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)

Although c-Jun NH(2)-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27(Kip1), without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-kappaB activation in a dose-dependent fashion, associated with phosphorylation of IkappaB kinase alpha (IKKalpha) and degradation of IkappaBalpha. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-kappaB activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-kappaB in MM cells.
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PMID:Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines. 1464 74

IFN-gamma (interferon-gamma) modulates IFN-alpha therapy in chronic hepatitis C infection; however, the underlying mechanism remains unclear. Here we demonstrate that long-term (3-6 days) but not short-term (up to 1 day) IFN-gamma treatment of human hepatoma Hep3B cells attenuates IFN-alpha activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3, but enhances IFN-gamma and interleukin 6 activation of STATs. Prolonged exposure to IFN-gamma also significantly induces STAT1 protein expression without affecting STAT2, STAT3 and ERK (extracellular-signal-regulated kinase) 1/2 protein expression. To determine the role of STAT1 protein overexpression in regulation of IFN-alpha signalling, Hep3B cells were stably transfected with wild-type STAT1. Overexpression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1, but surprisingly attenuates IFN-alpha activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation. This STAT1-mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant-negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-alpha activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-alpha-activated STAT2 translocation from IFN-alpha receptor 2 to IFN-alpha receptor 1, a critical step in IFN-alpha signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-gamma, are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-gamma treatment inhibits IFN-alpha-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-alpha treatment failure in hepatitis C patients.
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PMID:Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C. 1469 Apr 54

Crk-associated substrate (Cas) is highly phosphorylated by v-Src and plays a critical role in v-Src-induced cell transformation. In this study, we found that the Src homology (SH) 3 domain of Cas blocked v-Src-stimulated anchorage-independent cell growth, Matrigel invasion, and tumor growth in nude mice. Biochemical analysis revealed that the Cas SH3 domain selectively inhibited v-Src-stimulated activations of AKT and JNK, but not ERK and STAT3. Attenuation of the AKT pathway by the Cas SH3 domain rendered v-Src-transformed cells susceptible to apoptosis. Inhibition of the JNK pathway by the Cas SH3 domain led to suppression of v-Src-stimulated invasion. Taken together, our results indicate that the Cas SH3 domain has an anti-tumor function, which severely impairs the transforming potential of v-Src.
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PMID:Blockade of v-Src-stimulated tumor formation by the Src homology 3 domain of Crk-associated substrate (Cas). 1474 71

Estrogens affect the functioning of several non-reproductive tissues, the immune system in particular. In mammalian immunocytes, 17beta-estradiol (E2) has both dose- and cell-type specific effects and the responses to E2 seem to be mediated by rapid, non-genomic mechanisms; these may be initiated at either membrane or cytosolic locations, and can result in both direct local effects, such as modification of ion fluxes, and regulation of gene transcription secondary to activation of different kinase cascades, including mitogen activated protein kinases (MAPKs). In this work, the short-term effects of E(2) and the possible mechanisms of estrogen-mediated cell signaling were investigated in the hemocytes, the immune cells of the bivalve mollusc, the mussel Mytilus galloprovincialis Lam. The results show that E2 (25nM) caused a rapid and significant increase in hemocyte cytosolic [Ca2+]; lower concentrations (5 nM) showed a smaller, not significant effect. Both E2 concentrations affected the phosphorylation state of the components of tyrosine kinase-mediated signal transduction MAPK- and STAT- (signal transducers and activators of transcription) like proteins within 5-15 min from E2 addition. A greater effect and clearer time course were observed with 25 nM E2: in particular, E2 induced a transient increase in p-ERK2 MAPK and a persistent increase in p-p38 MAPK. Moreover, both STAT3 and STAT5 were tyrosine phosphorylated in response to E2. E2 (5 nM) induced both morphological (as evaluated by SEM) and functional changes (such as extracellular release of hydrolytic enzymes, lysosomal membrane destabilisation, and stimulation of the bactericidal activity) within 10-30 min from addition. Lysosomal membrane destabilisation induced by both E2 concentrations was abolished by hemocyte preincubation with the p38 MAPK inhibitor SB203580, and significantly reduced by PD98059 and Wortmannin (inhibitors of ERK MAPK and PI3-K, respectively), this suggesting that rapid activation of kinase cascades is involved in mediating the effects of E2 in mussel hemocytes. The antiestrogen Tamoxifen prevented or strongly reduced most, but not all, the effects of E2. Western blotting with heterologous anti-ERalpha-anti-ERbeta-antibodies revealed the presence of immunoreactive ERalpha- and ERbeta-like proteins in hemocyte protein extracts. Overall, our data support the hypothesis that the rapid effects and mechanisms of action of 17beta-estradiol are extremely conserved and that they may play a crucial role in endocrine-immune interactions in invertebrates.
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PMID:Rapid effects of 17beta-estradiol on cell signaling and function of Mytilus hemocytes. 1498 Jul 97

