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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown that the interaction of interleukin (IL)-5 with the receptor activates Lyn tyrosine kinase within 1 min and Jak2 tyrosine kinase within 1-3 min. IL-5 also stimulates GTP binding to p21ras. The signal is subsequently propagated through the activation of Raf-1, MEK, and MAP kinases as shown by their increased autophosphorylation in vitro and phosphorylation in situ. Jak2 kinase has been shown to phosphorylate STAT nuclear proteins. The activation of STAT nuclear factors was studied by electrophoretic mobility shift assay using a gamma activation site (GAS) probe. We found that IL-5 induces two GAS-binding proteins in eosinophils, one of which is STAT1. We conclude that IL-5 induced signals are propagated through two distinct pathways: (1) Lyn-->Ras-->Raf-1-->MEK-->MAP kinase and (2) Jak2-->STAT1.
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PMID:The interleukin-5/receptor interaction activates Lyn and Jak2 tyrosine kinases and propagates signals via the Ras-Raf-1-MAP kinase and the Jak-STAT pathways in eosinophils. 761 38

Thrombopoietin (Tpo) is a cytokine regulating megakaryocyte maturation and platelet formation. We studied Tpo-induced signal transduction, and found that Tpo induces phosphorylation of adapter molecules. Shc and Vav, and of serine/threonine kinases Raf-1 and mitogen-activated protein (MAP) kinases. Further, Tpo induced activation of Ras, MAP kinase kinase, MAP kinase and Pim-1. Taken together with other observations, we concluded that Tpo induces the activation of at least two distinct signaling pathways, a specific Tyk2-JAK2/STAT1-STAT3-STAT5 signaling cascade and a common Shc/Vav/Ras/Raf-1/MAP kinase kinase/MAP kinase signaling cascade.
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PMID:Thrombopoietin induces activation of at least two distinct signaling pathways. 854 84

Thrombopoietin (Tpo) is a cytokine which stimulates megakaryocyte maturation. We found that Tpo is constitutively and ubiquitously expressed in all tissues examined, including bone marrow stromal cells, even in thrombocytopenia, thrombosis and steady-state condition in mice. Thus, platelet level in circulation is not regulated by Tpo gene expression. Furthermore, when the purified megakaryocytes were cocultured with the stromal cells, most of the megakaryocytes adhered to the stromal cells and remained unchanged, while free megakaryocytes induced proplatelet formation. Thus the stromal cells in bone marrow secrete Tpo and stimulate megakaryocytopoiesis, but the interaction of megakaryocytes with the stromal cells may suppress platelet formation. Study on signal transduction through Mp1 revealed that Tpo induces activation of JAK2 and Tyk2, which in turn activate STAT1, STAT3 and STAT5. Further, Tpo stimulates transcription factors GATA-1 and NF-E2, which induce differentiation markers, GPIIb/IIIa and Pm-1. In addition, Shc, Vav, Ras, Raf-1, MAPKK, MAPK and Pim-1 are also activated. Thus, Tpo activates a lineage-specific cascade as well as a specific JAK-STAT cascade and a common signaling cascade.
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PMID:Regulation of megakaryocytopoiesis by thrombopoietin and stromal cells. 920 16

In vascular smooth muscle cells, the induction of early growth response genes involves the Janus kinase (JAK)/signal transducer and activators of transcription (STAT) and the Ras/Raf-1/mitogen-activated protein kinase cascades. In the present study, we found that electroporation of antibodies against MEK1 or ERK1 abolished vascular smooth muscle cell proliferation in response to either platelet-derived growth factor or angiotensin II. However, anti-STAT1 or -STAT3 antibody electroporation abolished proliferative responses only to angiotensin II and not to platelet-derived growth factor. AG-490, a specific inhibitor of the JAK2 tyrosine kinase, prevented proliferation of vascular smooth muscle cells, complex formation between JAK2 and Raf-1, the tyrosine phosphorylation of Raf-1, and the activation of ERK1 in response to either angiotensin II or platelet-derived growth factor. However, AG-490 had no effect on angiotensin II- or platelet-derived growth factor-induced Ras/Raf-1 complex formation. Our results indicate that: 1) STAT proteins play an essential role in angiotensin II-induced vascular smooth muscle cell proliferation, 2) JAK2 plays an essential role in the tyrosine phosphorylation of Raf-1, and 3) convergent mitogenic signaling cascades involving the cytosolic kinases JAK2, MEK1, and ERK1 mediate vascular smooth muscle cell proliferation in response to both growth factor and G protein-coupled receptors.
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PMID:Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II- and platelet-derived growth factor-induced vascular smooth muscle cell proliferation. 930 39

