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)

1. The effect of protein tyrosine kinase inhibitors on human adenosine A1 receptor-mediated [3H]-inositol phosphate ([3H]-IP) accumulation has been studied in transfected Chinese hamster ovary cells (CHO-A1) cells. 2. In agreement with our previous studies the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) stimulated the accumulation of [3H]-IPs in CHO-A1 cells. Pre-treatment with the broad spectrum tyrosine kinase inhibitor genistein (100 microM; 30 min) potentiated the responses elicited by 1 microM (199+/-17% of control CPA response) and 10 microM CPA (234+/-15%). Similarly, tyrphostin A47 (100 microM) potentiated the accumulation of [3H]-IPs elicited by 1 microM CPA (280+/-32%). 3. Genistein (EC50 = 13.7+/-1.2 microM) and tyrphostin A47 (EC50 = 10.4+/-3.9 microM) potentiated the [3H]-IP response to 1 microM CPA in a concentration-dependent manner. 4. Pre-incubation with the inactive analogues of genistein and tyrphostin A47, daidzein (100 microM; 30 min) and tyrphostin A1 (100 microM; 30 min), respectively, had no significant effect on the accumulation of [3H]-IPs elicited by 1 microM CPA. 5. Genistein (100 microM) had no significant effect on the accumulation of [3H]-IPs produced by the endogenous thrombin receptor (1 u ml(-1); 100+/-10% of control response). In contrast, tyrphostin A47 produced a small augmentation of the thrombin [3H]-IP response (148+/-13%). 6. Genistein (100 microM) had no effect on the [3H]-IP response produced by activation of the endogenous Gq-protein coupled CCK(A) receptor with the sulphated C-terminal octapeptide of cholecystokinin (1 microM CCK-8; 96+/-6% of control). In contrast, tyrphostin A47 (100 microM) caused a small but significant increase in the response to 1 microM CCK-8 (113+/-3% of control). 7. The phosphatidylinositol 3-kinase inhibitor LY 294002 (30 microM) and the MAP kinase kinase inhibitor PD 98059 (50 microM) had no significant effect on the [3H]-IP responses produced by 1 microM CPA and 1 microM CCK-8. 8. These observations suggest that a tyrosine kinase-dependent pathway may be involved in the regulation of human adenosine A1 receptor mediated [3H]-IP responses in CHO-A1 cells.
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PMID:Potentiation of adenosine A1 receptor-mediated inositol phospholipid hydrolysis by tyrosine kinase inhibitors in CHO cells. 984 44

Several types of kinase inhibitors were used to investigate the possible signaling pathways leading to the chemotaxis of rat peritoneal neutrophils toward macrophage inflammatory protein-2, cytokine-induced neutrophil chemoattractant-1, and platelet-activating factor. The chemotaxis and shape changes induced by each of these chemoattractants were strongly inhibited by a tyrosine kinase inhibitor (herbimycin A) and protein kinase C inhibitors (H-7 (1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride) and calphostin C). The formation of phosphatidyl 3,4,5-triphosphate in chemoattractant-stimulated neutrophils was completely inhibited by 100 nM of wortmannin, an inhibitor of phosphatidylinositol 3-kinase, whereas the chemotaxis toward each of these chemoattractants was partially inhibited (50% inhibition). The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK-1) inhibitor PD 98059 did not inhibit the neutrophil chemotaxis. These findings suggest that the activation of tyrosine kinase and protein kinase C strongly participates in neutrophil chemotaxis and that the activation of phosphatidylinositol 3-kinase is partially involved, but that the activation of mitogen-activated protein kinase is not involved in neutrophil chemotaxis. The cross-linking of the signaling pathways for chemotaxis toward each chemoattractant was also examined.
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PMID:Pharmacological analysis of protein kinases responsible for chemotaxis of rat peritoneal neutrophils. 985 86

