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)

Upon the corresponding ligand's stimulation, the cytokine receptors activate several signal pathways: JAK-STAT pathway, Ras-MAP kinase pathway and so on. Recently, we demonstrated that one of the STAT3 (signal transducer and activator of transcription-3) target genes could suppress the function of STAT3 and designated as SSI-1(STAT induced STAT inhibitor-1). SSI-1 is thought to play a critical role in negative feedback control of JAK-STAT signaling pathway. In the present study, we identified two novel human genes which products have homologous region in their SH2 domain and its COOH-terminal region to mouse SSI-1. Northern blotting analysis and functional studies demonstrated that SSI-2 and SSI-3 mRNA were also induced by cytokine stimulation and their forced expression in mouse myeloid leukemia cell, M1, suppressed the apoptotic effect of LIF, like SSI-1. We also demonstrated the structure of human SSI-1.
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PMID:Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. 926 33

The signaling pathways regulating blood vessel growth and development are not well understood. In the present report, an in vitro model was used to identify signaling pathways regulating capillary formation in embryonic endothelial cells. Basic fibroblast growth factor (bFGF) plus leukemia inhibitory factor (LIF) optimally stimulate the formation of capillary-like structures of the embryonic endothelial cell line IEM. LIF stimulation of IEM cells leads to activation of the Stat3 as well as the (P41/43)mitogen-activated protein kinase ((P41/43)MAPK) cascade, while bFGF does not activate Stat3 but does induce the (P41/43)MAPK cascade. Inhibition of Stat3 DNA-binding activity by expression of a dominant inhibitory Stat3 mutant increases the capillary outgrowth of the IEM cells induced by LIF. Increased Stat3 activity by overexpression of the wild-type Stat3 greatly reduced capillary outgrowth. In contrast, inhibition of the (P41/43)MAPK cascade using a MEK-1 inhibitor dramatically inhibits the LIF-induced capillary outgrowth. Moreover, the increased formation of capillary-like structures of the IEM cells mediated by Stat3 inhibition does not overcome the requirement for activation of the (P41/43)MAPK pathway for capillary outgrowth. Stat3 activity correlates with the LIF-induced expression of the negative feedback regulators of the Janus (JAK) family of tyrosine kinases, SOCS-1 and SOCS-3. These results provide evidence that Stat3 acts as a negative regulator of capillary outgrowth, possibly by increasing SOCS-1 or SOCS-3 expression. The contradictory signals stimulated by LIF could be necessary to control the intensity of the response leading to capillary outgrowth in vivo.
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PMID:LIF transduces contradictory signals on capillary outgrowth through induction of stat3 and (P41/43)MAP kinase. 1106 77

Erythroid homeostasis depends critically upon erythropoietin (Epo) and stem cell factor cosignaling in late progenitor cells. Epo bioresponses are relayed efficiently by minimal receptor forms that retain a single Tyr-343 site for STAT5 binding, while forms that lack all cytoplasmic Tyr(P) sites activate JAK2 and the transcription of c-Myc plus presumed additional target genes. In FDCER cell lines, which express endogenous c-Kit, the signaling capacities of such minimal Epo receptor forms (ER-HY343 and ER-HY343F) have been dissected to reveal: 1) that Epo-dependent mitogenesis, survival, and bcl-x gene expression via ER-HY343 depend upon the intactness of the Tyr-343 STAT5 binding site; 2) that ER-HY343-dependent bcl-x(L) gene transcription is enhanced markedly via c-Kit; 3) that socs-3, plfap, dpp-1, and cacy-bp gene transcription is induced via ER-HY343, whereas dpp-1 and cacy-bp gene expression is also supported by ER-HY343F; 4) that ectopically expressed SOCS-3 suppresses proliferative signaling by not only ER-HY343 but also c-Kit; and 5) that in FDCER and primary erythroid cells, c-Kit appears to provide the primary route to MAPK activation. Thus, integration circuits exist in only select downstream pathways within Epo and stem call factor receptor signaling.
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PMID:Integrative signaling by minimal erythropoietin receptor forms and c-Kit. 1112 55

