Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines of the interleukin 6 (IL-6) family, which activates the signal transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells. The signal transduction of gp130 involves the Janus tyrosine kinases (JAK) JAK1, JAK2 and Tyk2 and then the downstream effectors comprising the signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. We evaluated the effects of the JAK2 inhibitor tyrphostin AG490 on MM cells. We found that AG490 suppressed cell proliferation and induced apoptosis in IL-6-dependent MM cell lines. JAK2 kinase activity, ERK2 and STAT3 phosphorylation were inhibited. These results suggest that the chemical blocking of the gp130 signalling pathway at the JAK level could be a relevant therapeutic approach to MM.
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PMID:JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. 1092 36

Interleukin 6 (IL-6) is an important mediator of hepatocyte proliferation after hepatectomy. However, elevated IL-6 levels are found in patients with chronic liver disease. Therefore, it is unclear if hyperstimulation with IL-6 may have an influence on liver regeneration. We investigated whether a strong activation of IL-6-dependent pathways may change the course of hepatocyte proliferation after hepatectomy. Transgenic mice overexpressing the human soluble IL-6 receptor/gp80 (hsgp80) in hepatocytes were stimulated with or without hepatectomy with human IL-6 (hIL-6). Nuclear extracts were prepared and activation of gp130-dependent pathways was studied by Western blot and gel shift experiments. Cell cycle progression of hepatocytes after hepatectomy was investigated by monitoring cell cycle-specific factors. hIL-6 strongly activates Stat3 for more than 48 hours in human soluble hsgp80 transgenic mice. In contrast, no major differences were evident in the regulation of the Ras/MAP kinase pathway compared with wild-type (wt) mice. Also when hsgp80 mice were stimulated with hIL-6 3 hours before hepatectomy Stat3 is activated for more than 72 hours, whereas in unstimulated mice this event is restricted to the early hours. Strong activation of Stat3 resulted in a delay and inhibition of hepatocyte proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) staining and Cyclin A and E expression. This observation directly correlates with the induction of the cell cycle inhibitor p21. In summary, strong IL-6-dependent activation of Stat3 before hepatectomy results in delay and inhibition of cell cycle progression after hepatectomy. Therefore our results suggest that hyperstimulation with IL-6 can inhibit liver regeneration.
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PMID:Hyperstimulation with interleukin 6 inhibits cell cycle progression after hepatectomy in mice. 1096 Apr 43

We compared the role of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK)/p90(RSK) cascade in gp130-mediated cardiac hypertrophy with the contribution of the Janus kinase (JAK)/signal transduction and activation of transcription (STAT) and phosphatidylinositide 3-kinase (PI3-K) pathways. Primary cultured neonatal rat cardiomyocytes were stimulated with leukemia inhibitory factor (LIF). LIF sequentially activated Raf-1, MEK1/2, ERK1/2, and p90(RSK). We used PD-98059 (a specific MEK inhibitor), AG-490 (a JAK2 inhibitor), and wortmannin (a PI3-K inhibitor) to confirm that this cascade was independent of the JAK/STAT and PI3-K/p70 S6 kinase (S6K) pathways. PD-98059, AG-490, and wortmannin suppressed the LIF-induced increase in [(3)H]phenylalanine uptake by 54.7, 21.5, and 25.6%, respectively, and inhibited the increase in cell area by 61.2, 42.8, and 39.2%, respectively. Reorganization of myofilaments was predominantly suppressed by AG-490. LIF-induced expression of c-fos, brain natriuretic peptide, and skeletal alpha-actin mRNA was markedly suppressed by PD-98059 and moderately suppressed by wortmannin and AG-490. Atrial natriuretic peptide was significantly suppressed by AG-490. These findings indicate that this pathway is critically involved in protein synthesis, induction of c-fos, brain natriuretic peptide, and skeletal alpha-actin expression and is partially involved in myofilament reorganization and atrial natriuretic peptide induction in gp130-mediated cardiac hypertrophy.
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PMID:Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. 1100 50

The common use of the cytokine receptor gp130 has served as an explanation for the extremely redundant biological activities exerted by interleukin (IL)-6-type cytokines. Indeed, hardly any differences in signal transduction initiated by these cytokines are known. In the present study, we demonstrate that oncostatin M (OSM), but not IL-6 or leukemia inhibitory factor, induces tyrosine phosphorylation of the Shc isoforms p52 and p66 and their association with Grb2. Concomitantly, OSM turns out to be a stronger activator of ERK1/2 MAPKs. Shc is recruited to the OSM receptor (OSMR), but not to gp130. Binding involves Tyr(861) of the OSMR, located within a consensus binding sequence for the Shc PTB domain. Moreover, Tyr(861) is essential for activation of ERK1/2 and for full activation of the alpha(2)-macroglobulin promoter, but not for an exclusively STAT-responsive promoter. This study therefore provides evidence for qualitative differential signaling mechanisms exerted by IL-6-type cytokines.
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PMID:Non-redundant signal transduction of interleukin-6-type cytokines. The adapter protein Shc is specifically recruited to rhe oncostatin M receptor. 1101 27

