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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The growth inhibitory effects of exogenously added retinoic acid (RA) on various cultured human glioma cells was observed to be heterogenous, with an ID50 ranging from 10(-7) M to no response. The protein tyrosine kinase activity of epidermal growth factor receptor (EGF-receptor) appeared to parallel the cell's growth responsiveness to RA. Cells sensitive to RA-induced growth inhibition exhibited a dose-dependent decrease in EGF-receptor activity, whereas RA-resistant cells showed no alterations in EGF-receptor protein tyrosine kinase activity or expression. The modulation of EGF-receptor by RA was further examined with RA-sensitive (LG) and -resistant (NG-1) cell lines. Both cell lines were approximately equal in their ability to bind and internalize epidermal growth factor in the presence or absence of RA. Several independent assays suggested that the inhibition of EGF-receptor activity was independent of protein kinase C modulation as mediated by phorbol myristate acetate. However, alterations in associated glycoconjugates of EGF-receptor were observed among the sensitive cells but not the resistant cells. These results suggest RA-induced growth inhibition in sensitive cells may arise, at least in part, through alterations in EGF-receptor and structure.
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PMID:Inhibition of epidermal growth factor receptor activity by retinoic acid in glioma cells. 230 13

The neu oncogene, characterized by Weinberg and colleagues, is a transforming gene found in ethylnitrosourea-induced rat neuro/glioblastomas; its human proto-oncogene homologue has been termed erbB2 or HER2 because of its close homology with the epidermal growth factor receptor (EGF-R) gene (c-erbB1). Expression of the rat neu oncogene is sufficient for transformation of mouse NIH 3T3 fibroblasts in culture and for the development of mammary carcinomas in transgenic mice, but the neu proto-oncogene has not been associated with cell transformation. We constructed a vector for expression of a chimeric cDNA and hybrid protein consisting of the EGF-R extracellular, transmembrane and protein kinase C-substrate domains linked to the intracellular tyrosine kinase and carboxyl terminal domain of the rat neu cDNA. Upon transfection with the construct, NIH 3T3 cells gave rise to EGF-R antigen-positive cell clones with varying amounts of specific EGF binding. Immunofluorescence and immunoprecipitation using neu- and EGF-receptor specific antibodies demonstrated a correctly oriented and positioned chimeric EGF-R-neu protein of the expected apparent mol. wt on the surface of these cells. EGF or TGF alpha induced tyrosine phosphorylation of the chimeric receptor protein, stimulated DNA synthesis of EGF-R-neu expressing cells and led to a transformed cell morphology and growth in soft agar. In contrast, the neu proto-oncogene did not show kinase activity or transforming properties when expressed at similar levels in NIH 3T3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A chimeric EGF-R-neu proto-oncogene allows EGF to regulate neu tyrosine kinase and cell transformation. 256 7

The amino acid sequence of the Alzheimer disease amyloid precursor (ADAP) has been deduced from the corresponding cDNA, and hydropathy analysis of the sequence suggests a receptor-like structure with a single transmembrane domain. The putative cytoplasmic domain of ADAP contains potential sites for serine and threonine phosphorylation. In the present study, synthetic peptides derived from this domain were used as model substrates for various purified protein kinases. Protein kinase C rapidly catalyzed the phosphorylation of a peptide corresponding to amino acid residues 645-661 of ADAP [ADAP peptide(645-661)] on Ser-655. Ca2+/calmodulin-dependent protein kinase II phosphorylated ADAP peptide (645-661) on Thr-654 and Ser-655. This peptide was virtually ineffective as a substrate for cAMP-dependent protein kinase, cGMP-dependent protein kinase, casein kinase II, or insulin receptor protein-tyrosine kinase. When a homogenate of rat cerebral cortex was used as the source of protein kinase, phosphorylation of ADAP peptide(645-661) was stimulated by calcium/phosphatidylserine/diolein to a level 4.6-fold above the basal level of phosphorylation, consistent with a prominent stimulation by protein kinase C. Using rat cerebral cortex synaptosomes prelabeled with 32Pi, a 32P-labeled phosphoprotein of approximately equal to 135 kDa was immunoprecipitated by using antisera prepared against ADAP peptide(597-624), consistent with the possibility that the holoform of ADAP in rat brain is a phosphoprotein. Based on analogy with the effect of phosphorylation by protein kinase C of juxtamembrane residues in the cytoplasmic domain of the epidermal growth factor receptor and the interleukin 2 receptor, phosphorylation of ADAP may target it for internalization.
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PMID:Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+/calmodulin-dependent protein kinase II. 313 67

