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

tsJT16 is a G0/G1 ts mutant from the Fischer rat fibroblast line. It has a ts defect in a function operating early after growth stimulation with fetal bovine serum (FBS). A primarily induced gene product, p70, was not synthesized at 40 degrees C after stimulation with serum, while c-fos and c-myc mRNAs accumulated under the same condition. This paper reports that p70 was synthesized following stimulation of G0-arrested cells with platelet-derived growth factor, epidermal growth factor (EGF), and 12-0-tetradecanoylphorbol-13-acetate (TPA) at 34 degrees C, but not at 40 degrees C. However, it was synthesized at both temperatures after addition of A23187. In protein kinase C-deprived cells, peptide growth factors and A23187 induced p70 at 34 degrees C, whereas TPA did not. Fibroblast growth factor and insulin did not induce p70. Induction of c-fos and c-myc occurred at both temperatures after the stimulation with FBS, TPA or A23187. These results indicated that the defect in tsJT16 to induce p70 is likely to be located at the common downstream of protein kinase C-dependent and -independent pathways, but is independent from the pathway of calcium mobilization.
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PMID:A cell cycle ts mutant, tsJT16, is defective in p70 synthesis through protein kinase C-dependent and -independent pathways. 178 69

We evaluated the concurrent phosphorylation of reconstituted mixtures of three purified human placental calpactins (or lipocortins) by purified bovine brain protein kinase C (PKC). Calpactin-I (p36 or lipocortin-II), calpactin-II (p38 or lipocortin-I), and a 70-kilodalton calpactin-related protein, calpactin-p70, when present together as substrates for PKC, all demonstrated comparable kinetic parameters (Vmax values = 0.3-0.5 nmol phosphate incorporated/min), with calpactin-II and calpactin-p70 exhibiting lower apparent Km values (40 and 30 nM, respectively) than did calpactin-I (Km, 200 nM). Because of the higher Vmax/Km ratios for calpactin-II and calpactin-70 (12.5 and 10.0, respectively) compared with the ratio for calpactin-I (2.0), our data suggest that, intracellularly, where all three calpactins might be co-localized, the higher molecular mass calpactins could be preferred substrates for PKC. Nonetheless, the requirement for relatively high calcium concentrations (greater than or equal to 0.5 mM) suggests that PKC-mediated phosphorylation of the calpactins may take place only in restricted intracellular compartments, wherein calcium concentrations might transiently reach levels much higher than those that are normally found intracellularly (less than or equal to 0.25 mM).
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PMID:Simultaneous phosphorylation of three human calpactins by kinase C. 182 15

The human myeloid cell line MO7 requires either granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin 3 (IL-3) for proliferation. We have previously shown that both GM-CSF and IL-3 transiently induce tyrosine phosphorylation of a number of proteins, including two cytosolic proteins, p93 and p70, which are maximally phosphorylated 5-15 min after addition of growth factor to factor-deprived cells. GM-CSF-induced proliferation of MO7 cells was found to be inhibited by two activators of protein kinase C, phorbol 12-myristate 13-acetate (PMA) and bryostatin-1. PMA did not affect surface expression or affinity of the GM-CSF receptor but significantly inhibited GM-CSF- or IL-3-induced tyrosine phosphorylation of p93 and p70. In contrast, PMA augmented GM-CSF-induced tyrosine phosphorylation of another protein, p42. Pretreatment of cells with sodium orthovanadate to inhibit protein tyrosine phosphatases (PTPase) partially reversed the inhibitory effects of PMA. These results suggest that one aspect of GM-CSF and IL-3 signal transduction, protein tyrosine phosphorylation, can be inhibited by a mechanism which does not involve receptor down-regulation, and may involve either receptor down-regulation, and may involve either inhibition of a receptor-activated tyrosine kinase, activation of a protein tyrosine phosphatase, or both. This mechanism could be important in exerting control of proliferation of some types of hematopoietic cells.
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PMID:Phorbol 12-myristate 13-acetate inhibits granulocyte-macrophage colony stimulating factor-induced protein tyrosine phosphorylation in a human factor-dependent hematopoietic cell line. 184 78

Calpactin, or calpactin heavy chain (p36), reconstitute secretion in digitonin-permeabilized adrenal chromaffin cells after a reduction in their secretory potential resulting from the loss of cytosolic components. We have characterized the stimulatory effect of p36, which resulted in an increase in both the extent and the rate of exocytosis. A mixture of other annexins (p70 and p32) did not have any effect on secretion at similar or greater concentrations than p36. Controlled proteolysis of p36 using chymotrypsin was carried out, and the 33,000 molecular weight core and 3000 molecular weight tail peptide isolated. In contrast to p36, p33 had no effect on exocytosis, even at high calcium concentrations. The N-terminal tail peptide and a synthetic peptide based on the tail of p36 [Ac-calpactin-(1-15)-NH2] had no effect on endogenous secretion, or secretion stimulated by exogenous p36. The results show that both the tail and core domains are required for p36 to stimulate exocytosis. The tail domain is unlikely to be required for interaction with cellular components but probably has a regulatory effect on the core domain. Endogenous secretion and the stimulatory effect of p36 were markedly inhibited by depletion of ATP. The ATP requirement for p36 action was not due to a requirement for phosphorylation by protein kinase C (PKC), since the PKC inhibitor staurosporine partially inhibited endogenous secretion but did not affect the stimulation of exocytosis due to exogenous p36.
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PMID:The stimulatory effect of calpactin (annexin II) on calcium-dependent exocytosis in chromaffin cells: requirement for both the N-terminal and core domains of p36 and ATP. 214 64

