 1,2-diacylglycerol elevated in cells transformed by Ha-ras oncogene. 331 65

Microinjection of purified protein kinase C (PKC) into Swiss 3T3 fibroblasts pretreated with the phorbol ester phorbol-12,13-dibutyrate restores the mitogenic response of the cells to phorbol-12,13-dibutyrate (G. Pasti, J.C. Lacal, B.S. Warren, S.A. Aaronson, and P.M. Blumberg, Nature [London] 324:375-377, 1986). Our present studies demonstrate that the mitogenic activity of the H-ras oncogene in H-ras p21-microinjected quiescent cells is markedly reduced under conditions in which PKC is downregulated by chronic phorbol ester treatment. The ability to reconstitute the mitogenic response upon microinjection of both H-ras p21 and PKC implies involvement of functional PKC in the mitogenic activity of the H-ras oncogene product.
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PMID:Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product. 332 89

Multiple kinases interact at the multicomponent murine T cell antigen receptor. Antigen induces serine phosphorylation of the 21-kDa gamma glycoprotein and tyrosine phosphorylation of p21, a distinct 21-kDa chain. We demonstrate that tyrosine phosphorylation is due to kinase activation, and that all phosphorylated p21 is associated with the antigen receptor. We also show that antigen leads to polyphosphoinositide metabolism and subsequent protein kinase C activation. The two phosphorylation events can be dissociated by protein kinase C depletion, which eliminates phorbol 12-myristate 13-acetate-induced serine but not tyrosine phosphorylation. Activation of a third kinase, cyclic AMP-dependent protein kinase, inhibits both serine and tyrosine events, yet this inhibition can be modulated by addition of the protein kinase C activator, phorbol 12-myristate 13-acetate. Receptor-mediated signal transduction may be understood as the interaction of multiple stimulatory and inhibitory kinase activities.
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PMID:Multiple kinases and signal transduction. Phosphorylation of the T cell antigen receptor complex. 349 29

The Harvey (H)-ras oncogene product, p21, can be phosphorylated by protein kinase C in vitro at sites distinct from the site of autophosphorylation of p21. Serine was found to be the main phosphate acceptor. Kinetic studies revealed a high apparent affinity but a much lower turnover for the phosphorylation of p21 as compared with that of the phosphorylation of histone by protein kinase C. Indirect association between protein kinase C and p21 was suggested by the co-immunoprecipitation of both proteins with either anti-protein kinase C or anti-p21 antibodies.
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PMID:Phosphorylation of ras oncogene product by protein kinase C. 349 94


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