A STAT3 (signal transducer and activator of transcription 3)- and a MEK/Erk-mediated signal can be activated by cytokines, including IL-6 (interleukin-6), PDGF, and EGF. Recently, STAT3 and an ERK-signal were shown to co-operatively activate the c-fos gene. Activation of a truncated form of the IL-6 receptor subunit, gp130, that had only one YXXQ motif, induced both c-Fos and JunB in NIH3T3 cells through STAT3 without an apparent increase in the AP-1 (activator protein-1) activity. In contrast, concomitant stimulation of the STAT3 signal and a MEK/Erk-signal markedly increased AP-1 activity with enhanced c-Fos expression. Surprisingly, the c-Fos induced by the YXXQ-signal alone was localized to the cytoplasm, from which it translocated into the nucleus following TPA (12-O-tetradecanoyl-phorbol 13-acetate) treatment in a MEK/Erk-dependent manner. c-Fos that was expressed from a constitutive promoter localized to the nucleus and did not move into the cytoplasm in response to the YXXQ-signal. Rather, the YXXQ-signal was required during c-Fos production for it to be retained in the cytoplasm. Thus, the YXXQ-signal induces c-Fos expression through STAT3 and anchors the new c-Fos in the cytoplasm. In addition, the YXXQ-signal and an Erk signal co-operatively cause c-Fos activation in the nucleus.
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PMID:Cytoplasmic c-Fos induced by the YXXQ-derived STAT3 signal requires the co-operative MEK/ERK signal for its nuclear translocation. 1500 10

Most gastrointestinal stromal tumors (GISTs) express constitutively activated forms of the KIT receptor tyrosine kinase protein, resulting from oncogenic mutations in the extracellular, juxtamembrane, or kinase domains. KIT oncoproteins are detected early in GIST tumorigenesis, and most GIST patients respond well to treatment with the KIT kinase inhibitor imatinib mesylate (STI571, Gleevec). However, GISTs can develop resistance to imatinib, and additional therapeutic strategies are needed. Little is known about oncogenic KIT signal transduction in GISTs, and whether the type of KIT mutation accounts for selective activation of downstream signaling intermediates. We therefore evaluated KIT downstream signaling profiles in 15 primary GISTs with mutations in KIT exons 9, 11, 13, and 17, and in two human GIST cell lines. All GISTs showed constitutive phosphorylation at KIT tyrosine residues Y703 and Y721. Additionally, most GISTs showed activation of MAPK p42/44, AKT, S6K, STAT1, and STAT3. STAT5 and JNK were not demonstrably activated in any GIST. Using GIST in vitro models, we showed that activation of MAPK p42/44, AKT, and S6K was KIT dependent, whereas STAT1 and STAT3 phosphorylation was only partially dependent on KIT activation. Correlation of activated signaling pathways with the type of KIT mutation revealed low levels of AKT phosphorylation in exon 9 mutant GISTs in contrast to a subset of GISTs with exon 11 mutations. However, additional factors are likely to modify the engagement of signaling pathways in GISTs as suggested by the fact that four GISTs with identical KIT exon 9 mutations had differential activation of MAPK p42/44 and STAT proteins. In summary, in this first report on KIT signal transduction in primary GISTs and GIST cell lines, we identified pathways that are constitutively activated in a KIT-dependent manner and therefore warrant further study as molecular targets in GISTs.
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PMID:Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). 1500 86