Human monoblastoid leukemia U937 cells differentiate to monocyte/macrophage upon treatment with phorbol ester, 12-o-tetradecanoylphorbol-13-acetate (TPA). Previous studies, including our own, have demonstrated that drug-induced differentiation of leukemia cells is associated with genetic and enzymatic activations of protein tyrosine phosphatases (PTPases). In this study, to further investigate a relationship between PTPase activation and leukemic differentiation, we established TPA-resistant U937 variant UT16 cells. Unlike known TPA-resistant cells whose resistance is mainly due to lack or down modulation of protein kinase C (PKC), UT16 cells showed TPA-induced activation of PKC, Raf-1, and ERK/MAP kinases similar to the parental U937 cells. Interestingly, however, UT16 cells exhibited altered binding activity of AP-1 complexes, decreased ability to induce c-jun and c-fos gene expressions, and failure to differentiate to a monocytic lineage. Based on these observations, UT16 cells could be considered a novel type of TPA-resistant cell. Among UT16 cells, most of TPA-inducible PTPase genes, PTP-1C, PTP-MEG2, P19-PTP, HPTP epsilon, and PTP-U1, did not respond to TPA. Consistently, TPA increased PTPase enzymatic activity in U937 but not in UT16 cells. Taken together, activation of PTPases is well correlated with TPA-induced differentiation of U937 cells. These findings indicate that gene expression and enzymatic activity of some PTPase isozymes described here are regulated by a TPA-mediated signaling event and are likely to be used as biomarkers for the monocytic differentiation of myeloid leukemia cells.
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PMID:Phorbol ester-resistant monoblastoid leukemia cells with a functional mitogen-activated protein kinase cascade but without responsive protein tyrosine phosphatases. 747 24

Here, we present evidence that exposure of B-lineage lymphoid cells to low energy electromagnetic fields (EMF) stimulates the protein tyrosine kinases Lyn and Syk, results in tyrosine phosphorylation of multiple electrophoretically distinct substrates, and leads to downstream activation of protein kinase C (PKC). EMF exposure enhances protein tyrosine phosphorylation in Syk deficient but not in Lyn-deficient B-lineage lymphoid cells and stimulates Lyn kinase activity in wild-type as well as Syk-deficient B-lineage lymphoid cells. These results indicate that activation of Lyn kinase is sufficient and mandatory for EMF-induced tyrosine phosphorylation in B-lineage lymphoid cells. The PKC activity increases later than the Lyn activity and pretreatment with the PTK inhibitors genistein or herbimycin A abrogates the EMF-induced PKC signal. Thus, stimulation of Lyn is a proximal and mandatory step in EMF-induced activation of PKC in B-lineage lymphoid cells. Our observations prompt the hypothesis that a delicate growth regulatory balance might be altered in B-lineage lymphoid cells by EMF-induced activation of Lyn.
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PMID:Exposure of B-lineage lymphoid cells to low energy electromagnetic fields stimulates Lyn kinase. 749 32

A hypothesis of the mechanisms by which the protein cross-linking agents trigger apoptosis of lymphoid cells and proliferation of other cell types is proposed. It is assumed that both effects are triggered by aggregation of receptors on cell surface, which results from their cross-linking. This idea is substantiated by the example of one of these agents, ionizing radiation. As in the case of physiological agents, such as, antigens and growth factors, the aggregation of receptors induced by radiation activates receptor protein tyrosine kinases from which the signal is transduced to genes through protein kinase C. The hypothesis is consistent with the relationship between these effects and the PTK-PKC-dependent signal transduction pathway and its activation after irradiation.
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PMID:Cross-linking of cell surface receptors as a trigger or cell apoptosis and proliferation. 750 88

