Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Past work identified and characterized an apparently novel protein kinase activity (designated HMK) that is highly and transiently stimulated in PC12 pheochromocytoma cells by nerve growth factor (NGF). In vitro, HMK phosphorylates both high molecular weight microtubule-associated proteins and myelin basic protein. This study investigates the potential mechanisms of HMK regulation in intact PC12 cells and reveals the following. 1) HMK activation is independent of macromolecular synthesis while the subsequent post-induction suppression requires both RNA and protein synthesis. 2) Neither cAMP-dependent nor Ca2+/phospholipid-dependent protein kinases appear to play a role in regulation of HMK activity by NGF. 3) In vitro, HMK activity is inactivated by protein phosphatase 2A. 4) In vivo, HMK activation by NGF is inhibited by the kinase inhibitor, K-252a. (5) Vanadate, a tyrosine phosphatase inhibitor, induces HMK activity in intact cells, while okadaic acid, a serine/threonine phosphatase inhibitor, is much less efficacious. 6) Application of okadaic acid to vanadate-pretreated cells synergistically stimulates HMK activity to a level comparable to that achieved with NGF. (7) Activation of HMK by NGF is not significantly affected when cells are pretreated with okadaic acid. However, the subsequent NGF-promoted deactivation of HMK is greatly accelerated by okadaic acid. (8) NGF down-regulated HMK activity can be heterologously restimulated by exposure to vanadate and okadaic acid. These data suggest that phosphorylation plays a critical role in both the up- and down-regulation of HMK activity in NGF-treated cells. Moreover, suppression of HMK activity requires ongoing macromolecular synthesis and appears to occur by inactivation rather than degradation.
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PMID:The roles of macromolecular synthesis and phosphorylation in the regulation of a protein kinase activity transiently stimulated by nerve growth factor. 207 85

Eukaryotic cell cycle progression during meiosis and mitosis is extensively regulated by reversible protein phosphorylation. Many cell surface receptors for mitogens are ligand-stimulated protein-tyrosine kinases that control the activation of a network of cytoplasmic and nuclear protein-serine (threonine) kinases. Over 30 plasma membrane associated protein-tyrosine kinases are encoded by proto-oncogenes, i.e., genes that have the potential to facilitate cancer when disregulated. Proteins such as ribosomal protein S6, microtubule-associated protein-2, myelin basic protein, and casein have been used to detect intracellular protein-serine (threonine) kinases that are activated further downstream in growth factor signalling transduction cascades. Genetic analysis of yeast cell division control (cdc) mutants has revealed another 20 or so protein-serine (threonine) kinases. One of these, specified by the cdc-2 gene in Schizosaccharomyces pombe, has homologs that are stimulated during M phase in maturing sea star and frog oocytes and mammalian somatic cells. Furthermore, during meiotic maturation in these echinoderm and amphibian oocytes, this is followed by activation of many of the same protein-serine (threonine) kinases that are stimulated when quiescent mammalian somatic cells are prompted with mitogens to traverse from G0 to G1 phase. These findings imply that a similar protein kinase cascade may oversee progression at multiple points in the cell cycle.
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PMID:Protein kinase cascades in meiotic and mitotic cell cycle control. 208 30

The present study provides evidence that rat brain protein kinase C elicits a phosphotransferase activity towards histone and undergoes autophosphorylation in the absence of phosphatidylserine. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate binds to and activates protein kinase C in a phospholipid-free reaction. The apparent activation constant (Ka = 2.7 nM) is not modified by the absence of phospholipid but the maximum velocity is greatly decreased. The phosphotransfer reaction to exogenous substrates occurs in 0.5 mM ethylene-bis(oxyethylenenitrilo)tetraacetic acid, although autophosphorylation in these conditions requires the presence of Ca2+. The protein kinase C inhibitor (1-(5-isoquinolinesulfonyl)-2-methylpiperazine inhibits the reaction, whereas the cAMP-dependent protein kinase inhibitor is ineffective. In contrast to diacylglycerol, which is a poor activator, unsaturated fatty acids potently activate the phospholipid-free reaction. Moreover, the substrate specificity is markedly changed, e.g., myelin basic protein and histone types VI-S and VII-S appear to be relatively better substrates in the phospholipid-free reaction. The data presented indicate that protein kinase C (or some individual isoforms) may function, at least partially, without binding to membrane phospholipid and suggest that this novel characteristic of phorbol esters may account for their tumor-promoting activity.
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PMID:Phorbol esters mediate phospholipid-free activation of rat brain protein kinase C. 210 68