Previous studies have shown that addition of interleukin-3 (IL-3) abrogated the B-cell potential of primary colonies supported by IL-11, erythropoietin, IL-7 and steel factor. However, the mechanism by which IL-3 exerts its inhibitory role is not understood. Using a variant of the mouse pro-B cell line Ba/F3 which expresses both IL-3 and IL-11 receptors, we showed that pretreatment of these cells with IL-3 before stimulation by IL-11 suppressed the tyrosine phosphorylation and nuclear translocation of STAT3 (signal transducer and activator of transcription 3). This inhibition occurred within 30 min and required the synthesis of a negative regulator. The onset of IL-3-dependent inhibition was correlated temporally with the appearance of SOCS-3 (suppressor of cytokine signalling-3) protein. In addition, overexpression of SOCS-3 in the pro-B cell line effectively blocked STAT3 activation induced by IL-11. These findings establish that a cytokine (IL-3) that has been shown to modulate its own signal of activation is also able to down-regulate signalling activated by a different cytokine (IL-11). This cross-talk involves activation of the JAK (Janus kinase)/STAT signalling pathway, but not mitogen-activated protein kinase pathways, and is mediated, at least in part, by SOCS-3.
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PMID:Negative cross-talk between interleukin-3 and interleukin-11 is mediated by suppressor of cytokine signalling-3 (SOCS-3). 1113 84

Previously, by a yeast 2-hybrid screen, we identified signal transducer and activator of transcription 5b (Stat5b) as a substrate of the insulin receptor (IR). We demonstrated that refeeding of fasted mice leads to rapid activation of Stat5 proteins in liver, skeletal muscle, and fat, suggesting that Stat5b is a physiological target of insulin. Here, we show that injection of glucose or insulin into fasted mice leads to robust activation of both Stat5a and Stat5b in skeletal muscle. In C2C12 myotubes, we find that insulin stimulates tyrosine phosphorylation of Stat5a and Stat5b by 3-5-fold. This degree of Stat5 activation in vitro is significantly lower than what we observe in vivo and inversely correlates with IRS-1/2 levels. We can recapitulate robust insulin activation of Stat5 in C2C12 cells by stable overexpression of the human IR (hIR). To identify insulin-activated genes that are Stat5 targets, we also overexpressed an IR mutant (LA-hIR) that signals normally for mitogen-activated protein kinase- and phosphatidylinositol 3-kinase-dependent pathways but is deficient in Stat5 signaling in response to insulin. We demonstrate that insulin induces the expression of SOCS-2 mRNA in the wild type hIR but not in the LA-hIR-overexpressing cells. The induction of SOCS-3 by insulin is reduced but not lost in the LA-hIR cells. Therefore, our results suggest that insulin induction of SOCS-2, and in part SOCS-3 mRNA expression, is mediated by Stat5 and can be independent of mitogen-activated protein kinase and phosphatidylinositol 3-kinase-signaling pathways.
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PMID:Insulin Induction of SOCS-2 and SOCS-3 mRNA expression in C2C12 Skeletal Muscle Cells Is Mediated by Stat5*. 1127 66

During infection, the functional status of the innate immune system is tightly regulated. Although signals resulting in activation have been well characterized, counterregulative mechanisms are poorly understood. Suppressor of cytokine signaling (SOCS) proteins have been characterized as cytokine-inducible negative regulators of Janus kinase/STAT signaling in cells of hemopoietic origin. To analyze whether SOCS proteins could also be induced by pathogen-derived stimuli, we investigated the induction of SOCS-1 and SOCS-3 after triggering of macrophage cell lines, bone marrow-derived dendritic cells, and peritoneal macrophages with CpG-DNA. In this study, we show that CpG-DNA, but not GpC-DNA, induces expression of mRNA for SOCS-1 and SOCS-3 in vitro and in vivo. SOCS mRNA expression could be blocked by chloroquine and was independent of protein synthesis. Inhibitors of the mitogen-activated protein kinase pathway triggered by CpG-DNA were able to impede induction of SOCS mRNA. CpG-DNA triggered synthesis of SOCS proteins that could be detected by Western blotting. SOCS proteins were functional because they inhibited IFN-gamma as well as IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore, IFN-gamma-induced up-regulation of MHC class II molecules was also prevented. The same effects could be achieved by overexpression of SOCS-1. Hence, the results indicate a substantial cross-talk between signal pathways within cells. They provide evidence for regulative mechanisms of Janus kinase/STAT signaling after triggering Toll-like receptor signal pathways.
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PMID:Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. 1139 Apr 52

Oncostatin M (OSM) is known to inhibit the growth of melanocytes and early-stage melanomas, but this ability is lost with melanoma progression. The biological effects of OSM involve the activation of Janus kinases (Jak) and signal transducer and activator of transcription (STAT) factors. Since SOCS (suppressor of cytokine signaling) a recently described family of regulatory proteins, has been shown to act through down-regulation of Jak-STAT signaling, we investigated their putative role in the inhibition of OSM signaling in the human melanoma cell line A375. We observed that, among the SOCS family members examined, only SOCS-3 mRNA was strongly and rapidly induced by OSM. SOCS-3 protein was present within 1h and rapidly declined thereafter. Constitutive expression of SOCS-3 protein completely abolished the activation of the Jak-STAT signaling pathway as well as the Ras-MAP kinase pathway. As a result, A375 cells acquired an OSM-resistant phenotype. Our findings demonstrate that SOCS-3 is a potent regulator of OSM response and suggest that dysregulation of SOCS-3 expression could provide a mechanism for OSM resistance acquisition during tumour progression.
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PMID:Negative regulation of onconstatin M signaling by suppressor of cytokine signaling (SOCS-3). 1139 20

