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)

The mitogen-activated protein (MAP) kinases are serine-threonine protein kinases that are activated by tyrosine and threonine phosphorylation by the dual specificity protein kinase MEK (MAP kinase/ERK kinase). The present report describes the purification to near homogeneity and characterization of a protein tyrosine phosphatase from Xenopus laevis eggs that dephosphorylates MAP kinase phosphorylated by MEK. Bacterially expressed Xenopus MAP kinase phosphorylated by purified Xenopus MEK was used as substrate throughout the purification. The purification procedure included anion-exchange, cation-exchange, gel filtration, heparin-Sepharose, and chromatography on a column of thiophosphorylated MAP kinase-Sepharose, resulting in a > 3000-fold purification. Upon analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a protein of 47 kDa correlated with activity. The phosphatase showed absolute specificity toward phosphotyrosine and no activity toward phosphothreonyl-phosphoseryl residues of MAP kinase. The pH optimum of the enzyme was 7.0 with a Km of 9.0 microM for phosphorylated MAP kinase. The phosphatase was inhibited by ammonium molybdate (IC50, 2 microM), vanadate (IC50, 250 microM), millimolar concentrations of MnCl2, ZnCl2 and p-nitrophenylphosphate but not by okadaic acid or microcystin. This tyrosine phosphatase may be involved in deactivating MAP kinase in vivo.
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PMID:Purification and characterization of a mitogen-activated protein kinase tyrosine phosphatase from Xenopus eggs. 822 71

Tyrosine kinases and tyrosine phosphatases are abundant in central nervous system tissue, yet the role of these enzymes in the modulation of neuronal excitability is unknown. Patch-clamp studies of an Aplysia voltage-gated cation channel now demonstrate that a tyrosine phosphatase endogenous to excised patches determines both the gating mode of the channel and the response of the channel to protein kinase A. Moreover, a switch in gating modes similar to that triggered by the phosphatase occurs at the onset of a prolonged change in the excitability of Aplysia bag cell neurons.
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PMID:Mode-switching of a voltage-gated cation channel is mediated by a protein kinase A-regulated tyrosine phosphatase. 824 51

Members of the cdc25 phosphatase family are proposed to function as important regulators of the eukaryotic cell cycle, particularly in the induction of mitotic events. A new cdc25 tyrosine phosphatase, cdc25M1, has been cloned from a mouse pre-B cell cDNA library and characterized. The cdc25M1 protein consists of 465 amino acids with a predicted relative molecular mass (M(r)) of 51,750. Over the highly conserved carboxyl terminal region, the amino acid sequence similarity to the human cdc25 C or Hs1 isoform is 89%, while the overall similarity is 67%. The phosphatase active site is located within residues 367-374. Tissue expression of the cdc25M1 was highest in mouse spleen and thymus by northern blot analysis. The cdc25M1 mRNA was detected in a number of cloned mouse lymphocyte cell lines including both CD8+ and CD4+ cells. cdc25M1 mRNA was shown to be cell cycle-regulated in T cells following interleukin-2 (IL-2)-stimulation. Accumulation of cdc25M1 mRNA occurred at 48 h after IL-2 stimulation, when lymphocytes were progressing from S phase to G2/M phase of the cell cycle. This pattern of expression is in contrast to that observed for other protein tyrosine phosphatases expressed in T lymphocytes including CD45, LRP, SHP, and PEP. The elevation in cdc25M1 mRNA level occurred concomittant to the appearance of the hyperphosphorylated form of p34cdc2 protein kinase. A purified, bacterial-expressed recombinant cdc25M1 phosphatase domain catalyzed the dephosphorylation of p-nitrophenol phosphate, as well as [32P-Tyr] and [32P-Ser/Thr]-containing substrates. Preincubation of p34cdc2 kinase with cdc25M1 activated its histone H1 kinase activity in vitro. These results suggest that cdc25M1 may be involved in regulating the proliferation of mouse T lymphocytes following cytokine stimulation, through its action on p34cdc2 kinase.
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PMID:Cloning and characterization of a cdc25 phosphatase from mouse lymphocytes. 827 63