Growth factor activation of serine/threonine protein kinases was studied by treating quiescent Swiss 3T3 cells with epidermal growth factor (EGF) and examining cytosolic extracts for protein kinase activity under conditions inhibitory to calcium- and cyclic nucleotide-dependent kinases. Cytosolic extracts of cells stimulated for 5 min were fractionated by Mono Q fast protein liquid chromatography. Eight peaks of kinase activity were resolved, of which five were stimulated by EGF treatment of cells. These peaks were revealed using the synthetic peptide Arg-Arg-Leu-Ser-Ser-Leu-Arg-Ala (S6 peptide), 40 S ribosomal S6 protein, glycogen synthase, microtubule-associated protein 2, and myelin basic protein as substrates. The peaks varied in the kinetics of their activation by EGF and in their response to insulin. Selected peaks were resolved further by sizing gel chromatography. The results together indicate that at least seven distinct fractions of cytosolic kinase activities are stimulated in Swiss 3T3 cells by EGF. One of these, which phosphorylates both S6 protein and S6 peptide, is similar to the S6 kinase characterized previously in this cell line by others. Four additional activities that also phosphorylate the S6 protein and S6 peptide appear unrelated to this enzyme. Finally, two kinase activities that phosphorylate both myelin basic protein and microtubule associated protein 2 are EGF stimulated. One is similar to an insulin-stimulated microtubule-associated protein 2 kinase described in other cell lines whereas the other seems to represent a novel activity. Several of these EGF-stimulated activities were inactivated by protein phosphatases, suggesting that they might be regulated by phosphorylation.
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PMID:Identification of multiple epidermal growth factor-stimulated protein serine/threonine kinases from Swiss 3T3 cells. 214 53

Although CD45 resembles the low Mr protein tyrosine phosphatases (PTPases) from human placenta in its specificity for phosphotyrosyl residues and absolute dependence on sulfhydryl compounds for activity, it also exhibits a number of distinguishing features. Most notably, it displayed substrate specificity in vitro, preferentially dephosphorylating myelin basic protein, over the other substrates tested, with high specific activity. Limited trypsinization of CD45 generated active fragments of approximately 65 kDa that were apparently derived exclusively from the intracellular segment of the molecule. These retained high activity against myelin basic protein, suggesting that this is an intrinsic feature of the PTPase domains and not the result of secondary interactions between the substrate and the putative ligand binding structure. With reduced carboxamidomethylated and maleylated lysozyme as substrate, CD45 was stimulated up to 12-fold by basic compounds such as spermine; divalent metal ions were also stimulatory, most notably Zn2+, which was previously identified as a potent inhibitor of the low Mr PTPases. CD45 was phosphorylated to high stoichiometry by casein kinase-2 (up to 1.5 mol/mol) and also by glycogen synthase kinase 3 (approximately 0.3 mol/mol) and protein kinase C (approximately 0.1 mol/mol); in all cases, no alteration in enzyme activity was detected following these modifications. Autophosphorylated preparations of epidermal growth factor receptor, insulin receptor, and p56lck protein tyrosine kinases were also substrates for CD45 in vitro.
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PMID:CD45, an integral membrane protein tyrosine phosphatase. Characterization of enzyme activity. 216 57

Acidic fibroblast growth factor (aFGF) receptor was purified from plasma membranes of bovine liver using Triton X-100 extraction, wheat germ lectin-Sepharose 4B gel affinity chromatography, and DEAE-cellulose anion-exchange chromatography. As previously reported for the aFGF receptor in murine fibroblasts (Huang, S. S., and Huang, J. S. (1986) J. Biol. Chem. 261, 9568-9571), the purified aFGF receptor was also found to be a 135-kDa glycoprotein which showed an intrinsic and ligand-stimulated autophosphorylation activity. The 32P-labeled aFGF receptor was specifically immunoprecipitated by anti-FGF receptor (anti-flg/bek/cek gene product) antiserum. In contrast to other growth factor receptors/protein tyrosine kinases, the protein tyrosine kinase activity (autophosphorylation) of the aFGF receptor was stimulated (approximately 1.5-fold) by low concentrations of Mn2+, Mg2+, and Ca2+ (optimal concentrations of approximately 0.1, approximately 0.1, and 1 microM, respectively) but inhibited by higher concentrations of Mn2+, Mg2+, Ca2+, and pyrophosphate (greater than or equal to 20, greater than or equal to 50, greater than or equal to 10, and greater than or equal to 100 microM, respectively). However, addition of Mn2+ and pyrophosphate at a ratio of 1:1 not only reversed the inhibitory effect but also enhanced the kinase activity about 3-4-fold. The apparent Km of ATP for intrinsic and ligand-stimulated protein kinase activity of the aFGF receptor was estimated to be 25 microM. The preferred exogenous substrates for the protein tyrosine kinase activity of the aFGF receptor were found to be myelin basic protein and histone. Poly-L-arginine, an inhibitor for aFGF binding to the receptor, appeared to stimulate the mitogenesis or cell growth of responsive cells by mimicking aFGF activity.
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PMID:Acidic fibroblast growth factor receptor purified from bovine liver is a novel protein tyrosine kinase. 216 90

