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)

In Xenopus oocytes, initiation of maturation is dependent on reduction of cyclic AMP-dependent protein kinase (PKA) activity and the synthesis of the mos proto-oncogene product. Mos is required during meiosis I for the activation of both maturation-promoting factor (MPF) and mitogen-activated protein kinase (MAPK). Here we show that injection of the catalytic subunit of PKA (PKAc) prevented progesterone-induced synthesis of endogenous Mos as well as downstream MPF and MAPK activation. However, PKAc did not prevent injected soluble Mos product from activating MAPK. While MAPK is activated during Mos-PKAc coinjection, attendant MPF activation is blocked. Additionally, PKAc caused a potent block in the electrophoretic mobility shift of cdc25 that is associated with phosphatase activation. This inhibition of cdc25 activity was not reversed by progesterone, Mos, or MPF. We conclude that PKAc acts as a negative regulator at several points in meiotic maturation by preventing both Mos translation and MPF activation.
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PMID:Protein kinase A acts at multiple points to inhibit Xenopus oocyte maturation. 800 49

Receptor-bound growth factors elicit intracellular signals that lead to the phosphorylation and activation of numerous intracellular kinases and transcription factors with consequent changes in patterns of gene expression. Several oncogene products are able to mimic these signals, resulting in cell transformation and proliferation. For example, the introduction of oncogenic forms of Raf-1 kinase into fibroblasts induces transformation and leads to the constitutive expression of, among others, the c-fos proto-oncogene. Here it is shown that the elevation of c-fos promoter activity brought about by v-raf is mediated by TCF/Elk-1, which forms a ternary complex with SRF at the serum response element and is a substrate for mitogen-activating protein kinases in vitro. In NIH 3T3 fibroblasts, v-raf activates Erk2, and overexpression of an interfering mutant of Erk2 both blocks the ability of v-raf to activate the c-fos promoter and suppresses transformation. Mutation of individual mitogen-activating protein kinase phosphoacceptor sites in TCF/Elk-1 also compromises v-raf-activated expression of a Gal-Elk/Gal-chloramphenicol acetyltransferase reporter system. However, in at least one instance the introduction of glutamate, but not aspartate, at a phosphoacceptor site is compatible with activation. These results provide compelling evidence that phosphorylation of TCF/Elk-1 by Erk2 is a major link in the Raf-1 kinase-dependent signal transduction pathway that activates c-fos expression.
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PMID:Inhibition of v-raf-dependent c-fos expression and transformation by a kinase-defective mutant of the mitogen-activated protein kinase Erk2. 800 80

Malignant B lymphocytes from patients with B-chronic lymphocytic leukaemia (B-CLL) or hairy cell leukemia (HCL) are refractory in vitro to mitogenic stimulation by several agents which trigger proliferation of normal B cells. Tumour necrosis factor (TNF) is a growth factor for these malignant cells, although the proliferative response is usually small. TNF regulates some of its cellular responses via induction of the transcription factors NF kappa B and AP-1 (jun/fos). The induction of NF kappa B by TNF is mediated via a novel signalling pathway involving the generation of reactive oxidative intermediates. Induction of jun and fos proteins (polypeptide components of AP-1) are mediated via pathways involving protein kinase C and the protein kinase encoded by the raf proto-oncogene. Here we have used an electrophoretic mobility shift assay to show that TNF induced NF kappa B in malignant cells isolated from 3/3 HCL and 15/15 B-CLL patients. By contrast, phorbol myristate acetate (PMA), a direct activator of protein kinase C, failed to activate this transcription factor in 1/1 HCL and 5/5 B-CLL isolates. The induction of jun and fos proteins (as detected by Western blot analysis) showed greater heterogeneity. Nuclear jun was induced by TNF in 5/12 chronic B cell leukaemia isolates. PMA induced this protein in 4/5 samples. Nuclear fos was induced by TNF in only 2/12 isolates and by PMA in 2/5. The data suggest that the pathways for the activation of jun and fos by TNF are defective in some B-CLL and HCL cells and that these defects may be heterogeneous. The induction of AP-1 is crucial in securing the mitogenic response to TNF. It is therefore plausible that these lesions may contribute to the refractory nature of B-CLL and HCL cells to proliferative stimuli in vitro.
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PMID:Regulation of transcription factors NF kappa B and AP-1 following tumour necrosis factor-alpha treatment of cells from chronic B cell leukaemia patients. 804 32