Some biochemical events following the binding of prolactin (PRL) to its receptor in normal human leukocytes were investigated. PRL enhanced JAK2 phosphorylation in peripheral blood mononuclear cells (PBMC) but not in granulocytes. PRL also induced phosphorylation of Stat-5 in PBMC and Stat-1 in granulocytes. Subsequent binding of Stat-5- and of Stat-1-like molecules to a GAS responsive element from the beta-casein promoter was detected by EMSA. p38 MAPK (but not p42/p44 MAPK) was activated by PRL in both leukocyte populations. PRL induced iNOS and CIS mRNA expression in granulocytes. Increased expression of IRF-1 and SOCS-2 was observed in granulocytes and of SOCS-3 and iNOS in PBMC. Similar effects were obtained with ovine and human PRL. Antiserum to PRL reduced iNOS and IRF-1 expression induced by PRL in granulocytes and reduced iNOS expression in PBMC. Also, pretreatment of granulocytes with a p38 MAPK inhibitor (SB 203580) prevented in part PRL-induced iNOS and IRF-1 expression. In PBMC, the p38 inhibitor decreased PRL-induced iNOS gene expression. These results indicate that PRL-induced gene regulation in leukocytes requires the activation of at least two different pathways: the Stat and the MAP kinase pathways. Moreover, although PRL activates Stat in both leukocyte types, signal transduction is different in granulocytes and in PBMC. Most importantly, PRL modulates the expression of genes crucial to leukocyte function. The present findings reinforce the concept that PRL has "cytokine-like" activity in human leukocytes.
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PMID:Cytokine-like effects of prolactin in human mononuclear and polymorphonuclear leukocytes. 1169 20

The gp130 cytokine receptor activates a cardiomyocyte survival pathway during the transition to heart failure following the biomechanical stress of pressure overload. Although gp130 activation is observed transiently during transverse aortic constriction (TAC), its mechanism of inactivation is largely unknown in cardiomyocytes. We show here that suppressor of cytokine signaling 3 (SOCS3), an intrinsic inhibitor of JAK, shows biphasic induction in response to TAC. The induction of SOCS3 was closely correlated with STAT3 phosphorylation, as well as the activation of an embryonic gene program, suggesting that cardiac gp130-JAK signaling is precisely controlled by this endogenous suppressor. In addition to its cytoprotective action, gp130-dependent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory factor (LIF). To our knowledge, this is the first clear evidence that these two separate cardiomyocyte phenotypes induced by gp130 activation lie downstream of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress-inducible gene in cardiac muscle cells and that it directly modulates stress-induced gp130 cytokine receptor signaling as the key molecular switch for a negative feedback circuit for both myocyte hypertrophy and survival.
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PMID:Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. 1171 37

Neurons in vivo are exposed to a variety of different growth factors and cytokines. A principal signalling pathway for ciliary neurotrophic factor (CNTF)-like cytokines is the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) system of kinases and transcription factors. In the human cell line (SH-SY5Y), STAT1 and STAT3 activation by CNTF-like cytokines showed tyrosine phosphorylation peaking at 0.5 h and inactivating within 2 h. Tyrosine phosphorylation of the receptor-associated tyrosine kinases Jak1 and Jak2 showed a similar time course of activation and inactivation in response to CNTF. The STAT1 response to the non-CNTF-like cytokine, interferon-gamma (IFN-gamma) did not inactivate. Inactivation to CNTF was not due to a decrease in CNTF receptor subunit gp130 or in levels of Jak1 or Jak2. STAT inactivation was inhibited by the protein kinase blocker H7 and a tyrosine phosphatase blocker, but not by inhibitors of protein kinase C, mitogen-activated protein kinase (MAPK) kinase, mTOR-P70/S6 kinase or phosphatidyl inositol-3-kinase (PI-3 kinase). Surprisingly, CNTF caused only a minor increase in levels of suppressors of cytokine signalling, SOCS-1 and SOCS-3. CNTF pretreatment desensitized the cells to the CNTF-like cytokines, leukemia inhibitory factor and oncostatin-M but not to IFN-gamma. These results reveal a complex level of regulation of shared signalling pathways for cytokines that is dependent on both the type of cell and cytokine.
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PMID:Activation and inactivation of signal transducers and activators of transcription by ciliary neurotrophic factor in neuroblastoma cells. 1188 86


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