Angiotensin II (Ang II) and basic fibroblast growth factor (bFGF) are important modulators of cell growth under physiological and pathophysiological conditions. We and others have previously shown that these growth factors increase insulin-like growth factor-1 receptor (IGF-1R) number and mRNA in vascular smooth muscle cells and that this effect is transcriptionally regulated. To study the mechanisms and the signaling pathways involved, IGF-1R promoter reporter constructs were transiently transfected in CHO-AT1 cells that overexpress angiotensin AT1 receptors. Our findings indicate that Ang II and bFGF significantly increased IGF-1R promoter activity up to 7- and 3-fold, respectively. The effect induced by Ang II was mediated via a tyrosine kinase-dependent mechanism, since tyrphostin A25 largely inhibited the Ang II-induced increase in promoter activity. In addition, co-transfection of dominant negative Ras, Raf, and MEK1 or pretreatment with the MEK inhibitor PD 98059 dose-dependently decreased both the Ang II- and bFGF-induced increase in IGF-1R transcription and protein expression, suggesting that the Ras-Raf-mitogen-activated protein kinase kinase pathway is required for both growth factors. Reactive oxygen species have been shown to act as second messengers in Ang II-induced signaling, and activation of the transcription factor NF-kappaB is redox-sensitive. While co-transfection of dominant negative IkappaBalpha mutant completely inhibited the Ang II-induced increase in transcription, it had no effect on the bFGF signaling. In contrast, co-transfection studies indicated that the transcription factors STAT1, STAT3, and c-Jun and the Janus kinase 2 kinase are required in the signaling pathway of bFGF, whereas only dominant c-Jun inhibited the Ang II-induced effect. In summary, these data demonstrate that Ang II and bFGF increase IGF-1R gene transcription via distinct as well as shared pathways and have important implications for understanding growth-stimulatory effects of these growth factors on vascular cells.
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PMID:Distinct and common pathways in the regulation of insulin-like growth factor-1 receptor gene expression by angiotensin II and basic fibroblast growth factor. 992 Aug 98

Activation of cytosolic phospholipase A(2 )(cPLA(2)) is a prerequisite for the formation of the transcription factor complex interferon-stimulated gene factor 3 (ISGF3) in response to interferon-alpha (IFN-alpha). Here we show that p38 mitogen-activated protein kinase (MAPK), an activator of cPLA(2), is essential for both IFN-alpha and IFN-gamma signalling. SB203580, a specific inhibitor of p38, was found to inhibit ISGF3 formation but had no apparent effects on signal transducer and activator of transcription (STAT)1 homodimer formation. Regardless of this, the antiviral activities of both IFN-alpha and IFN-gamma were attenuated by SB203580. Treatment with either IFN led to rapid and transient activation of p38. Both IFNs induced STAT1 Ser727 phosphorylation, which was inhibited by SB203580 but not by an extracellular signal related kinase (ERK)1/2 inhibitor (PD98059). In an inducible 3T3-L1 clone, expression of dominant-negative p38 led to defective STAT1 serine phosphorylation and diminished IFN-gamma-mediated protection against viral killing. Reporter activity mediated by ISGF3 or STAT1 homodimer was diminished by SB203580 and enhanced by a constitutively active mutant of MKK6, the upstream activator of p38. Therefore, p38 plays a key role in the serine phosphorylation of STAT1 and transcriptional changes induced by both IFNs.
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PMID:p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. 1052 4

Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate specificity and restricted expression. MMP-13 is specifically expressed by transformed human keratinocytes in squamous cell carcinomas in vivo and its expression correlates with their invasion capacity. Here, we show, that interferon-gamma (IFN-gamma) markedly inhibits expression of MMP-13 by human cutaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal keratinocytes (A-5 cells) at the transcriptional level. In addition, IFN-gamma inhibits collagenase-1 (MMP-1) expression in these cells. IFN-gamma abolished the enhancement of MMP-13 and MMP-1 expression by transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), and inhibited invasion of A-5 cells through type I collagen. IFN-gamma also rapidly and transiently activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by specific MEK1,2 inhibitor PD98059 partially (by 50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13 expression by IFN-gamma. Furthermore, Ser-727 phosphorylation of STAT1 by ERK1,2, or independently of ERK1,2 activation is associated with marked reduction in MMP-13 expression. These observations identify a novel role for IFN-gamma as a potent inhibitor of collagenolytic activity and invasion of transformed squamous epithelial cells, and show that inhibition of MMP-13 expression by IFN-gamma involves activation of ERK1,2 and STAT1.
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PMID:Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-gamma is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1. 1064 3