An hepatic protein kinase that phosphorylates microtubule-associated protein 2 (MAP-2) on Ser/Thr residues is markedly activated after intraperitoneal injection of cycloheximide in the rat. The enzyme has been purified greater than 10,000-fold to near homogeneity and corresponds to a 54-kDa polypeptide, based on auto-phosphorylation, renaturation of activity from sodium dodecyl sulfate gels, and gel filtration. The protein kinase activity is unaffected by prior autophosphorylation, Ca2+, diacylglycerol and phospholipids, cyclic nucleotides, staurosporine, and protein kinase inhibitor, but can be totally and specifically deactivated by the Ser/Thr protein phosphatase 2A. The enzyme is inhibited completely but reversible by transition metals and p-chloromercuribenzoate, and is strongly stimulated by poly-L-lysine toward most, but not all protein substrates. The activity of the cycloheximide-stimulated MAP-2 kinase (pp54 MAP-2 kinase) toward potential polypeptide substrates was compared to that of an insulin-stimulated MAP-2 kinase (pp42 MAP-2 kinase). Although both MAP-2 kinases exhibited little or no ability to phosphorylate histones and casein, the two kinases had a distinguishable substrate specificity. At comparable MAP-2 phosphorylating activities, pp42 MAP-2 kinase, but not pp54 MAP-2 kinase, phosphorylated and activated the Xenopus S6 protein kinase II. Moreover, pp42 MAP-2 kinase phosphorylated myelin basic protein at 10-12-fold higher rates than did pp54 MAP-2 kinase. Cycloheximide-activated pp54 MAP-2 protein kinase appears to be a previously uncharacterized protein kinase that is itself regulated through Ser/Thr phosphorylation and, perhaps, polypeptide regulators with basic domains. The identity of the upstream regulatory elements and the native substrates remain to be established.
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PMID:pp54 microtubule-associated protein 2 kinase. A novel serine/threonine protein kinase regulated by phosphorylation and stimulated by poly-L-lysine. 217 Mar 74

We have previously found and characterized a mitogen-activated, serine/threonine-specific protein kinase that specifically phosphorylates microtubule-associated protein 2 (MAP2) in vitro, which we call here MAP2 kinase [Hoshi, M., Nishida, E. & Sakai, H. (1988) J. Biol. Chem. 263, 5396-5401; Hoshi, M., Nishida, E. & Sakai, H. (1989) Eur. J. Biochem. 184, 477-486]. In this study, we have found another serine/threonine-specific protein kinase that is activated by various mitogens. The activated kinase utilized microtubule-associated protein 1B (MAP1B) as the major substrate in vitro, so we tentatively call it MAP1B kinase (M1BK). M1BK was maximally activated 20-30 min after treatment of quiescent rat fibroblastic 3Y1 cells with epidermal growth factor (EGF), while MAP2 kinase was maximally activated within 5-10 min of EGF treatment. The EGF-activated M1BK was eluted at about 0.15 M NaCl on a DEAE-cellulose column, while the activated MAP2 kinase was eluted at about 0.1 M NaCl under the conditions used. The EGF-activated M1BK was eluted as a single peak just after the activated MAP2 kinase on an HPLC gel-filtration column. Histone, casein and ribosomal protein S6 were very poor substrates for the M1BK, while MAP2 and myelin basic protein were moderate substrates. The M1BK activity in cell extracts was inhibited by Ca2+, glycerol 2-phosphate and Zn2+, and slightly enhanced by heparin. These data suggested that M1BK is distinct from previously described mitogen-activated kinases such as MAP2 kinase, casein kinase II and S6 kinase. Pretreatment with cycloheximide or puromycin did not block the M1BK activation by EGF. Furthermore, incubation of the EGF-activated M1BK with acid phosphatase inactivated the kinase activity. Therefore, M1BK may be activated by phosphorylation in EGF-treated cells. In addition to EGF, 12-O-tetradecanoylphorbol 13-acetate, platelet-derived growth factor and insulin-like growth factor-I also induced the activation of M1BK in quiescent cells.
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PMID:Activation of a serine/threonine kinase that phosphorylates microtubule-associated protein 1B in vitro by growth factors and phorbol esters in quiescent rat fibroblastic cells. 222 68

