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)

Endogenous ceramide (CER) was generated by treatment of cultured fibroblasts with sphingomyelinase (SMase) from Bacillus cereus. A 30 min treatment with 0.1-0.3 U/ml SMase induced a dose-dependent increase in the intracellular level of CER. The activation of the transcription factors signal transducer and activator of transcription (STAT) 1 and STAT3 by SMase was investigated by determination of the phosphorylation state by immunoblot, and of DNA binding activity by electrophoretic mobility shift assay. SMase treatment induced a dose-dependent Tyr-phosphorylation of STAT1/3. SMase also enhanced STAT1/3 DNA binding activity in a dose-dependent manner. Concomitantly, SMase enhanced the Tyr-phosphorylation of Janus kinase (JAK) 2, a Tyr-kinase localized upstream of STATs in the JAK/STAT pathway. The Tyr-kinase inhibitor genistein and the JAK inhibitor AG490 both prevented JAK2 Tyr-phosphorylation, together with STAT1 and STAT3 Tyr-phosphorylation and binding activity. The SMase-induced increase in STAT1/3 binding activity was prevented by methyl-beta-cyclodextrin, a cholesterol binding agent that causes a loss of compartmentalization of the molecules located in caveolae. This increase was also prevented by the MEK inhibitor PD98059, thus demonstrating the role of the MEK/ERK pathway in this system. Besides ERK, SMase activated other signaling kinases such as JNK and p38. Exogenous natural CER also activated STAT1/3 binding activity, which indicates that most probably, endogenous CER is the second messenger involved in the effect of SMase. These results describe a crosstalk between the SMase/CER and the JAK/STAT signaling pathways and include JAK2 within the range of CER-activated intracellular kinases.
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PMID:Activation of the JAK/STAT pathway by ceramide in cultured human fibroblasts. 1168 91

The STAT proteins are a family of latent transcription factors that are activated by a wide variety of cytokines. Upon receptor engagement, STATs become tyrosine phosphorylated, translocate to the nucleus, and induce expression of target genes. In addition to tyrosine phosphorylation, maximal activation of some STAT proteins requires serine phosphorylation within the transactivation domain. Here we focus on STAT phosphorylation after engagement of the erythropoietin receptor (EPO-R). In Ba/F3-EPO-R cells, EPO induces tyrosine and serine phosphorylation of STAT1, STAT3, STAT5A, and STAT5B. Identical regions of the EPO-R couple to both tyrosine and serine phosphorylation of each cognate STAT protein. A proximal region of the EPO-R lacking cytoplasmic tyrosines couples to STAT1 and STAT3 phosphorylation as well as ERK and p38(HOG) activation, but not JNK/SAPK. STAT1 serine phosphorylation was perturbed by inhibition of ERK and p38 pathways, whereas only inhibition of ERK activation blocked STAT3 serine phosphorylation in response to EPO. STAT5A/B phosphorylation is downstream of EPO-R Tyr(343), however, STAT5A/B serine phosphorylation is unaffected by either ERK or p38 inhibition. Physiological responses induced by EPO may depend on regulation of serine phosphorylation of the STAT molecules by p38(HOG) and the ERK family of kinases as well as additional serine/threonine kinases.
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PMID:Regulation of erythropoietin-induced STAT serine phosphorylation by distinct mitogen-activated protein kinases. 1187 80

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

The effects of salicylate on the phosphorylation and nuclear translocation of signal transducers and activators of transcription (STATs) induced by interferon-gamma (IFN-gamma) were studied in rat cardiac fibroblasts as a possible model for the anti-inflammatory effects of salicylate on this signaling pathway. Salicylate inhibited the tyrosine phosphorylation of both STAT1 and STAT3, but had a more pronounced effect on STAT3 activation. Salicylate pretreatment prevented both the nuclear translocation and the DNA-binding activity of STAT1 and STAT3, assessed by immunoblotting and gel shift assays, respectively. In addition to causing phosphorylation at tyrosine residues, IFN-gamma also phosphorylated STAT3 and STAT1 at serine 727. Salicylate attenuated both tyrosine and serine phosphorylations of STAT3, and also suppressed extracellular signal-regulated kinase (ERK) activation, implicating the effect of salicylate on ERK as a possible mechanism for attenuating STAT3 activation. The possibility that salicylate might affect signaling cascades by altering the redox state of the cells was examined, and its effects differed from those of other reducing agents. Salicylate did attenuate the effects of hydrogen peroxide on STAT phosphorylation, consistent with a mechanism involving an interaction between salicylate and reactive oxygen species within the cell.
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PMID:Selective inhibition of STAT3 phosphorylation by sodium salicylate in cardiac fibroblasts. 1196 May 96