A cDNA clone, predicted to encode a variant form of the type 1 fibroblast growth factor receptor (FGFR1) containing a dipeptide Val-Thr (VT) deletion at amino acid positions 423 and 424 located within the juxtamembrane region, was isolated from a Xenopus embryo (stage 8 blastula) library. Sequence analysis of genomic DNA encoding a portion of the FGFR1 juxtamembrane region demonstrated that this variant form arises from use of an alternative 5' splice donor site. RNase protection analysis revealed that both VT- and VT+ forms of the FGFR1 were expressed throughout embryonic development, the VT+ being the major form. Amino acid position 424 is located within a consensus sequence for phosphorylation by a number of Ser/Thr kinases. We demonstrate that a VT+ peptide was specifically phosphorylated by protein kinase C (PKC) in vitro, but not by protein kinase A (PKA). A VT- peptide, on the other hand, was not a substrate for either enzyme. Phosphorylation levels of in vitro synthesized FGFR-VT+ protein by PKC were twice that of FGFR-VT- protein. In a functional assay, Xenopus oocytes expressing FGFR-VT- or FGFR-VT+ protein were equally able to mobilize intracellular Ca2+ in response to basic fibroblast growth factor (bFGF). However, pretreatment with phorbol 12-myristate 13-acetate significantly reduced this mobilization in oocytes expressing FGFR-VT+ while having little effect on oocytes expressing FGFR-VT-. These findings demonstrate that alternative splicing of Val423-Thr424 generates isoforms which differ in their ability to be regulated by phosphorylation and thus represents an important mechanism for regulating FGFR activity.
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PMID:Cloning of a fibroblast growth factor receptor 1 splice variant from Xenopus embryos that lacks a protein kinase C site important for the regulation of receptor activity. 755 2

Ninety minutes after i.v. injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) into rats, phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide anion (O2-) secretion was enhanced in suspensions of in vivo LPS-treated alveolar macrophages (AM phi) when compared with saline (SAL)-treated AM phi. The purpose of this investigation was to dissect the in vitro mechanism of PMA-stimulated O2- generation in both LPS and SAL-treated rat AM phi, with a panel of inhibitors of protein kinase C (PKC), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), phospholipase A2 (PLA2), cyclooxygenase (CO) and 5-lipoxygenase (5-LO). The following agents blocked PMA-stimulated O2- generation in both LPS- and SAL-treated AM phi (expressed as percentage of control): 1) PKC inhibitors: staurosporine: 100 nM, 7.0% (LPS) and 5.6% (SAL); sphingosine: 10 microM, 21% (LPS) and 10.5% (SAL); 2) PTK inhibitor: genistein: 100 microM, 44% (LPS) and 31% (SAL); 3) PTP inhibitors: phenylarsine oxide, 10 microM, 12.1% (LPS) and 18% (SAL); diamide, 1000 microM, 10.1% (LPS) and 10.5% (SAL); and 4) PLA2 inhibitors: manoalide: 1 microM, 29.3% (LPS) and 5.2% (SAL); scalaradial: 1 microM, 7.7% (LPS) and 7.1% (SAL); and WAY 125,984: 10 microM, 17.1% (LPS) and 14.5% (SAL). In addition, it was observed that exogenously added arachidonic acid (AA)-stimulated O2- generation in a time- and dose-dependent manner in both LPS and SAL-treated AM phi. The following inhibitors enhanced or did not affect PMA-stimulated O2- generation in LPS- and SAL-treated AM phi (expressed as percentage of of control): 1) PSP inhibitors: okadaic acid: 0.5 microM, 117% (LPS) and 153% (SAL); calyculin A: 1 microM, 112% (LPS) and 101% (SAL); 2) CO and 5-LO inhibitors: indomethacin: 10 microM, 107% (LPS) and 90% (SAL); WY 50, 295: 1 microM, 99% (LPS) and 103% (SAL); and 3) the PTP inhibitor orthovanadate upon prolonged preincubation. In both in vivo LPS- or SAL-primed AM phi, PMA-stimulated O2- generation appears to be modulated by PKC, PLA2, AA, PTK, PTP and PSP. No modulatory role was evident for either CO or 5-LO metabolites. These findings might bear on the design of therapeutic approaches for the modulation of O2- release by AM phi in the early stages of sepsis and adult respiratory distress syndrome.
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PMID:Modulation of superoxide generation in in vivo lipopolysaccharide-primed rat alveolar macrophages by arachidonic acid and inhibitors of protein kinase C, phospholipase A2, protein serine-threonine phosphatase(s), protein tyrosine kinase(s) and phosphatase(s). 761 27

