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)

Urokinase-type plasminogen activator (uPA) gene transcription is increased > or = 50-fold in chicken embryo fibroblasts (CEF) following transformation by the protein tyrosine kinase pp60v-src. Protein phosphorylation appears to play a critical role in uPA gene expression in these cells; protein kinase C-activating phorbol esters cooperate with pp60v-src to synergistically increase uPA mRNA, whereas cyclic AMP (cAMP)-dependent protein kinase-activating agents (e.g., 8-bromo cAMP) repress uPA mRNA levels. To explore the relationship between transforming oncogenes and uPA gene expression, uPA mRNA levels were measured in CEF infected with selected avian retroviruses. We report that v-ras and the transforming protein tyrosine kinases v-src, v-yes, and v-ros all increase cellular uPA mRNAs. However, transformation with the protein tyrosine kinase encoded by v-erbB, or the nuclear proteins encoded by v-jun, v-ski, or v-myc, did not increase uPA mRNA detectably. Ras and all of the protein tyrosine kinases analyzed, including the v-erbB product, but none of the nuclear oncoproteins sensitized cells to phorbol ester induction of uPA gene expression. Thus, increased uPA gene expression is not simply a secondary consequence of cell transformation but, rather, is regulated or comodulated by only a subset of oncogene products. Analysis of cells expressing site-directed mutants of pp60v-src showed that the induction of the uPA gene is dependent on protein tyrosine kinase catalytic activity, myristylation, and plasma membrane localization. However, these properties together are not sufficient; an additional feature in the src homology 2 domain is also required. The major sites of serine phosphorylation, serines 12 and 17, and the autophosphorylation site, tyrosine 416, are not essential for uPA gene induction. However, the reduction of uPA mRNA in pp60v-src-transformed cells by 8-bromo cAMP is dependent on tyrosine 416.
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PMID:Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases. 768 54

The expression of thyroglobulin and other thyroid-specific markers depends upon the activation of protein kinase A (PKA) by cyclic AMP. A rat thyroid cell line dedifferentiates when transformed with Ki-ras oncogene. The decrease in thyroglobulin gene expression parallels a reduction in the level of PKA nuclear catalytic subunit. We find that the activity of cAMP-responsive elements and thyroglobulin promoters is down-regulated in Ras-transformed cells. Transcription of a third cAMP-regulated gene, H-ferritin, is similarly reduced. cAMP-responsive element and H-ferritin expression were stimulated when intracellular cAMP levels were increased. Reactivation of the thyroglobulin promoter required depletion of PKC in addition to increased cAMP. We also find that v-Ras activation leads to a significant increase in membrane-bound PKC. These data support the idea that v-Ras via PKC inhibits the transmission of cAMP-PKA signals to the nucleus. We suggest that the thyroglobulin promoter is more sensitive than other cAMP-dependent promoters to reduced nuclear levels of PKA catalytic subunit.
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PMID:Ki-ras oncogene interferes with the expression of cyclic AMP-dependent promoters. 771 89