The proto-oncogenes c-fms and c-kit belong to a family of growth factor receptors possessing protein kinase activity. It has been shown that transfection of a c-fms gene carrying a point mutation at codon 301, leads to a ligand-independent transformation of mouse NIH3T3 cells. In human acute myeloid leukemia (AML), point mutations at codon 301 of the c-fms gene have been observed implying an important role in the transformation process. The possibility of a point mutation of the c-kit proto-oncogene was investigated. We sequenced a segment of the c-kit proto-oncogene coding for a part of the extracellular domain. This segment was 40.7% homologous to the c-fms region encompassing codon 301. c-DNA was prepared from peripheral blood or bone marrow cells from 25 patients with AML, from four patients with myelodysplastic syndrome (MDS) and from three human myeloid cell lines. The region of interest was amplified with two rounds of polymerase chain reactions (PCR) with nested primers and directly sequenced. No point mutations were found in the investigated samples. Thus, point mutations in this segment of the c-kit gene do not seem to play an important role in the transformation process of human acute leukemia.
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PMID:Absence of point mutations in a functionally important part of the extracellular domain of the c-kit proto-oncogene in a series of patients with acute myeloid leukemia (AML). 812 54

Downstream mediators of insulin signaling are thought to include multiple cytoplasmic serine/threonine kinases such as the product of the cellular proto-oncogene c-raf-1. To investigate a role for the Raf-1 protein kinase in insulin-stimulated glucose transport, a gene encoding an oncogenically activated Raf-1 mutant was introduced into 3T3-L1 fibroblasts by retroviral gene transfer. Expression of activated Raf-1 in differentiated 3T3-L1 adipocytes markedly increases hexose uptake compared to control adipocytes or those infected with the retroviral vector. Basal 2-deoxyglucose uptake in adipocytes expressing activated Raf-1 is approximately 40-fold higher than in parental adipocytes, and insulin further increases uptake about 1.2-fold. As determined by the plasma membrane "sheet" assay, Raf-1-expressing adipocytes contain greatly elevated levels of the ubiquitous glucose transporter (GLUT1) on the cell surface in the absence or presence of insulin. Total cellular GLUT1 protein is increased about 5-fold. In contrast, activated Raf-1 affects neither the expression of the "insulin-responsive" glucose transporter (GLUT4) nor its cellular distribution; GLUT4 is virtually undetectable on the plasma membrane in the absence of insulin and translocates normally following the addition of hormone. These data suggest that activation of Raf-1 mediates the chronic effect of insulin on hexose uptake but is not sufficient for the rapid translocation of GLUT4. Moreover, the differential effects of activated Raf-1 expression on the two transporter isoforms define divergent signaling pathways by which insulin regulates glucose transport in cultured adipocytes.
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PMID:A role for Raf-1 in the divergent signaling pathways mediating insulin-stimulated glucose transport. 814 13

Many growth factors whose receptors are protein tyrosine kinases stimulate the MAP kinase pathway by activating first the GTP-binding protein Ras and then the protein kinase p74raf-1. p74raf-1 phosphorylates and activates MAP kinase kinase (MAPKK). To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. This represents the first characterization of sites phosphorylated by this proto-oncogene product. Ser217 and Ser221 lie in a region of the catalytic domain where the activating phosphorylation sites of several other protein kinases are located. Among MAPKK family members, this region is the most conserved, suggesting that all members of the family are activated by the phosphorylation of these sites. A 'kinase-dead' MAPKK1 mutant was phosphorylated at the same residues as the wild-type enzyme, establishing that both sites are phosphorylated directly by p74raf-1, and not by autophosphorylation. Only the diphosphorylated form of MAPKK1 (phosphorylated at both Ser217 and Ser221) was detected, even when the stoichiometry of phosphorylation by p74raf-1 was low, indicating that phosphorylation of one of these sites is rate limiting, phosphorylation of the second then occurring extremely rapidly. Ser217 and Ser221 were both phosphorylated in vivo within minutes when PC12 cells were stimulated with nerve growth factor. Analysis of MAPKK1 mutants in which either Ser217 or Ser221 were changed to glutamic acid, and the finding that inactivation of maximally activated MAPKK1 required the dephosphorylation of both serines, shows that phosphorylation of either residue is sufficient for maximal activation.
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PMID:Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. 815