We have recently described that oncostatin M (OSM), a member of the IL-6 family of cytokines, induces the differentiation of human glioma cells in culture. In order to extend this studies, we analyzed the effect of OSM on other human glioma cell lines including A172, U343-MG and T98G. All of these cell lines express the receptor components of OSM and leukemia inhibitory factor (LIF) gp130, LIFR and the OSM specific OSMRbeta. Therefore, we expected these cell lines to respond to OSM and LIF. Using specific antibodies recognizing proteins of the janus kinase (Jak-)/signal transducers and activator of transcription (Stat-) signaling cascade that has been shown to transduce the signals of the IL-6 cytokines to the nucleus, we could show that Jak1, Jak2 and Tyk2, as well as the Stat proteins Stat1, Stat3 and Stat5b were phosphorylated in all three cell lines by OSM and, at least in part, by LIF. Activation of the Stat proteins was also detected by EMSA which revealed complex formation on the Stat3 DNA-binding element and on a Stat5 binding site. Consistent with our recent findings, OSM treatment also induced the activation of the MAPK erk2 and the tyrosine phosphatase SHP-2 in cells of the A172, T98G and U343-MG cell lines. Although this activation pattern was very close to what we had observed in the GOS3 glioma cells, only T98G showed a growth inhibition in response to OSM while the A172 and the U343-MG cell lines did not respond to OSM treatment in terms of growth inhibition.
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PMID:Activation of the Jak-Stat- and MAPK-pathways by oncostatin M is not sufficient to cause growth inhibition of human glioma cells. 1103 52

Multiple myeloma (MM) is a B-cell neoplasia that is associated with an increased level of bone resorption. One important mediator of bone remodelling, insulin-like growth factor (IGF-I), has been shown to stimulate the proliferation of human myeloma cells. However, the mechanisms of action of IGF-I in these cells have not been determined. Using interleukin (IL)-6-dependent myeloma cell lines, we show IGF-I to be as potent a survival and proliferation factor as IL-6. We demonstrated that IGF-I functions independently of the IL-6 transducer gp130 and that these two cytokines have additive effects. Moreover, inhibition of the IGF-I pathway did not modulate the proliferative effect of IL-6. Accordingly, we found that IL-6 and IGF-I activated distinct downstream signalling molecules: IL-6 activated STAT3 phosphorylation, whereas IGF-I treatment resulted in the phosphorylation of IRS-1. Interestingly, these signalling pathways appear to converge as both cytokines activated the ras/MAPK pathway. Thus, IGF-I acts as a potent survival and proliferation factor for myeloma cells by stimulating an IL-6-independent signalling cascade. These data, together with the finding that, in vivo, IGF-I is normally expressed in close proximity to myeloma cells within the bone matrix, strongly suggest a role for this cytokine in the pathophysiology of multiple myeloma.
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PMID:Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. 1112 11

Adult cardiac myocytes are terminally differentiated cells that are no longer able to divide. Accumulating data support the idea that apoptosis in these cells is involved in the transition from cardiac compensation to decompensated heart failure. Since a number of neurohormonal factors are activated in this state, these factors may be involved in the positive and negative regulation of apoptosis in cardiac myocytes. beta1-Adrenergic receptor and angiotensin type 1 receptor pathways, nitric oxide and natriuretic peptides are involved in the induction of apoptosis in these cells, while alpha1- and beta2-adrenergic receptor and endothelin-1 type A receptor pathways and gp130-related cytokines are antiapoptotic. The myocardial protection of the latter is mediated, at least in part, through mitogen-activated protein kinase-dependent pathways, compatible with the findings in other cell types. In contrast, signaling pathways leading to apoptosis in cardiac myocytes are distinct from those in other cell types. The cAMP/PKA pathway induces apoptosis in cardiac myocytes and blocks apoptosis in other cell types. The p300 protein, a coactivator of p53, mediates apoptosis in fibroblasts but appears to play a protective role in differentiated cardiac myocytes. The inhibition of myocardial cell apoptosis in heart failure may be achieved by directly blocking apoptosis signaling pathways or by modulating neurohormonal factors involved in their regulation. These may provide novel therapeutic strategies in some forms of heart failure.
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PMID:Neurohormonal regulation of myocardial cell apoptosis during the development of heart failure. 1114 5