A meiosis-activated myelin basic protein (MBP) kinase was purified approximately 8700-fold from soluble post-germinal vesicle breakdown extracts from maturing oocytes of the sea star Pisaster ochraceus. Purification to apparent homogeneity was achieved by sequential chromatography on DEAE-cellulose, hydroxylapatite, phosphocellulose, phenyl-Sepharose, heparin-Sepharose, polylysine-Sepharose, and Mono-Q. The final product exhibited an apparent molecular mass of approximately 42 kDa by both native gradient and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and this precisely correlated with the chromatographic behavior of the recovered MBP kinase activity on a Superose 6/12 column. The kinase utilized the MBP as the major substrate with little or no phosphorylation of histones (H1, H2A, or H2B), casein, phosvitin, protamine, or 40 S ribosomal proteins. The purified enzyme was relatively insensitive to high concentrations of beta-glycerol phosphate, calmodulin, EGTA, NaCl, sodium fluoride, dithiothreitol, spermine, and heparin but was quite sensitive to inhibition by metal ions such as Mn2+, Zn2+, and Ca2+. The true Km values for ATP and myelin basic protein were determined to be 58 and 25 microM, respectively, using double-reciprocal plots. The purified enzyme was unable to utilize GTP in place of ATP. The enzyme was shown to rapidly undergo autophosphorylation. The autophosphorylation was sensitive to alkali treatment implying that phosphate was incorporated on serine/threonine residues. The properties of this MBP kinase are reminiscent of a protein kinase that is also activated in a cyclic fashion at M-phase during the early cell divisions of sea star and sea urchin embryos (Pelech, S. L., Tombe, R., Meijer, L., and Krebs, E. G. (1988) Dev. Biol. 130, 26-36).
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PMID:Purification and characterization of a maturation-activated myelin basic protein kinase from sea star oocytes. 229 20

A cell-free assay has been developed to detect and characterize a nerve growth factor (NGF)-stimulated protein kinase activity in PC12 cells that phosphorylates high molecular weight microtubule-associated proteins (HMW-MAPs). The activity was partially purified and separated from other endogenous nonregulated HMW-MAP kinase activities by chromatography on heparin-Sepharose and Mono-Q resin. Characterization of the NGF-activated kinase (designated HMK) revealed the following features. 1) Both MAP1 and MAP2 are phosphorylated with approximately equal efficiencies. 2) Activation reaches a plateau within 3 min of NGF treatment and persists for approximately 60 min; subsequently, a substantial decline occurs by 5 h. 3) Maximal activation reaches 15-20-fold; activation is nearly as high with fibroblast growth factor, an agent that mimics NGF in promoting PC12 cell neuronal differentiation. 4) Epidermal growth factor and depolarizing levels of K+ stimulate HMK activity by only 2-4-fold; additional agents without PC12 cell differentiation activity (insulin, phorbol ester, and a permeant cAMP analogue) do not stimulate HMK activity. 5) The divalent cation requirement shows a preference for Mn2+ over Mg2+. 6) There is inhibition by 10 mM 2-aminopurine but not by 6-thioguanine, heparin, or NaF. 7) HMW-MAPs and myelin basic protein are effective substrates while histones IIIs and H1, dephospho-beta-casein, and S6 protein are not phosphorylated by HMK. These and other features appear to distinguish HMK from a variety of other well-characterized protein kinases as well as from other previously described NGF-activated kinases. The properties of HMK indicate that it could play a role in the signaling pathway for growth-factor-promoted neuronal differentiation.
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PMID:Nerve growth factor and fibroblast growth factor selectively activate a protein kinase that phosphorylates high molecular weight microtubule-associated proteins. Detection, partial purification, and characterization in PC12 cells. 239 35


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