The Met proto-oncogene product is a tyrosine kinase receptor whose ligand is hepatocyte growth factor (HGF). The Met protein is first synthesized in the hepatocytes as a single chain precursor, or p170MET proreceptor, and is then processed to a mature heterodimer receptor consisting of an extracellular alpha subunit (p50 alpha MET) and a transmembrane beta subunit (p 145 beta MET). The beta subunit has a protein kinase domain which is activated through phosphorylation on tyrosine residue by the binding of HGF to the receptor. In order to elucidate the function of the Met gene product in hepatic disorders, we analyzed the expression and tyrosine phosphorylation of the Met protein on regeneration and carcinogenesis of the liver. For studies on carcinogenesis we used human hepatoma tissues, and for studies on regeneration we used rat hepatectomy. Two antibodies were used for western blotting; a mouse monoclonal anti-phosphotyrosine antibody, which recognizes phosphorylated tyrosine residue in proteins, and a polyclonal rabbit anti-Met antibody, which recognizes the C-terminus of both the Met beta chains and proreceptor. To compare the amount of protein in each experiment, the results of western blotting were evaluated using an image analyzing system. In experiments involving rats with partial hepatectomy, a decreased expression of the proreceptor with a decreased amount of tyrosine phosphorylation was observed within 12 hours of hepatectomy. However, there were no significant changes of the Met beta subunit during the experiment. These data suggest that the Met proreceptor is decreased in the early stages of liver regeneration. In experiments on human samples surgically removed from 18 patients with hepatocellular carcinoma, the met proteins, p 145 beta MET and p 160 MET proreceptor, were expressed both in cancer tissues (12/18, and 10/18, respectively) and in non-cancer tissues (8/18, and 15/18, respectively). From the comparative analyses of the intensity of the signals in cancerous region against those of non-cancerous region in the 18 individual cases, it was demonstrated that expression of p 160 MET proreceptor was increased in non-cancerous region more significantly than in cancerous region (p < 0.05). On the contrary, expression of p145 beta MET was increased in cancerous region more significantly than in non-cancerous region (p < 0.05), except for a few cases of poorly differentiated carcinomas in which p 145 beta MET signal was not detected. These findings suggested that a processing pathway from the proreceptor to the mature Met receptor is amplified in carcinogenesis of the liver.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Analysis of the hepatocyte growth factor receptor in regeneration and oncogenesis of hepatocytes]. 815 55

Ligation of Ag receptors in T and B lymphocytes initiates signal transduction cascades which alter the expression of genes that regulate cellular proliferation and differentiation. The transmission of signals from the membrane to the nucleus is mediated principally through the action of protein tyrosine and serine/threonine kinases. We have identified and characterized a novel serine/threonine kinase that phosphorylated the proto-oncogene product, c-Fos, and is termed Fos kinase. Fos kinase was rapidly activated after ligation of the CD3 and CD2 receptors in Jurkat and normal human T lymphocytes and in response to IL-6 and anti-IgM in the human B cell lines AF10 and Ramos, respectively. The phorbol ester, PMA, was also a potent inducer of Fos kinase activity in all of the above populations, suggesting that PKC plays a role in the regulation of this enzyme. Fos kinase phosphorylates c-Fos at a site near the C-terminus, as well as a peptide derived from this region (residues 359-370, RKGSSSNEPSSD), and Fos peptide competitively inhibited c-Fos phosphorylation. Fos kinase was shown to be distinct from other identified serine/threonine kinases, including protein kinase A, protein kinase C, casein kinase II, MAP kinases, p70S6K and p90RSK. Fos kinase was purified by anion exchange chromatography and exhibited an apparent M(r) = 65,000 and isoelectric point = 6.1. Fos kinase may play a role in transcriptional regulation through its capacity to phosphorylate c-Fos at a site required for expression of the transcriptional transrepressive activity of this molecule. Moreover, its rapid activation suggests it may have a wider role within signal transduction cascades in lymphocytes.
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PMID:Activation of a novel serine/threonine kinase that phosphorylates c-Fos upon stimulation of T and B lymphocytes via antigen and cytokine receptors. 815 58