Rat eosinophil survival was prolonged by recombinant rat IL-5 prepared by the baculovirus expression system. The IL-5-induced prolongation of eosinophil survival was dose-dependently inhibited by the protein synthesis inhibitor cycloheximide, the DNA-dependent RNA synthesis inhibitor actinomycin D, and the tyrosine kinase inhibitor herbimycin A. The MEK-1 inhibitor PD98059 inhibited IL-5-induced phosphorylation of both p44 and p42 MAP kinases, but the IL-5-induced prolongation of eosinophil survival was not inhibited. In contrast, the JAK2 inhibitor AG490 inhibited the IL-5-induced prolongation of eosinophil survival. Treatment of eosinophils with IL-5 resulted in phosphorylation of STAT5 but not STAT1, and the IL-5-induced phosphorylation of STAT5 was inhibited by AG490. These findings suggest that recombinant rat IL-5 activates JAK2 tyrosine kinase, which phosphorylates STAT5, and induces protein synthesis required for the prolongation of rat eosinophil survival.
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PMID:Analysis of the prolongation of rat eosinophil survival induced by recombinant rat interleukin-5. 1086 6

The effect of ultraviolet A (UVA) radiation on the DNA-binding activity of the transcription factor STAT1 was studied by electromobility shift assay in the human keratinocyte cell line NCTC 2544. The STAT1-binding activity exhibited a biphasic pattern as a function of UVA doses. For UVA doses lower than 0.6 J/cm(2), a dose-dependent increase in STAT1 activity was observed. In a second phase, with higher UVA doses (1.5 to 9 J/cm(2)), the activity decreased and reached control value at 6 J/cm2. The enhancement of STAT1 activity was transient, peaked at 1 h after UV irradiation, and regularly decreased to control value 24 h after UV. Genistein, a tyrosine kinase inhibitor, H7, a serine/threonine kinase inhibitor, and PD 98059, a MEK inhibitor, prevented the UVA-induced enhancement of STAT1-binding activity, suggesting the involvement of Tyr, Ser/Thr kinases, and MEK in the observed effect. Immunoblot analysis directly demonstrated that the amount of Tyr-phosphorylated STAT1 was parallel to its DNA-binding activity. Immunoblot analysis also demonstrated the nuclear transport of STAT1 after UVA irradiation at low doses. At high doses, a decrease in the STAT1 level was observed both in the cytoplasmic and the nuclear compartments, suggesting that the inactivation was due to a degradation process. UVA irradiation initiated a dose-dependent increase in lipid peroxidation products and reactive oxygen species. Furthermore, the involvement of the oxidative stress in the UVA-induced effect on STAT1 activity is suggested by the protective action of the antioxidants alpha-tocopherol and N-acetylcysteine on both the activation phase (UVA doses lower than 1.5 J/cm(2)) and the inhibitory phase. By contrast, the pro-oxidant drug buthionine sulfoximine enhanced the effect of UVA on STAT1-binding activity. Since STATs are known as transducers of cytokine action, the enhancement of STAT1 activity by low doses of UVA might be related to the proinflammatory effect of solar radiations at the skin level.
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PMID:Biphasic effect of UVA radiation on STAT1 activity and tyrosine phosphorylation in cultured human keratinocytes. 1092 61

The growth-stimulating effects of thrombin are mediated primarily via activation of a G protein-coupled receptor, PAR-1. Because PAR-1 has no intrinsic tyrosine kinase activity, yet requires tyrosine phosphorylation events to induce mitogenesis, we investigated the role of the Janus tyrosine kinases (JAKs) in thrombin-mediated signaling. JAK2 was activated rapidly in rat vascular smooth muscle cells (VSMC) treated with thrombin, and signal transducers and activators of transcription (STAT1 and STAT3) were phosphorylated and translocated to the nucleus in a JAK2-dependent manner. AG-490, a JAK2-specific inhibitor, and a dominant negative JAK2 mutant inhibited thrombin-induced ERK2 activity and VSMC proliferation suggesting that JAK2 is upstream of the Ras/Raf/MEK/ERK pathway. To elucidate the functional significance of JAK-STAT activation, we studied the effect of thrombin on heat shock protein (Hsp) expression, based upon the following: 1) reports that thrombin stimulates reactive oxygen species production in VSMC; 2) the putative role of Hsps in modulating cellular responses to reactive oxygen species; and 3) the presence of functional STAT1/3-binding sites in Hsp70 and Hsp90beta promoters. Indeed, thrombin up-regulated Hsp70 and Hsp90 protein expression via enhanced binding of STATs to cognate binding sites in the Hsp70 and Hsp90 promoters. Together, these results suggest that JAK-STAT pathway activation is necessary for thrombin-induced VSMC growth and Hsp gene expression.
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PMID:Thrombin regulates vascular smooth muscle cell growth and heat shock proteins via the JAK-STAT pathway. 1127 37


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