The interaction between stromal and epithelial cells is critical for the initiation and progression of prostate cancer, but the molecular determinants responsible for the cross-talk between these two cell types remain largely unknown. Here, we used a co-culture cell assay to identify messengers involved in the cross-talk between human prostate stromal PS30 and epithelial LNCaP cells. Stimulation with lysophosphatidic acid (LPA) activates the mitogenic ERK signaling pathway in PS30, but not LNCaP, cells. The co-culture of PS30 and LNCaP cells results in the activation of ERK in LNCaP cells and that is further increased in response to stimulation with LPA. Physiologic relevance of the interaction between PS30 and LNCaP cells is demonstrated using LNCaP xenograft tumor assays. Animals implanted with a mixture of both cell types develop larger tumors with higher frequency compared with those injected with LNCaP cells alone. Conditioned medium transfer experiments reveal the PS30-derived inducing factor is soluble and promotes mitogenic ERK and STAT3 signaling pathways in LNCaP cells. Protein analysis demonstrates that treatment of the PS30 cells with LPA induces synthesis of interleukin 6 (IL-6). Antibody neutralization experiments reveal that IL-6 is responsible for the LPA-induced mitogenic signaling and growth of the LNCaP cells. Our findings reveal that the LPA-regulated secretion of IL-6 is an important messenger linking stromal and epithelial prostate cells, which may be exploited for the effective treatment of patients with advanced prostate cancer.
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PMID:Interleukin 6 mediates the lysophosphatidic acid-regulated cross-talk between stromal and epithelial prostate cancer cells. 1502 19

STAT3 is frequently overexpressed and constitutively activated by tyrosine phosphorylation during malignant transformation. Despite the clear importance of STAT3 in cell proliferation and survival in diverse human cancers, its possible contribution to tumor cell adhesion, motility and invasion remains hypothetical. We therefore compared the transforming properties of STAT3wt, its constitutively activated dimeric form STAT3C, and the dominant negative mutant STAT3-Y705F in human colorectal HCT8/S11 cancer cells. Both STAT3wt and STAT3C exert a permissive action to the proinvasive activity of the scatter factor HGF in HCT8/S11 cells. In contrast, the monomeric and cytoplasmic mutant Y705F induces a constitutive invasive phenotype through Wnt/Rho-independent and EGFR/PI3-kinase-dependent pathways. Accordingly, Y705F decreases cell-cell homotypic adhesions, and increases cell motility and scattering, as well as lamellipodia-type cellular extensions. STAT3-Y705F-transfected HCT8/S11 cells display an increased tyrosine phosphorylation of the cell-cell adhesion regulator beta-catenin and its dissociation from the invasion suppressor E-cadherin at cell-cell contacts. Our data imply that both invasion promoter and repressor genes are controlled by the canonical STAT3 transcription pathways. Disruption of this cascade by Y705F reveals the proinvasive potential of altered forms of STAT3 as a persistent signaling adaptor in cytokine/transforming growth factor receptor scaffolds and oncogenic pathways.
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PMID:Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell-cell adhesion complexes. 1507 88