1,25-Dihydroxyvitamin D3's (D3) potential mitogenic mechanism of action was pursued in cultured rat hepatic Ito cells, a fibrogenic effector cell which proliferates in vivo during liver injury and fibrogenesis. D3 stimulated Ito cell DNA synthesis and potentiated platelet-derived growth factor-induced mitogenesis. D3's enhancement of [3H]thymidine incorporation was associated with nuclear Egr expression. Recent studies have causally linked the activated proto-oncogene c-Raf with downstream Egr induction. The serine-threonine kinase Raf protein is phosphorylation-activated by a large array of agonists including plasma membrane and cytoplasmic tyrosine kinases but has not previously been associated with the steroid superfamily of mediators. To consider potential prenuclear acute pathways of D3-induced stimulation, the activation of Raf was examined following D3 exposure. D3 induced Raf activation as assessed via (a) enhanced Raf phosphorylation following in vivo 32P labeling, (b) enhanced kinase function utilizing exogenous histone 1 protein as substrate, and (c) the shift in Raf physical localization changing from a diffuse cytoplasmic distribution to a perinuclear domain. A similar activation of Raf kinase was found in 3T3 cells exposed to D3 with enhanced histone phosphorylation detectable within 1 min following stimulation. The proximal cascade leading to Raf kinase activation may involve a protein kinase activity was severely attenuated by stimulated kinase activity was severely attenuated by previous phorbol ester treatment for 20 h or staurosporine pretreatment.
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PMID:1,25-Dihydroxyvitamin D3 activates Raf kinase and Raf perinuclear translocation via a protein kinase C-dependent pathway. 822 76

For successful allogenic pregnancy to occur, suppression of maternal defense responses toward the fetus are vital. Suppressor factors elaborated by decidual cells or immune cells may facilitate this suppression. In order for appropriate cellular responses to occur an intact signal transduction/second messenger system must be present. The calcium/phospholipid-dependent protein kinase, Pk-C, plays an important role in regulating immune responses, and may also be important in regulating uterine cell responses and implantation events. Pk-C activation is necessary for IL-2 synthesis and IL-2 receptor synthesis through activation of the proto-oncogenes c-jun and c-fos. These proto-oncogene gene products combine to form the heterodimer AP-1 which then activates IL-2 gene transcription for both peptide and receptor. If Pk-C activity becomes abrogated then appropriate cell responsiveness is diminished. We have shown that Pk-C activity is decreased in the particulate fraction of 4-7 day pregnant spleen, thymus and draining lymph node (DLN) cells. Spleen cells did not exhibit any change in cytosolic Pk-C activity, the thymus was found to have a decrease in both cytosol and particulate fractions, and the DLN cells exhibited a translocation effect whereby particulate Pk-C decreased and cytosolic Pk-C activity increased. Supernatant from 3-day cultures of DLN cells from pregnant animals was shown to inhibit proliferation of spleen cells. In addition, the supernatant was able to directly lower Pk-C activity. We hypothesize that DLN cells secrete a factor(s) that is able to suppress immune response through abrogation of Pk-C activity, thereby decreasing AP-1 formation resulting in decreased IL-2 synthesis and IL-2 receptor synthesis.
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PMID:Pregnancy-associated, lymphocyte-derived suppressor factor inhibits protein kinase C activity. 822 96


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