We have examined the negative regulation of the 44-kDa mitogen-activated protein kinase (MAP kinase), also known as extracellular signal-regulated protein kinase 1 (ERK1), in NIH3T3 cells transfected with an expression plasmid encoding the human insulin receptor (NHIR cells). In these cells ERK1 activation is induced by two distinct stimuli, insulin and tumor-promoting agent (TPA). While insulin was found to be more potent than TPA for ERK1 activation, both stimuli produced the same transient activation pattern with a rapid peak (reached within 5 min) followed by a fast decrease within 20 min. By performing reconstitution experiments with immunoprecipitated ERK1 and lysates from NHIR cells, we showed that extracts from untreated cells exhibit an ERK1 inhibitory activity. Interestingly, this inhibitor was found to be regulated by insulin and TPA with a profile that is the mirror image of ERK1 activity. This repressing activity was sensitive to tyrosine phosphatase inhibitors, such as sodium orthovanadate and zinc acetate, but it was not affected by serine/threonine phosphatase inhibitors, such as sodium fluoride and okadaic acid. Moreover, it was possible to observe in extracts of NHIR cells an activity dephosphorylating ERK1. The time course of this phosphatase activity was comparable to that of the ERK1 inhibition, suggesting that the repressing activity could reflect a dephosphorylating action. Interestingly, phosphatase 2A treatment of extracts from 5-min TPA-treated cells (where the ERK1 inhibitor was weak) was able to induce an increase in the ERK1 repressing activity. This suggests that serine/threonine dephosphorylation of ERK1 inhibitor leads to an increase in its activity. In summary, we have shown that NHIR cells contain a regulatable ERK1 inhibitor, which is likely to be due to tyrosine phosphatase(s). We would like to suggest that such activities are key components in the fine-tuning of the MAP kinase cascade.
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PMID:Insulin and tumor-promoting agent regulate an inhibitor of the 44-kDa mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1 in fibroblasts. 828 32

In rheumatoid arthritis and other inflammatory diseases we and others have found that gamma delta T cells express activation antigens, suggesting that they are involved in the pathogenesis of these disorders. In this study we have stimulated peripheral blood mononuclear cells from normal donors with recombinant interleukin-2 (rIL-2) to see whether such a stimulus alone could activate gamma delta T cells. Short-term exposure (24-96 h) to rIL-2 selectively stimulated the gamma delta but not the alpha beta T cells to express activation antigens (CD69, CD25 and HLA-DR). Long-term culture (2 weeks) in rIL-2-containing medium caused a selective increase in the proportion of the gamma delta T cells and a corresponding reduction of the fraction of alpha beta T cells. Limiting dilution analysis revealed that approximately 1/60 of the gamma delta T cells responded to IL-2 in contrast to only 1/250 of the alpha beta T cells. Comparison of the expression of the IL-2 receptor (IL-2R) alpha and beta chains showed that there was a similar expression of the alpha chain on gamma delta and alpha beta T cells whereas the relative density of the beta chain was more than twice as high on gamma delta T cells. Both the IL-2-induced proliferation of gamma delta T cells and the expression of activation antigens on these cells could be inhibited by an anti-IL-2R beta monoclonal antibody (mAb) but not by an anti-IL-2R alpha mAb. Expression of CD69 on gamma delta T cells was dependent neither on the presence of B cells, monocytes, nor alpha beta T cells. Finally, we found that the IL-2-induced expression of CD69 was inhibited by activation of cAMP-dependent protein kinase and by inhibition of the Src-family of the tyrosine protein kinase, but not by inhibition of protein kinase C or by activation of the CD45 associated tyrosine phosphatase. The ability of gamma delta T cells to be activated by IL-2 is a feature which they have in common with natural killer cells. Moreover, it may be possible that the expression of activation antigens on gamma delta T cells in inflammatory diseases is an epiphenomenon secondary to IL-2 produced by activated alpha beta T cells.
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PMID:Selective activation of resting human gamma delta T lymphocytes by interleukin-2. 837 Mar 91

