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)

Reactive astrogliosis is the most prominent macroglial response to diverse forms of CNS injury. We assessed a potential role for the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway because it represents a common effector for several major families of transmembrane receptors implicated in astrogliosis. Immunohistochemical detection of activated ERK/MAPK in a series of human neurosurgical specimens utilizing phosphorylation state-dependent antibodies consistently revealed intense immunoreactivity in reactive astrocytes in both subacute and chronic lesions, including infarct, mechanical trauma, chronic epilepsy, and progressive multifocal leukoencephalopathy. Neurons, oligodendroglia, and most inflammatory cells showed little or no detectable activation. These observations suggest a testable hypothesis: activation of the ERK/MAPK pathway is an obligatory step for the triggering and/or persistence of reactive astrogliosis.
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PMID:ERK/MAP kinase is chronically activated in human reactive astrocytes. 1061 45

To become migratory, cells must reorganize their connections to the substratum, and during locomotion they must break rear attachments. The molecular and biochemical mechanisms underlying these biophysical processes are unknown. Recent studies have implicated both extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase and calpain (EC 3.4.22.17) in these processes, but it is uncertain whether these are two distinct pathways acting on different modes of motility. We report that cell deadhesion involved in epidermal growth factor (EGF) receptor-mediated fibroblast motility requires activation of M-calpain downstream of ERK/MAP kinase signaling. NR6 fibroblasts expressing full-length wild type epidermal growth factor receptor required both calpain and ERK activation, as demonstrated by pharmacological inhibitors (calpeptin and calpain inhibitor I and PD98059, respectively) for EGF-induced deadhesion and motility. EGF induced rapid activation of calpain that was preventable by molecular inhibition of the Ras-Raf-MEK but not phospholipase Cgamma signaling pathway, and calpain was stimulated by transfection of constitutively active MEK. Enhanced calpain activity was not mirrored by increased calpain protein levels or decreased levels of its endogenous inhibitor calpastatin. The link between ERK/MAP kinase signaling and cell motility required the M-isoform of calpain (calpain II), as determined by specific antisense-mediated down-regulation. These data promote a previously undescribed signaling pathway of ERK/MAP kinases activating calpain to destabilize cell-substratum adhesions in response to EGF stimulation.
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PMID:Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway. 1064 90

Mitogen-activated protein kinases (MAPKs) play important roles in cell proliferation, differentiation, and apoptosis. Important functional roles for MAPKs in postmitotic cells have recently been suggested. In the present study, we investigated the effect of aging on the brain ERK (extracellular signal-regulated kinase) and p38 MAPK signaling pathways of Fischer 344 rats. The results show that basal tyrosine-phosphorylated ERK1/ERK2 in cortex of 24-month-old rats was reduced by 36%-59%, compared to 6- and 12-month-old rats (p<.05, 24- vs. 12- or 6-month-old rats). Similarly, the phosphotransferase activities of ERK and p38 MAPK, measured by in vitro immunocomplex kinase assays using myelin basic protein (MBP) as substrate, were shown to be reduced approximately 50% and 59% respectively, in the cerebrocortex of 24-month-old rats (p<.01, 24- vs. 12- or 6-month-old rats). The reductions in basal ERK and p38 MAPK activities are not due to altered protein levels of these kinases as assessed by Western analysis. Immunohistochemically, no age-related differences in ERK expression and cellular distribution were observed However, cytosolic ERK tended to aggregate in brain neurons of aged rats. In contrast brain tyrosine-phosphorylated PLCgamma1 did not change with age. Activation of ERK in response to EGF or PMA was also reduced in cortical brain slices of 24-month-old rats. These results demonstrate an age-associated selective impairment in the MAPK signaling pathways. Moreover, lifelong caloric restriction completely prevented the age-related decrease in basal brain ERK activity and diminished the age-related reduction of p38 MAPK activity. Taken together, these data indicate that ERK and p38 MAPK signaling pathways are impaired in the aged brain and that lifelong caloric restriction modulates these defects in brain intracellular signaling pathways.
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PMID:Age-associated impairment in brain MAPK signal pathways and the effect of caloric restriction in Fischer 344 rats. 1064 63