The aim of this study was to test the possible modification of beta-adrenergic receptor kinase (beta ARK) activity by second messengers and/or their downstream components. Using human mononuclear leukocytes (MNL), we found that calcium ionophores could elevate beta ARK activity by about 80% in a protein kinase C (PKC)-dependent manner. This was confirmed by the ability of the PKC activator phorbol 12-myristate 13-acetate (PMA) to produce a similar effect, suggesting a PKC-dependent modulation of beta ARK activity. In vitro experiments with purified proteins showed that PKC could directly phosphorylate beta ARK1 with an apparent Km for beta ARK1 of 6 nM. The ability of beta ARK1 to phosphorylate rhodopsin was 61% greater when it was phosphorylated by PKC. The level of phosphorylation of beta ARK1 immunoprecipitated from MNL and Sf9 cells overexpressing this kinase was enhanced by about 2-3-fold after PMA treatment. Functional significance of PKC-dependent increase in beta ARK activity ws demonstrated by beta-adrenergic receptor (beta AR) homologous desensitization experiments in MNL. beta AR desensitization, as induced by exposure to 10 microM isoproterenol (5 min at 37 degrees C), was increased from 42 +/- 10% in control to 68 +/- 8% in PMA-pretreated MNL. beta ARK inhibitor heparin (160 micrograms/ml) prevented the augmenting effect of PMA on beta AR desensitization. These results show that beta ARK activity can be increased through phosphorylation by PKC, thus indicating that beta ARK can be preconditioned to modulate the subsequent cellular responsiveness to receptor activation, providing the cell with a mechanism by which specific homologous desensitization can be regulated heterologously.
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PMID:Phosphorylation and activation of beta-adrenergic receptor kinase by protein kinase C. 762 97

Rapid and long term effects of protein kinase C alpha activation on receptor tyrosine kinase signaling parameters were investigated in human 293 embryonic fibroblasts and mouse NIH 3T3 cells. Within minutes of phorbol 12-myristate 13-acetate treatment, epidermal growth factor receptor and HER2 tyrosine phosphorylation was decreased, while platelet-derived growth factor receptor and insulin receptor autophosphorylation was upregulated. These effects are not mediated by protein kinase C-dependent receptor tyrosine kinase phosphorylation but apparently by activation or inactivation of receptor tyrosine kinase-specific phosphatases, as indicated by neutralization of these phenomena upon treatment of cells with sodium orthovanadate. In contrast to these short term effects, sustained activation of protein kinase C alpha by phorbol 12-myristate 13-acetate results in translocation of protein kinase C from the cytosol to the membrane fraction where it forms stable complexes with all receptor tyrosine kinases investigated. Ligand-induced receptor tyrosine kinase/protein kinase C association in NIH 3T3 fibroblasts is accompanied by a mobility shift of the receptor, indicating phosphorylation by activated protein kinase C. This phenomenon correlates with the disappearance of receptor tyrosine kinases from the cell surface, implying that this interaction plays a role in the process of receptor internalization and degradation. Interestingly, ligand-stimulated receptor down-regulation is also enhanced by overexpression of phospholipase C gamma, which strongly indicates a role for this common receptor tyrosine kinase substrate in negative regulation of growth factor signals.
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PMID:Rapid and long-term effects on protein kinase C on receptor tyrosine kinase phosphorylation and degradation. 764 54


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