Although G-protein- and protein kinase-mediated pathways have been reported to activate phospholipase D (PLD) following cell stimulation, the relation between these activation pathways and the mechanistic details of lipase stimulation remain unknown. We have studied activation of PLD by GTP gamma S (guanosine 5'-O-(thiotriphosphate)), and its potentiation by ATP, in a cell-free system derived from U937 human promonocytic leukocytes. ATP, in the micromolar to millimolar range, significantly augmented GTP gamma S-stimulated PLD activity (2.6-fold) and the combination resulted in a 15-fold increase in PLD activity compared to control. ATP alone did not stimulate PLD activity. Measurement of endogenous cytosolic ATP levels and nucleotide depletion with activated charcoal demonstrated that stimulation of PLD by GTP gamma S proceeds by both ATP-dependent and -independent pathways. Nucleotide specificity data suggested that the ATP-dependent pathway involves kinase activity. The tyrosine phosphatase inhibitor vanadate augmented PLD activity stimulated by GTP gamma S/ATP by 41% (p < 0.01). Conversely, the tyrosine kinase inhibitors genistein and herbimycin A decreased PLD activity stimulated by GTP gamma S/ATP by 58 and 35%, respectively (p < 0.001 for each). Mixing experiments utilizing subcellular fractions from herbimycin A-treated cells suggested that the relevant tyrosine kinase activity is membrane-associated. Despite its role in ATP-induced potentiation, tyrosine kinase activity is neither necessary nor sufficient for activation of PLD in this system. Protein kinase C (PKC) is unlikely to play a role in potentiation by ATP as PKC activity is not stimulated under conditions of maximal PLD activation.
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PMID:ATP-induced potentiation of G-protein-dependent phospholipase D activity in a cell-free system from U937 promonocytic leukocytes. 837 59

Interaction of interferon alpha (IFN alpha) with its cell surface receptor rapidly activates the formation of the transcription complex ISGF3, which subsequently translocates to the nucleus and stimulates the expression of a variety of early response genes. We have recently developed a cell-free system where IFN alpha can activate the formation of ISGF3 in vitro. This system has enabled us to demonstrate that the component of the ISGF3 transcription complex which is modified by IFN alpha treatment (ISGF3 alpha) is membrane-associated and that its activation involves a protein kinase. Using a combination of specific tyrosine kinase and phosphatase inhibitors and monoclonal anti-phosphotyrosine antibodies we now are able to demonstrate that IFN alpha-activated transcription involves at least a two-step process where a membrane-associated tyrosine phosphatase and a tyrosine kinase lead to modification of ISGF3 alpha and subsequent formation of the complete complex. Furthermore, formation of the ISGF3 complex is specifically disrupted by protein tyrosine phosphatase and can be reversibly dissociated by the phosphotyrosine analogue phenylphosphate. The latter observation suggested that SH2 and/or SH3 domains may be required for the stable formation of this transcription complex.
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PMID:In vitro activation of the transcription factor ISGF3 by interferon alpha involves a membrane-associated tyrosine phosphatase and tyrosine kinase. 845 30