A mutant Escherichia coli lipopolysaccharide (LPS) lacking myristoyl fatty acid markedly stimulates the activity of manganese superoxide dismutase (MnSOD) without inducing tumor necrosis factor alpha (TNFalpha) production by human monocytes (Tian et al., 1998, Am J Physiol 275:C740.), suggesting that induction of MnSOD and TNFalpha by LPS are regulated through different signal transduction pathways. The protein tyrosine kinase (PTK)/mitogen-activated protein kinase (MAPK) pathway plays an important role in the LPS-induced TNFalpha production. In the current study, we determined the effects of PTK inhibitors, genistein and herbimycin A, on the induction of MnSOD and TNFalpha in human monocytes. Genistein (10 microg/ml) and herbimycin A (1 microg/ml) markedly inhibited LPS-induced protein tyrosine phosphorylation, phosphorylation and nuclear translocation of MAPK (p42 ERK, extracellular signal-regulated kinase), and increases in the steady state level of TNFalpha mRNA as well as TNFalpha production. In contrast, at similar concentrations, genistein and herbimycin A had no effect on the LPS-induced activation of nuclear factor kappaB (NFkappaB) and induction of MnSOD (mRNA and enzyme activity) in human monocytes. In addition, inhibition of NFkappaB activation by gliotoxin and pyrrodiline dithiocarbamate, inhibited LPS induction of TNFalpha and MnSOD mRNAs. These results suggest that (1) while PTK and MAPK are essential for the production of TNFalpha, they are not necessary for the induction of MnSOD by LPS, and (2) while activation of NFkappaB alone is insufficient for the induction of TNFalpha mRNA by LPS, it is necessary for the induction of TNFalpha as well as MnSOD mRNAs.
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PMID:Differential induction of tumor necrosis factor alpha and manganese superoxide dismutase by endotoxin in human monocytes: role of protein tyrosine kinase, mitogen-activated protein kinase, and nuclear factor kappaB. 1065 5

Conditioned medium from stimulated microglia and from the monocyte/macrophage cell line (RAW 264.7; MC-CM) promotes the differentiation of cholinergic neurons from undifferentiated progenitors in the septal nuclei and adjacent basal forebrain (BF). We have studied the regulation of this process by measuring the activity of choline acetyltransferase (ChAT) in cultured BF taken from embryonic day 16 rat brain. Inhibition of either xanthine oxidase with allopurinol or nitric oxide synthase with N(G)-monomethyl-l-arginine produces a small but significant improvement in the efficacy of MC-CM while inclusion of pyrrolidine dithiocarbamate, a hydroxyl radical scavenger widely used as an antioxidant, lowers MC-CM-induced ChAT activity. Addition of nerve growth factor (NGF) but not brain-derived neurotrophic factor or glial-derived neurotrophic factor together with MC-CM has a synergistic effect on both ChAT activity and ChAT mRNA, raising ChAT activity as much as 29-fold and ChAT mRNA almost 15-fold. While MC-CM raised mRNA for trkA, the effect was not synergistic with NGF. mRNA for the common neurotrophin receptor (p75NTR) showed a modest synergistic increase. Blockade of the Ras/Raf/ERK [extracellular signal-regulated kinase, also known as mitogen-activated protein [(MAP) kinase] signal transduction pathway with either PD28059 (an inhibitor of MAP kinase/ERK kinase kinase or MEK) or N-acetyl-S-farnesyl-l-cysteine (an inhibitor of Ras farnesylation and, hence, activation) inhibited the action of MC-CM. Moreover, a subpopulation of cells responded rapidly to MC-CM with an increased appearance of phosphorylated ERK. Because NGF also utilizes this pathway, synergy may occur along this signal transduction pathway.
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PMID:Macrophage cell-conditioned medium promotes cholinergic differentiation of undifferentiated progenitors and synergizes with nerve growth factor action in the developing basal forebrain. 1068 94