Microchemotaxis chambers were used to investigate whether one aspect of ciliary neurotrophic factor CNTF's role as a lesion factor might be to promote the initial early recruitment of macrophages, which express the signal transducing receptor components, gp130 and LIFRbeta. CNTFRalpha alone, or in combination with CNTF, elicited concentration-dependent macrophage chemotaxis that was inhibited by a neutralizing gp 130 antibody. IL-6, but not LIF, similarly promoted gp 130-dependent macrophage chemotaxis. Stimulation of macrophages with either CNTFRalpha in combination with CNTF or IL-6 alone resulted in tyrosine phosphorylation of an approximately 130 kD protein, presumed to be gp130. Macrophage chemotaxis induced by the combination of CNTFRalpha and CNTF was inhibited in a dose-dependent fashion by wortmannin, LY294002 or PD98059, suggesting the involvement of the phosphoinositide-3 kinase and mitogen-activated protein kinase signaling proteins. As CNTFRalpha and CNTF are present, or have immediate access to nerves after injury, these data point to the possibility that this soluble receptor alone or in combination with its ligand may promote the initial early recruitment of macrophages in vivo.
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PMID:CNTFR alpha alone or in combination with CNTF promotes macrophage chemotaxis in vitro. 1116 90

This review discusses the rapidly progressing field of cardiomyocyte signal transduction and the regulation of the hypertrophic response. When stimulated by a wide array of neurohumoral factors or when faced with an increase in ventricular-wall tension, individual cardiomyocytes undergo hypertrophic growth as an adaptive response. However, sustained cardiac hypertrophy is a leading predictor of future heart failure. A growing number of intracellular signaling pathways have been characterized as important transducers of the hypertrophic response, including specific G protein isoforms, low-molecular-weight GTPases (Ras, RhoA, and Rac), mitogen-activated protein kinase cascades, protein kinase C, calcineurin, gp130-signal transducer and activator of transcription, insulin-like growth factor I receptor pathway, fibroblast growth factor and transforming growth factor beta receptor pathways, and many others. Each of these signaling pathways has been implicated as a hypertrophic transducer, which collectively suggests an emerging paradigm whereby multiple pathways operate in concert to orchestrate a hypertrophic response
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PMID:Cytoplasmic signaling pathways that regulate cardiac hypertrophy. 1118 61

Interleukin (IL)-6, a multifunctional regulator of immune response, hematopoiesis, and acute phase reactions, has also been shown to regulate cancer cell proliferation. We have investigated IL-6 signaling pathways and cellular responses in the T47D breast carcinoma cell line. The IL-6-type cytokines, IL-6 and oncostatin M, simultaneously inhibited cell proliferation and increased cell migration. In T47D cells, IL-6 stimulated the activation of Janus-activated kinase 1 tyrosine kinase and signal transducers and activators of transcription (STAT) 1 and STAT3 transcription factors. Expression of dominant negative STAT3 in the cells strongly reduced IL-6-mediated growth inhibition but did not prevent IL-6-induced cell migration. IL-6 treatment led to activation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase (PI3K) pathways. Inhibition of MAPK or PI3K activity reversed IL-6- and oncostatin M-stimulated migration. Because cross-talk between cytokine receptors and members of the ErbB family of receptor tyrosine kinases has been described previously, we have examined their interaction in T47D cells. Down-regulation of ErbB receptor activity, through the use of specific pharmacological inhibitors or dominant negative receptor constructs, revealed that IL-6-induced MAPK activation was largely dependent on epidermal growth factor (EGF) receptor activity, but not on ErbB-2 activity. Using a monoclonal antibody that interferes with EGF receptor-ligand interaction, we have shown that in T47D cells, IL-6 cooperates with an EGF receptor autocrine activity loop for signaling through the MAPK and PI3K pathways and for cell migration. Both the tyrosine phosphatase SHP-2 and the multisubstrate docking molecule Gab1, which are potential links between IL-6 and the MAPK/PI3K pathways, were constitutively associated with the active EGF receptor. On IL-6 stimulation, SHP-2 and Gab1 were recruited to the gp130 subunit of the IL-6 receptor and tyrosine phosphorylated, allowing downstream signaling to the MAPK and PI3K pathways. Thus, in T47D breast carcinoma cells, IL-6 acts in synergy with EGF receptor autocrine activity to signal through the MAPK/PI3K pathways. Cooperation between IL-6 and the EGF receptor in T47D breast carcinoma cells illustrates how a combination of multiple stimuli, either exogenous or endogenous, may result in synergistic cellular responses.
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PMID:Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. 1119 91


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