Activation of mitogen-activated protein kinase (MAP kinase) plays an important role in the cellular effects of nerve growth factor (NGF). Although the precise pathway by which NGF activates MAP kinase is not clear, several enzymes have been identified that may form a linear phosphorylation cascade, in which MAP kinase is activated by MAP kinase kinase (MEK). A key enzyme that links the ras-GTP complex to MEK is widely believed to be the raf kinase. However, immunoprecipitation experiments in PC-12 cells revealed that raf is not the major NGF-dependent MEK kinase [Zheng, Ohmichi, Saltiel and Guan (1994) Biochemistry 33, 5595-5599]. We have identified a protein kinase from PC-12 cells that catalyses both the phosphorylation and activation of MEK. This activity is stimulated 3-fold in cells treated with NGF. The partial purification on FPLC and characterization of this MEK kinase indicate that it is distinct from raf, MEK, MAP kinase and other previously described NGF-stimulated protein kinases. The activity of this enzyme is unaffected by direct addition to the assay of heparin, staurosporine, K252A and the heat-stable cyclic AMP-dependent kinase peptide inhibitor, but is slightly inhibited by NaF and calcium ions. Comparison of its behaviour on gel permeation and sucrose-density gradients indicates a molecular mass in the region of 50,000 Da. Moreover, isoelectric focusing of the enzyme revealed a pI of approx. 7.3. The kinase activity is specific for ATP as substrate with a Km of 11 microM, and requires Mg2+ as a cofactor. Analysis of the activation of this enzyme in PC-12 cells transfected with a dominant inhibitory mutant of p21ras suggests that this MEK kinase resides downstream of ras in the MAP kinase activation pathway. Moreover, site-directed mutation of the residues on MEK that are phosphorylated by raf does not completely abrogate phosphorylation by the MEK kinase, suggesting that this enzyme may share some phosphorylation sites with raf, but also phosphorylates MEK on other sites.
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PMID:Nerve growth factor stimulates a novel protein kinase in PC-12 cells that phosphorylates and activates mitogen-activated protein kinase kinase (MEK). 773 91

Growth of thyroid cancer cells is stimulated by various growth factors via signal transduction pathways. TSH, EGF, IGF, and TGF-alpha stimulate and TGF-beta inhibits thyroid cell growth. TSH stimulates thyroid cells via both the adenylate cyclase-PKA and the PLC-PKC-Ca signal transduction pathways. TSH-r, ras, gsp, ret, trk, and myc are oncogenes that are activated in some thyroid neoplasms. P53 and RB are tumor suppressor genes that are inactivated in some thyroid cancers.
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PMID:Thyroid growth factors, signal transduction pathways, and oncogenes. 774 50

Insulin's interaction with its receptor initiates a multitude of cellular effects on metabolism, growth, and differentiation. We recently described an insulin-mediated inhibition of nuclear protein phosphatase 2A (PP-2A), which is associated with an increase in phosphorylation of the transcription factor cAMP response element-binding protein. To clarify the role of nuclear PP-2A inhibition in the insulin signaling cascade, we examined the regulation of this phosphatase activity by insulin in Rat-1 fibroblasts overexpressing normal (HIRc) or mutant human insulin receptors (delta CT cells, deletion of a 43-amino acid C-terminal domain). The delta CT cells represent an excellent model of impaired metabolic and intact mitogenic action of insulin. Insulin inhibited nuclear PP-2A activity and enhanced cAMP response element-binding protein phosphorylation in HIRc cells, but not in delta CT cells. The delta CT cells exhibited normal ras activation and blunted mitogen-activating protein kinase phosphorylation and activation in response to insulin (16-fold in HIRc cells vs. 3-fold in delta CT cells), indicating that the mitogen-activating protein kinase pathway is important for the regulation of nuclear PP-2A activity by insulin. We conclude that insulin inhibits nuclear PP-2A activity, and that the carboxy-terminal domain of the insulin receptor is important for this effect.
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PMID:Insulin inhibits nuclear phosphatase activity: requirement for the C-terminal domain of the insulin receptor. 775 Apr 68