Proliferation of T lymphocytes in response to antigen/MHC complexes is dependent upon the presence of a co-stimulatory signal; in its absence, T cells are rendered unresponsive to specific antigen CD28 is a T cell surface glycoprotein that acts as a co-stimulatory molecule when combined with signals initiated by the T cell receptor CD3 complex. While the biochemical signaling events following CD28 stimulation are still poorly defined, monoclonal antibodies (mAb) directed against CD28 have been shown to transduce a variety of early signals that are different in the presence of cross-linking antibody or the presence of phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC). Stimulation of human T cells with cross-linked anti-CD28 mAb alone resulted in the activation of 70-kDa (p70) S6 kinase, a rapamycin-sensitive serine/threonine kinase that is believed to be important for cell cycle progression. Activation of p70 S6 kinase through CD28 was inhibited by rapamycin. Activation of p70 S6 kinase also increased in response to cross-linked CD3, but followed a more rapid time course than activation via CD2. Cyclosporin A and FK506 had no effect on p70 S6 kinase activity initiated via either pathway. The combination of cross-linked CD28 and cross-linked CD3 had no more than an additive effect on the induction of p70 S6 kinase activity. Thus, recruitment of p70 S6 kinase activity appears to represent a common signal transduction event shared by both the CD28 and CD3 pathways of T cell activation.
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PMID:Cross-linking CD28 leads to activation of 70-kDa S6 kinase. 752 38

Neu differentiation factors (NDF) are a novel family of polypeptide factors which activate sub-class I tyrosine kinase receptors. In all mammary epithelial cells analysed in this study, NDF activates the same signalling pathways while it induces different, cell-specific biological effects. In AU565 cells which are growth inhibited, as well as in T47D or HC11 cells which proliferate in response to NDF, the MAP kinase isoforms p44ERK1 and p42ERK2 and the p70/p85 S6 kinase are activated. NDF stimulates tyrosine phosphorylation and the in vitro kinase activity of ErbB-2. When PKC is activated by TPA, NDF is no longer able to activate ErbB-2 in T47D cells, leading to a blockage of cell proliferation. Activation of ErbB-2 by point mutation, or by monoclonal antibodies, also stimulates both the MAPK and the p70/p85 S6 kinase pathways. The same monoclonal antibodies can induce AU565 cell differentiation. In summary, during growth or differentiation of mammary epithelial cells, NDF stimulates several independent signalling pathways which can also be triggered by ErbB-2 stimulation alone. PKC activation blocks the biological effect induced by NDF through negative modulation of ErbB-2.
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PMID:NDF/heregulin activates MAP kinase and p70/p85 S6 kinase during proliferation or differentiation of mammary epithelial cells. 782 69

A substrate protein of protein kinase C with an apparent molecular mass of 70 kDa has been purified from bovine brain. This protein shares several properties with a major substrate of protein kinase C (myristoylated alanine-rich C kinase substrate; MARCKS). It is heat-stable and copurifies with MARCKS during various steps (ammonium sulfate precipitation and gel filtration). However, its elution from a calmodulin affinity column is different from that of MARCKS. It can be eluted by high ionic strength in the presence of calcium, whereas MARCKS can be eluted only in the absence of calcium. Its earlier elution from a reversed phase column suggests that p70 is less hydrophobic than MARCKS. The electrospray mass spectrum revealed an actual mass of 31,550 +/- 6.5 Da, very far from the apparent molecular mass in SDS-polyacrylamide gel electrophoresis (70,000 Da). This mass is about 200 Da smaller than that of MARCKS determined by mass spectrometry analysis (Manenti, S., Sorokine, O., Van Dorsselaer, A., and Taniguchi, H. (1992) J. Biol. Chem. 267, 22310-22315), close to the value expected for the change due to N-terminal myristoylation (210 Da). N-terminal amino acid sequencing showed that the N terminus is not blocked, and the sequence found for the 10 first amino acids is identical to that deduced from the cDNA sequence of bovine MARCKS. These data clearly establish that this protein is a non-myristoylated form of MARCKS and that the absence of the myristoyl moiety at the N terminus lowers the affinity to calmodulin. The purification performed both from the membrane and the cytoplasmic fractions of bovine brain indicated that this non-myristoylated form represents 20-30% of the MARCKS protein in the cytoplasmic fraction, and less than 5% in the membrane one.
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PMID:Isolation of the non-myristoylated form of a major substrate of protein kinase C (MARCKS) from bovine brain. 846 17