Phorbol 12-myristate 13-acetate (PMA)-induced differentiation of human erythroleukemic K562 cells is characterized by growth arrest, morphological change, and expression of megakaryocyte-specific proteins. We examined the possible involvement of cell cycle regulators with PMA-induced growth arrest and megakaryocytic differentiation of K562 cells. The concentrations of cyclin D1 and p21Waf1/Cip1 were dramatically increased, whereas those of cyclin B1 and cdc2 were decreased, by PMA treatment. The concentrations of most cyclin-dependent kinases (Cdk2, Cdk4, and Cdk6), however, were unchanged by PMA treatment. PD98059, a specific inhibitor of MEK1, partially prevented the increase in cyclin D1 caused by PMA and fully reversed the down-regulation of cyclin B1 protein seen in response to PMA treatment. Thus, it is demonstrated here that the PMA-mediated changes of cyclin D1 and B1 are the result of a persistent increase in extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) activity.
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PMID:ERK/MAPK pathway is required for changes of cyclin D1 and B1 during phorbol 12-myristate 13-acetate-induced differentiation of K562 cells. 1068 62

Antigen stimulation of mast cells via the IgE receptor, FcepsilonRI, results in the recruitment of the cytosolic tyrosine kinase, Syk, and the activation of various signaling cascades. One of these, the extracellular signal-regulated kinase (ERK2) cascade, is inhibited by low concentrations of the immunosuppressant drug, dexamethasone, probably at a step prior to the activation of Raf-1 (Rider, L. G., Hirasawa, N., Santini, F., and Beaven, M. A. (1996) J. Immunol. 157, 2374-2380). We now show that treatment of cultured RBL-2H3 mast cells with nanomolar concentrations of dexamethasone causes dissociation of the Raf-1.heat shock protein 90 (Hsp90) complex. Raf-1 bereft of this protein fails to associate with the membrane or Ras in antigen-stimulated cells. Upstream events such as the Syk-dependent phosphorylation of Shc, the engagement of Shc with the adapter protein, Grb2, and the activation of Ras itself are unaffected. Interestingly, the counterpart of Raf-1 in the c-Jun N-terminal kinase (JNK) cascade, MEKK-1 (mitogen-activated protein kinase/ERK kinase), is similarly associated with Hsp90, and this association as well as the activation of MEKK-1 are disrupted by dexamethasone treatment. Disruption of the ERK and JNK cascades at the level of Raf-1 and MEKK-1 could account for the inhibitory action of dexamethasone on the generation of inflammatory mediators in stimulated mast cells.
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PMID:Disruption of Raf-1/heat shock protein 90 complex and Raf signaling by dexamethasone in mast cells. 1070 72

Ras plays an important role in a variety of cellular functions, including growth, differentiation, and oncogenic transformation. For instance, Ras participates in the activation of Raf, which phosphorylates and activates mitogen-activated protein kinase kinase (MEK), which then phosphorylates and activates extracellular signal-regulated kinase (ERK), a mitogen-activated protein (MAP) kinase. Activation of MAP kinase appears to be essential for propagating a wide variety of extracellular signals from the plasma membrane to the nucleus. N17Ras, a GDP-bound dominant negative mutant, is used widely as an interfering mutant to assess Ras function in vivo. Surprisingly, we observed that expression of N17Ras inhibited the activity and phosphorylation of Elk-1, a physiological substrate of MAP kinases, in response to phorbol myristate acetate. The activity and phosphorylation of the MAP kinase hemagglutinin epitope (HA)-ERK1 were not affected by N17Ras in response to the same stimulus. Additionally, expression of N17Ras, but not L61S186Ras, a GTP-bound interfering mutant, inhibited MEK-induced Elk-1 phosphorylation, suggesting that inhibition of Elk-1 may be unique to GDP-bound Ras mutants. Finally, we observed that V12Ras-induced focus formation in NIH3T3 cells is inhibited by coexpression of GDP-bound Ras mutants, such as N17, A15, and N17N69. Therefore, N17Ras and V12 Ras may be codominant with respect to Elk-1 activation and cellular transformation. These results indicate that N17Ras appears to have at least two distinguishable functions: interference with endogenous Ras activation and inhibition of Elk-1 and transfomation. Furthermore, our data imply the possibility that GDP-bound Ras, like N17Ras, may have a direct role in signal transduction.
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PMID:The dominant negative Ras mutant, N17Ras, can inhibit signaling independently of blocking Ras activation. 1072 31