Activation of the mitogen-activated protein kinase (MAPK) pathway is believed to play a critical role in normal and pathophysiologic proliferation of mesangial cells. Recent studies have shown that MAP kinase activation by growth factors in other cell types involves activation of the low molecular weight G-protein ras and the protooncogene serine kinase c-raf-1. In this study the role of this pathway in rat renal mesangial cells was assessed. 20ng/ml of platelet-derived growth factor (PDGF), 10(-8) mol/L epidermal growth factor (EGF) as well as phorbol ester (10(-6) mol/L PMA) rapidly activated MAP kinase by 3-4 fold in these cells. PDGF and EGF, but not PMA were able to activate c-raf-1 and ras activity. Stimulation with inflammatory mediator PGE2 (50 mumol/L) or elevation of Intracellular cAMP by treatment of cells with forskolin (25 mumol/L) markedly blunted activation of MAP kinase induced by PDGF and EGF, but not PMA. Consistent with this observation, PGE2 abolished growth factor induced activation of c-raf-1. However, ras activation induced by growth factor was not affected by PGE2 and forskolin. These results suggest that MAP kinase activation can occur by at least two separate pathways in mesangial cells. Tyrosine kinase receptors activate MAP kinase through activation of ras and raf. This pathway can be blocked by PGE2 and elevation of cAMP, presumably by interfering with the ability of ras to activate raf. In addition, activation of protein kinase C by phorbol esters can activate MAP kinase in a ras/raf-independent manner. This pathway is not sensitive to inhibition by PGE2 or cAMP. It is likely that activation of each of these pathways, both resulting in a stimulated MAP kinase, will have different physiologic consequences in mediating mesangial cells growth.
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PMID:[Inhibition of growth factor stimulation of mitogen-activated protein kinase by prostaglandin E2 in rat renal mesangial cells]. 778 49

Follistatin is a 35-kilodalton monomer isolated from follicular fluid that acts on pituitary gonadotropes to suppress the production of FSH. Transfection of rat granulosa cells with specific oncogenes, such as simian virus 40 (SV40) DNA and Ha-ras oncogene, leads to their immortalization concomitant with preservation of their capacity for inducible steroidogenesis. Experiments were designed to investigate the regulation of follistatin messenger RNA (mRNA) accumulation upon stimulation with forskolin, 2-O-tetradecanol-phorbol-13-acetate (TPA), FSH, and hCG in four different granulosa cell lines. Granulosa cells were transfected with SV40 DNA alone (POGS5); with SV40 DNA and Ha-ras oncogene (POGRS1); with SV40 DNA, Ha-ras oncogene, and LH/CG receptor (GLHR15); or with FSH receptor (GFSHR17) expression plasmid. Cells were cultured to reach confluence and then stimulated for 6 or 24 h with ovine FSH (oFSH; 0.004-4 nM), hCG (9 nM), forskolin (50 microM), and TPA (50 nM), alone or in combination. In the POGS5 cell line, forskolin caused a 15-fold stimulation of follistatin mRNA after 24-h incubation. The POGRS1 cell line showed a time-dependent stimulation of follistatin gene expression induced by both forskolin (5.7-fold) and TPA (9.4-fold). In the GFSHR17 cells, forskolin, oFSH, and TPA induced an increase in follistatin mRNA. When oFSH (1.6 nM) was added to cells treated with forskolin (50 microM) or TPA (50 nM), no additional stimulation was observed. The GLHR15 cell line treated with hCG showed a 2.7-fold increase in follistatin mRNA accumulation within 6 h. Our data demonstrate that 1) follistatin mRNA is detectable and induced by forskolin and TPA in transformed granulosa cell lines that do not express the FSH or LH receptors; 2) in the GFSHR17 cell line, FSH, forskolin, and TPA caused a time- and dose-dependent regulation of the gene; and 3) follistatin gene expression is up-regulated by hCG in the GLHR15 cell line. We conclude that these transformed steroidogenic cell lines can serve as a useful model to study the regulation of follistatin gene expression, a peptide known to regulate pituitary and ovarian hormone secretion and differentiation of granulosa cells by its activin-binding action. Moreover, this gene can be regulated in immortalized granulosa cells by both the protein kinase A and protein kinase C pathways, although these cells express the large T antigen and the Ha-ras oncogenic proteins.
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PMID:Regulation of follistatin messenger ribonucleic acid in steroidogenic rat granulosa cell lines. 778 14