An active ribosomal protein S6 kinase has been highly purified from the membranes of rabbit reticulocytes by chromatography of the Triton X-100 extract on DEAE-cellulose, SP-Sepharose Fast Flow, and by FPLC on Mono Q and Superose-12. The S6 kinase elutes around 40 000 daltons upon gel filtration on Superose-12 or Sephacryl S-200. It has a subunit molecular weight of 40-43 kDa as determined by protein kinase activity following denaturation/renaturation in SDS-polyacrylamide gels containing S6 peptide. It also phosphorylates translational initiation factors eIF-2 and eIF-4F, glycogen synthase, histone 1, histone 2B, myelin basic protein, but not prolactin, skeletal myosin light chain, histone 4, tubulin, and casein. Apparent Km values have been determined to be 15 microM for ATP, 1.2 microM for S6 and 10 microM for S6 peptide. Two-dimensional tryptic phosphopeptide mapping shows the same sites on S6 are phosphorylated as those identified previously with proteolytically activated multipotential S6 kinase from rabbit reticulocytes, previously denoted as protease activated kinase II. Examination of relative rates of phosphorylation and kinetic constants of synthetic peptides based on previously identified phosphorylation sites, indicates a minimum substrate recognition sequence to be arginine at the n - 3 position. Based on these characteristics, including molecular weight and an expanded substrate specificity, the membrane S6 kinase can be distinguished from the p90 (Type I) and p70 (Type II) S6 kinases, and from protein kinase C and the catalytic subunit of cAMP-dependent protein kinase.
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PMID:A membrane-bound protein kinase from rabbit reticulocytes is an active form of multipotential S6 kinase. 859 70

The ventricular myocyte is a terminally-differentiated cell that can no longer undergo cell division. In response to a variety of stimuli, including exposure to endothelin-1, phenylephrine or mechanical stretch, the myocyte increases its size and its complement of organized myofibrils. These adaptational changes during myocyte hypertrophy are accompanied by distinct changes in gene expression. The signalling cascades that initiate these changes are currently under intensive investigation. Many hypertrophic agonists activate protein kinase C (PKC). Transfection of ventricular myocytes with constitutively-active PKC isoforms initiates the changes in gene expression typical of the hypertrophic response. Similarly, the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway can be activated by a variety of hypertrophic agents. Transfection of ventricular myocytes with components of this pathway has demonstrated that MAPK is essential for the changes in gene expression associated with the development of hypertrophy. However a Ras-dependent, but Raf-independent, pathway may regulate the organization of the contractile apparatus. Other protein kinases, such as ribosomal S6 kinases, p90RSK or p70/p85S6K, which are poorly characterized in the ventricular myocyte, may also regulate changes in gene expression. Further research is required to investigate cross-talk between these signal transduction pathways so that the spatial and temporal relationships that integrate the multiple signaling events leading to the adaptational growth of the ventricular myocyte may be understood.
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PMID:The role of protein kinases in adaptational growth of the heart. 862 39

Insulin activates rapidly a complex cascade of lipid and protein kinases leading to stimulation of mitogenic and metabolic events. Here we describe a renaturable kinase of 65 kDa (PK65) that becomes rapidly activated by insulin in differentiated L6 muscle cells (myotubes) and can phosphorylate histones immobilized in polyacrylamide gels. Insulin activation of PK65 was abolished by the tyrosine kinase inhibitor erbstatin and by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, but was unaffected by inhibitors of protein kinase C or of the activation of p70(S6K). Recently, a number of protein kinases have been described which become activated through interaction with the small GTP-binding proteins Rac and Cdc42 (21-ctivated inases, or PAKs) and lead to activation of the stress-induced mitogen-activated protein kinase (MAPK) p38 MAPK. Two different polyclonal antibodies recognizing the carboxyl-terminal or the Rac-binding domain of a 65-kDa PAK (PAK65) immunoprecipitated the myotube PK65. The insulin-induced activation of PK65 in myotubes was detectable following immunoprecipitation of the kinase. Furthermore, PK65 associated with and became activated by glutathione S-transferase-Cdc42Hs in the presence of GTPgammaS (guanosine 5'-3-O-(thio)triphosphate). In myotubes insulin also induced tyrosine phosphorylation of p38 MAPK. However, this phosphorylation was insensitive to wortmannin, indicating that p38 MAPK is not activated by PK65 in insulin-stimulated cells. The results suggest that insulin activates in muscle cells a renaturable kinase (PK65) closely related to PAK65. Tyrosine kinases and PI 3-kinase act upstream of PK65 in the insulin signaling cascade. Insulin activates p38 MAPK in myotubes, but this occurs by a pathway independent of PI 3-kinase and PK65.
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PMID:Insulin activates a p21-activated kinase in muscle cells via phosphatidylinositol 3-kinase. 870 68


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