The tissue inhibitor of metalloproteinase-1 (TIMP1) is expressed in a subset of malignant lymphomas and can inhibit tumor spread and promote cell survival. Recent data suggest that TIMP1 expression may be regulated by signal transducer and activator of transcription (STAT)-3. Thus, we tested the hypothesis that TIMP1 expression is related to STAT3 activation in lymphomas, with a focus on anaplastic large cell lymphomas (ALCLs), which are known to express high levels of phosphorylated/active STAT3 (pSTAT3). Specific inhibition of STAT3 with a dominant-negative construct led to concentration-dependent down-regulation of TIMP1 expression in two anaplastic lymphoma kinase (ALK)(+) ALCL cell lines, Karpas 299 and SU-DHL-1. Using cDNA microarrays, ALK(+) ALCL cell lines consistently expressed the highest TIMP1 level among 29 lymphoma cell lines of various subtypes. The association between TIMP1 expression and high level of STAT3 activation was validated by Western blots and immunostaining using antibodies specific for pSTAT3 and TIMP1. We further evaluated the relationship between TIMP1 expression and STAT3 activation in 43 ALCL tumors (19 ALK(+) and 24 ALK(-)) using immunohistochemistry and a tissue microarray. The TIMP1(+) group had a mean of 64% pSTAT3(+) cells as compared to 23% pSTAT3(+) cells in the TIMP1(-) group (P = 0.002). As expected, TIMP1 positivity was higher in the ALK(+) group (15 of 19, 79%) compared with the ALK(-) group (5 of 24, 21%; P = 0.0002) because NPM-ALK restricted to ALK(+) tumors was previously shown to activate STAT3. In conclusion, STAT3 directly contributes to the high level of TIMP1 expression in ALK(+) ALCL, and TIMP1 expression correlates with high level of STAT3 activation in ALCL. TIMP1, as a downstream target of STAT3, may mediate the anti-apoptotic effects of STAT3.
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PMID:Signal transducer and activator of transcription-3 activation contributes to high tissue inhibitor of metalloproteinase-1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. 1616 Oct 18

Estrogens and estrogenic chemicals can affect several vertebrate non-reproductive functions, the immune response in particular. We have previously shown that in the hemocytes of the marine mollusc Mytilus the natural estrogen 17beta-estradiol (E(2)) can affect the immune function through rapid tyrosine kinase-mediated signalling pathways converging on phosphorylation of both mitogen activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs), whose activation plays a key role in the immune response. In this work the effects of synthetic estrogens (such as DES), estrogenic chemicals (such as Bisphenol A, Nonylphenol), and plant estrogens (genistein) on mussel hemocytes were evaluated. The results demonstrate that all the EDCs tested exert in vitro effects similar to those of E(2) on lysosomal membrane stability, although at concentrations 1000 times higher than those of the natural estrogen. When the effects of DES, BPA, and NP on tyrosine kinase-mediated cell signalling were investigated, estrogenic compounds showed distinct effects on the phosphorylation state of MAPK and STAT members. In particular, only DES, like E(2), induced p38 MAPK phosphorylation, whereas BPA and NP seem to have opposite effects. Moreover, different EDCs significantly decreased the tyrosine phosphorylation state of STAT3 and STAT5, showing a distinct effect with respect to E(2). Experiments with specific kinase inhibitors showed that activation of p38 MAPK, but also of ERK MAPK and PI3-kinase, plays a key role in mediating the effect of DES. On the other hand, the effects of NP were partly mediated by ERK MAPK activation. BPA-induced lysosomal membrane destabilisation was unaffected by either MAPK or PI3-K inhibitors. However, hemocyte pre-treatment with the PKC inhibitor GF109203X prevented the effects of both BPA and NP, this indicating that kinase pathways other than those involving MAPKs are also responsible for mediating the effects of certain EDCs. Overall, the results support the hypothesis that EDCs may rapidly modulate the function of mussel hemocytes through activation of transduction pathways involving different kinase-mediated cascades. Moreover, the effects of EDCs on the phosphorylation state of transcription factor STATs suggest that these compounds may lead to changes in gene expression secondary to modulation of kinase/phosphatases. Our data address to the importance of investigating full range responses to estrogenic chemicals and may help understanding their basic mechanisms of action in ecologically relevant invertebrate species.
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PMID:Environmental estrogens can affect the function of mussel hemocytes through rapid modulation of kinase pathways. 1524 52


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