Polymorphonuclear leukocyte (PMNL) phagocytosis mediated by FcgammaRII proceeds in concert with activation of the mitogen-activated protein (MAP) kinase, extracellular signal-regulated kinase ERK2. We hypothesized that myosin light chain kinase (MLCK) could be phosphorylated and activated by ERK, thereby linking the MAP kinase pathway to the activation of cytoskeletal components required for pseudopod formation. To explore this potential linkage, PMNLs were challenged with antibody-coated erythrocytes (EIgG). Peak MLCK activity, 3-fold increased over controls, occurred at 4 to 6 minutes, corresponding with the peak rate of target ingestion and ERK2 activity. The MLCK inhibitor ML-7 (10 micromol/L) inhibited both phagocytosis and MLCK activity to basal values, thereby providing further support for the linkage between the functional response and the requirement for MLCK activation. The MAPK kinase (MEK) inhibitor PD098059 inhibited phagocytosis, MLCK activity, and ERK2 activity by 80% to 90%. To directly link ERK activation to MLCK activation, ERK2 was immunoprecipitated from PMNLs after EIgG ingestion. The isolated ERK2 was incubated with PMNL cytosol as a source of unactivated MLCK and with MLCK substrate; under these conditions ERK2 activated MLCK, resulting in phosphorylation of the MLCK substrate or of the myosin light chain itself. Because MLCK activates myosin, we evaluated the effect of directly inhibiting myosin adenosine triphosphatase using 2,3-butanedione monoxime (BDM) and found that phagocytosis was inhibited by more than 90% but MLCK activity remained unaffected. These results are consistent with the interpretation that MEK activates ERK, ERK2 then activates MLCK, and MLCK activates myosin. MLCK activation is a critical step in the cytoskeletal changes resulting in pseudopod formation.
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PMID:Regulation of polymorphonuclear leukocyte phagocytosis by myosin light chain kinase after activation of mitogen-activated protein kinase. 1073 14

Recent studies have revealed that a variety of malignant tumors express Fas and/or its ligand FasL. However, tumor cells expressing Fas are not always susceptible to Fas-mediated cell death, and the biological significance of simultaneous expression of Fas and FasL in the same tumor is not known. In the present study, we addressed this question in three glioma cells lines, A-172, T98G, and YKG-1, which express both Fas and FasL endogenously and their Fas transfectants. We report here that: (a) in gliomas, [3H]TdR incorporation was enhanced by anti-Fas IgM monoclonal antibody CH-11 and conversely inhibited by anti-FasL monoclonal antibody NOK-2; (b) cross-linking of Fas with CH-11 drove both cell cycle progression and apoptosis as demonstrated by the induction of the S-G2 phase of DNA and RNA and fragmented nuclei; (c) phosphorylation of extracellular signal-regulated kinase (ERK), but not of c-Jun NH2-terminal kinase or p38, was induced by cross-linking of Fas; (d) a mitogen-activated protein kinase/ERK kinase 1 (MEK1) inhibitor PD98059 completely blocked CH-11-induced ERK phosphorylation as well as cell cycle progression without affecting induction of apoptosis; and (e) a broad-spectrum caspase inhibitor Z-Asp-CH2-DCB inhibited CH-11-induced ERK phosphorylation, cell cycle progression, and apoptosis. These results indicate that Fas-mediated caspase activation elicits two independent cellular responses; one is to induce apoptosis and another is to promote cell cycle progression; the latter is closely linked to the MEK-ERK pathway. Together, our data strongly suggest that FasL may play a role as an autocrine growth factor in gliomas.
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PMID:Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation. 1074 52


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