Airway remodeling, as manifested by an increase in airway smooth muscle mass, mucous gland hyperplasia, and subepithelial fibrosis, contributes to the airway hyperresponsiveness and fixed obstruction seen in some asthmatic patients. Here we investigated whether the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway contributes to platelet-derived growth factor (PDGF)-stimulated mitogenesis of human airway smooth muscle cells (HASMC). PDGF treatment of quiescent HASMC resulted in the rapid tyrosine phosphorylation and DNA binding of STAT1 and STAT3. This phosphorylation was blocked by inhibition of Src and JAK2 kinases. In addition, STAT activation by PDGF was found to be redox dependent. Moreover, PDGF-induced thymidine uptake was completely blocked by pretreatment of HASMC with the STAT kinase inhibitors AG-490, SU-6656, and PP2. Interestingly, the JAK pathway was required for HASMC mitogenesis independently of mitogen-activated protein kinase activation. Inhibition of the Src and JAK kinases blocked PDGF-stimulated gene expression of the STAT target genes cyclin D1 and c-myc. These results indicate that the JAK-STAT pathway contributes to PDGF-induced mitogenesis, and thus this pathway may be important in the airway remodeling seen in some asthmatic patients.
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PMID:Role of the JAK-STAT pathway in PDGF-stimulated proliferation of human airway smooth muscle cells. 1200 86

STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration. We wanted to know whether STAT3 was also required for liver regeneration but disruption of the STAT3 gene during embryonic stages causes lethality. Therefore, an albumin promoter-driven Cre-loxP recombination system was used to create a STAT3 deletion in the adult mouse liver to study the role of STAT3 in liver regeneration. After partial hepatectomy, there was virtually no STAT3 RNA or protein induction in Alb(+) STAT3(fl/fl) livers. STAT3 DNA binding activity was also absent in Alb(+) STAT3(fl/fl) livers. Unlike in control livers, STAT1 was activated in STAT3 conditional-mutant livers posthepatectomy. Hepatocyte DNA synthesis at 40 h posthepatectomy in Alb(+) STAT3(fl/fl) livers was reduced to approximately one-third of the control. Alb(+) STAT3(fl/fl) livers had abnormalities in immediate-early gene activation that largely correlated with but were not identical to those seen in IL-6-/- livers. G(1) phase cyclins including cyclins D1 and E had lower expression levels in Alb(+) STAT3(fl/fl) livers, indicating an abnormal G(1) to S phase transition. Therefore, STAT3 accounts for part of the DNA synthetic response of the hepatocytes during liver regeneration, which cannot be compensated for by induction of STAT1. Normal activation of the MAPK pathway in Alb(+) STAT3(fl/fl) livers reinforces the fact that at least part of the effect of IL-6 on hepatocyte proliferation is not mediated by STAT3. This study provides the first in vivo evidence that STAT3 promotes cell cycle progression and cell proliferation under physiological growth conditions.
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PMID:STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration. 1203 49

Interleukin 6 (IL-6) has been shown to be a key growth factor for myeloma cells. To study IL-6 signal transduction in multiple myeloma (MM), we employed chimeric receptors composed of the epidermal growth factor receptor (EGFR) extracellular domain, gp130 transmembrane domain, and full-length or truncated gp130 cytoplasmic domains lacking regions previously shown to be necessary for MAPK, STAT1, and STAT3 activation. The IL-6-dependent KAS-6/1 MM cell line was transfected with various chimeric receptor constructs and assayed for EGF responsiveness. EGF stimulation surprisingly stimulated DNA synthesis in all transfectants, regardless of receptor length. When cell proliferation was assayed instead, only transfectants capable of inducing high levels of STAT3 activation proliferated in response to EGF. Additional studies revealed that EGF stimulation resulted in tyrosine phosphorylation of endogenous gp130 in cells expressing the chimeric receptor. Replacing the gp130 transmembrane region with the EGFR transmembrane domain diminished but did not disrupt this interaction. This receptor interaction was also observed in the IL-6-dependent MM cell line ANBL-6. In summary, although our results suggest that STAT activation is crucial in gp130-mediated proliferation of myeloma cells, these results must be interpreted with caution given our demonstration of the interaction between chimeric and endogenous receptors in myeloma cells. Importantly, this interaction has not been noted in studies utilizing the same gp130 chimeric receptor system in non-MM cells.
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PMID:Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach. 1204 Apr 52