Prostaglandin F2 alpha (PGF2 alpha) stimulates DNA synthesis in osteoblasts through phospholipase-C-dependent increases in intracellular calcium and protein kinase-C (PKC) activity. We present evidence that stimulation of protein tyrosine phosphorylation by PKC is an additional component of the signaling pathways involved in PGF2 alpha-stimulated DNA synthesis in MC3T3-E1 osteoblast-like cells. Mitogenic doses of PGF2 alpha (42 nM) rapidly induced tyrosine phosphorylation of multiple substrates in these osteoblast-like cells. PGF2 alpha stimulated tyrosine phosphorylation of new proteins with apparent mol wt of 87, 80, 50, 47, 36, and 33 kilodaltons and up-regulated phosphorylation of preexisting tyrosine components with mol wt of 123, 112, 68, and 56 kilodaltons. Stimulation of PKC by 1.6 microM phorbol 12-myristate 13-acetate mimicked the pattern of PGF2 alpha-induced protein tyrosine phosphorylation, whereas PKC-deficient cells (induced by overnight pretreatment with 16 microM phorbol 12-myristate 13-acetate) were refractory to PGF2 alpha-stimulated protein tyrosine phosphorylation and DNA synthesis. The tyrosine kinase inhibitors tyrphostin and genistein blocked PGF2 alpha-stimulated DNA synthesis and protein tyrosine phosphorylation, and the tyrosine phosphatase inhibitor orthovanadate prolonged PGF2 alpha-stimulated tyrosine phosphorylation; these findings are consistent with activation of a putative tyrosine kinase. Calcium/calmodulin antagonists also inhibited PGF2 alpha-stimulated DNA synthesis, but the calcium-signaling pathway played no role in PGF2 alpha-induced tyrosine phosphorylation. Our findings suggest that cross-talk between receptor-mediated activation of PKC and protein tyrosine phosphorylation is an important distal signaling pathway necessary for PGF2 alpha-induced DNA synthesis in osteoblast-like cells.
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PMID:Prostaglandin F2 alpha-induced mitogenesis in MC3T3-E1 osteoblasts: role of protein kinase-C-mediated tyrosine phosphorylation. 846 49

Resistance to FCE 24517 is not related to the emergence of any of the most frequently observed phenotypes. We have found that two resistant cell lines (L1210/24517 murine leukaemia and LoVo/24517 human colon adenocarcinoma) present congenital modifications in tyrosyl phosphatase and kinase activities. Moreover, the cytotoxic activity of FCE 24517 is increased in combination with a tyrosine phosphatase inhibitor and decreased in combination with protein kinase inhibitors, this being in agreement with the hypothesis that the activity of this drug is strictly dependent on the presence of tyrosine phosphorylated protein(s).
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PMID:Decreased tyrosine phosphorylation in tumour cells resistant to FCE 24517 (tallimustine). 851 67

The experiments reported herein have characterized the signaling pathway leading to stimulation of type I protein kinase A isozyme (PKA-I) activity during the early events of Ag receptor-mediated T cell activation. Inhibitor studies demonstrated that receptor-initiated activation of nonreceptor protein tyrosine kinases, phosphorylation and activation of phospholipase C-gamma 1, and activation of protein kinase C occur temporally and precede PKA-I activation. Bypass of both the TCR/CD3 complex and IL-1R and direct activation of protein kinase C by a phorbol ester can also activate PKA-I. To confirm that PKA-I activation via the TCR/CD3 complex and IL-1R requires antecedent protein tyrosine kinase-catalyzed phosphorylation of phospholipase C-gamma 1, we used wild-type and CD45-deficient (mutant J45.01) Jurkat T cell lines. Unlike wild-type Jurkat T cells, the absence of CD45 tyrosine phosphatase resulted in the failure of receptor-mediated activation of PKA-I activity and of IL-2 mRNA transcription in the mutant J45.01 Jurkat cell line. In conclusion, our data support the concept that a signal derived from ligand binding to both the TCR/CD3 complex and IL-1R receptor mediates rapid activation of the PKA-I isozyme in primary T lymphocytes by sequential activation of an intracellular pathway comprised of CD45 phosphatase/protein tyrosine kinase/polyphosphoinositide/Ca2+/protein kinase C pathway rather than via the conventional surface receptor/stimulatory G protein system.
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PMID:Activation of type I protein kinase A during receptor-mediated human T lymphocyte activation. 854 99


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