Mitogen-activated protein kinases (MAPKs) are activated upon a variety of extracellular stimuli in different cells. In macrophages, colony-stimulating factor 1 (CSF-1) stimulates proliferation, while bacterial lipopolysaccharide (LPS) inhibits cell growth and causes differentiation and activation. Both CSF-1 and LPS rapidly activate the MAPK network and induce the phosphorylation of two distinct ternary complex factors (TCFs), TCF/Elk and TCF/SAP. CSF-1, but not LPS, stimulated the formation of p21ras. GTP complexes. Expression of a dominant negative ras mutant reduced, but did not abolish, CSF-1-mediated stimulation of MEK and MAPK. In contrast, activation of the MEK kinase Raf-1 was Ras independent. Treatment with the phosphatidylcholine-specific phospholipase C inhibitor D609 suppressed LPS-mediated, but not CSF-1-mediated, activation of Raf-1, MEK, and MAPK. Similarly, down-regulation or inhibition of protein kinase C blocked MEK and MAPK induction by LPS but not that by CSF-1. Phorbol 12-myristate 13-acetate pretreatment led to the sustained activation of the Raf-1 kinase but not that of MEK and MAPK. Thus, activated Raf-1 alone does not support MEK/MAPK activation in macrophages. Phosphorylation of TCF/Elk but not that of TCF/SAP was blocked by all treatments that interfered with MAPK activation, implying that TCF/SAP was targeted by a MAPK-independent pathway. Therefore, CSF-1 and LPS target the MAPK network by two alternative pathways, both of which induce Raf-1 activation. The mitogenic pathway depends on Ras activity, while the differentiation signal relies on protein kinase C and phosphatidylcholine-specific phospholipase C activation.
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PMID:Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages. 779 56

To identify proteins that bind to the Ras-related protein R-ras we performed a yeast two-hybrid cDNA library screen. Several clones were obtained encoding the C-terminal region of the guanine nucleotide dissociation stimulator for Ral (RalGDS). The R-ras-binding domain of RalGDS (RalGDS-RBD) is distinct from the conserved catalytic exchange factor regions. Using the two-hybrid system, we show that RalGDS-RBD interacts with H-ras, K-ras, and Rap, and with active but not with inactive point mutants of these Ras-like GTPases. Moreover, using purified proteins, we demonstrate the direct GTP-dependent interaction of the Ras-like GTPases with RalGDS-RBD and full-length RalGDS in vitro. Furthermore, we show that RalGDS-RBD and the Ras-binding domain of Raf-1 compete for binding to the Ras-like GTPases. These data indicate that RalGDS is a putative effector molecule for R-ras, H-ras, K-ras, and Rap.
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PMID:Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. 780 86

We have explored the relationship of changes in proliferative responses of human mammary epithelial cells to a phorbol ester (TPA) and to 8-Br-cAMP, which modulate the activities of protein kinases A and C (PKA and PKC), with breast tumour progression. Treatment with TPA had no effect on nontumorigenic cell lines established from human fibrocystic biopsies and apparently normal tissue around a tumour. In contrast, TPA strongly inhibited the proliferation of numerous human tumorigenic breast cell lines. Treatment with 8-Br-cAMP decreased the proliferation of all studied nontumorigenic and tumorigenic cell lines. We have also studied the effect of TPA and 8-Br-cAMP on growth of epithelial cells in short-term culture obtained from surgical human mammary biopsies with different states of breast disease. Both drugs enhanced growth of normal breast cells but had no significant effects on cells from biopsies with benign breast disease. In contrast, all examined cultures from breast cancer biopsies were strongly inhibited by 8-Br-cAMP. Otherwise, TPA had an inhibitory effect only in the case of invasive ductal carcinoma of grade III. Malignant Ha-ras-transformation of nontumorigenic TPA-insensitive breast HBL-100 cells induced an inhibitory effect of TPA. In addition, a TPA-insensitive MCF7 clone was much less tumorigenic in athymic mice than the parental strain shown to be inhibited by TPA. These data suggest that the two intracellular transduction pathways change at different stages of breast pathogenesis. Alterations in the PKA pathway are early events and are probably important to cell immortalization but do not necessarily lead to malignant development. In contrast, changes in PKC pathway are rather later events associated with advanced malignant transformation.
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PMID:Proliferative responses of epithelial cells to 8-bromo-cyclic AMP and to a phorbol ester change during breast pathogenesis. 792 5


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