IL (interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling. In this report, we analyzed the signal transduction pathways activated in response to IL-22 in a rat hepatoma cell line, H4IIE. We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10. However our results unraveled some differences between IL-22 and IL-10 signaling. Using antibodies specific for the phosphorylated form of MEK1/2, ERK1/2, p90RSK, JNK, and p38 kinase, we showed that IL-22 activates the three major MAPK pathways. IL-22 also induced serine phosphorylation of STAT3 on Ser(727). This effect, which is not shared with IL-10, was only marginally affected by MEK1/2 inhibitors, indicating that other pathways might be involved. Finally, by overexpressing a STAT3 S727A mutant, we showed that serine phosphorylation is required to achieve maximum transactivation of a STAT responsive promoter upon IL-22 stimulation.
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PMID:Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. 1208

The mechanism of proinflammatory activation of human monocytes by plasmin is unknown. Here we demonstrate that in human primary monocytes, plasmin stimulates mitogen-activated protein kinase (MAPK) signaling via phosphorylation of MAPK kinase 3/6 (MKK3/6) and p38 MAPK that triggers subsequent DNA binding of transcription factor activator protein-1 (AP-1). The AP-1 complex contained phosphorylated c-Jun and ATF2, and its DNA binding activity was blocked by the p38 MAPK inhibitor SB203580. In addition, plasmin elicits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, as detected by phosphorylation of JAK1 tyrosine kinase and STAT1 and STAT3 proteins. Plasmin-induced DNA binding of STAT1 and STAT3 was blocked by SB203580 and AG490, inhibitors of p38 MAPK and JAK, respectively, but not by U0126, an inhibitor of MKK1/2. DNA binding of NF-kappaB remained unaffected by any of these inhibitors. The plasmin-induced signaling led to expression of monocyte chemoattractant protein-1 (MCP-1) and CD40, which required activation of both p38 MAPK and JAK/STAT signaling pathways. Additionally, signaling through both p38 MAPK and JAK is involved in the plasmin-mediated monocyte migration, whereas the formylmethionylleucylphenylalanine-induced chemotaxis remained unaffected. Taken together, our data demonstrate a novel function of the serine protease plasmin in a proinflammatory signaling network.
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PMID:The serine protease plasmin triggers expression of MCP-1 and CD40 in human primary monocytes via activation of p38 MAPK and janus kinase (JAK)/STAT signaling pathways. 1209 96

Neuronal cell membranes are particularly rich in gangliosides, which play important roles in brain physiology and pathology. Previously, we reported that gangliosides could act as microglial activators and are thus likely to participate in many neuronal diseases. In the present study we provide evidence that JAK-STAT inflammatory signaling mediates gangliosides-stimulated microglial activation. Both in rat primary microglia and murine BV2 microglial cells, gangliosides stimulated nuclear factor binding to GAS/ISRE elements, which are known to be STAT-binding sites. Consistent with this, gangliosides rapidly activated JAK1 and JAK2 and induced phosphorylation of STAT1 and STAT3. In addition, gangliosides increased transcription of the inflammation-associated genes inducible nitric-oxide synthase, ICAM-1, and MCP-1, which are reported to contain STAT-binding elements in their promoter regions. AG490, a JAK inhibitor, reduced induction of these genes, nuclear factor binding activity, and activation of STAT1 and -3 in gangliosides-treated microglia. AG490 also inhibited gangliosides-induced release of nitric oxide, an inflammation hallmark. Furthermore, AG490 markedly reduced activation of ERK1/2 MAPK, indicating that ERKs act downstream of JAK-STAT signaling during microglial activation. However, AG490 did not affect activation of p38 MAPK. We also report that the sialic acid residues present on gangliosides may be one of the essential components in activation of JAK-STAT signaling. The present study indicates that JAK-STAT signaling is an early event in gangliosides-induced brain inflammatory responses.
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PMID:JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells. 1219 95


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