Retinoic acid (RA) has profound effects on epidermal homeostasis; however, the molecular mechanisms by which retinoids regulate keratinocyte cell proliferation and differentiation are not well understood. Here we report that mRNA expression of heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF family of growth factors, is induced by RA in human keratinocytes and skin, and is overexpressed in the context of epidermal hyperplasia in vivo. Treatment of normal adult human keratinocytes with micromolar concentrations of RA significantly induced the expression of HB-EGF. The response was efficiently blocked by specific inhibitors of ErbB tyrosine kinase activity, MAP kinase kinase (MEK), or p38 stress-activated protein kinase. RA also enhanced the induction of HB-EGF mRNA in human skin organ culture, an ex vivo model system displaying many similarities to wound healing in vivo. HB-EGF transcripts were markedly increased in human skin by topical treatment with RA under conditions known to provoke epidermal hyperplasia. HB-EGF transcripts were also markedly overexpressed in the hyperplastic epidermis of psoriatic lesions, relative to normal skin. These results support the hypothesis that the effects of RA on epidermal hyperplasia are mediated at least in part by HB-EGF, and suggest that signal transduction mechanisms other than or in addition to nuclear RA receptors contribute to this effect.
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PMID:Retinoid regulation of heparin-binding EGF-like growth factor gene expression in human keratinocytes and skin. 985 42

Cell motility is induced by many growth factors acting through cognate receptors with intrinsic tyrosine kinase activity (RPTK). However, most of the links between receptor activation and the biophysical processes of cell motility remain undeciphered. We have focused on the mechanisms by which the EGF receptor (EGFR) actuates fibroblast cell motility in an attempt to define this integrated process in one system. Our working model is that divergent, but interconnected pathways lead to the biophysical processes necessary for cell motility: cytoskeleton reorganization, membrane extension, formation of new adhesions to substratum, cell contraction, and release of adhesions at the rear. We postulate that for any given growth factor some of the pathways/processes will be actively signaled and rate-limiting, while others will be permissive due to background low-level activation. Certain couplings have been defined, such as PLCgamma and actin modifying proteins being involved in cytoskeletal reorganization and lamellipod extension and MEK being implicated in detachment from substratum. Others are suggested by complementary investigations in integrin-mediated motility, including rac in membrane protrusion, rho in new adhesions, myosin II motors in contraction, and calpain in detachment, but have yet to be placed in growth factor-induced motility. Our model postulates that many biochemical pathways will be shared between chemokinetic and haptokinetic motility but that select pathways will be activated only during RPTK-enhanced motility.
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PMID:Epidermal growth factor receptor-mediated motility in fibroblasts. 985 37

Extracellular signal-regulated kinases (ERK, also known as mitogen-activated protein kinases) are serine-threonine kinases transducing signals elicited upon ligand binding to several tyrosine kinase-associated receptors. We have reported that ERK2 phosphorylation and activation follows engagement of the low affinity receptor for the Fc portion of IgG (CD16) on NK cells, and is necessary for CD16-induced TNF-alpha mRNA expression. Here, we analyzed the involvement of ERK in NK cell-mediated cytotoxicity and IFN-gamma expression induced upon stimulation with targets cells, coated or not with Abs. Our data indicate that, as with immune complexes, ERK2 phosphorylation occurs in human primary NK cells upon interaction with target cells sensitive to granule exocytosis-mediated spontaneous cytotoxicity, and that this regulates both target cell- and immune complex-induced cytotoxicity and IFN-gamma mRNA expression. A specific inhibitor of mitogen-activated protein kinase kinase reduced both spontaneous and Ab-dependent cytotoxicity in a dose-dependent manner involving, at least in part, inhibition of granule exocytosis without affecting effector/target cell interaction and rearrangement of the cytoskeleton proteins actin and tubulin. Involvement of ERK in the regulation of Ca2+-dependent cell-mediated cytotoxicity was confirmed, using a genetic approach, in primary NK cells infected with a recombinant vaccinia virus encoding an ERK inactive mutant. These data indicate that the biochemical pathways elicited in NK cells upon engagement of receptors responsible for either spontaneous or Ab-dependent recognition of target cells, although distinct, utilize ERK as one of their downstream molecules to regulate effector functions.
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PMID:Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases. 986 93

Cross-linking the high affinity IgE receptor Fc epsilonRI of basophils and mast cells activates receptor-associated protein-tyrosine kinases and stimulates a signaling cascade leading to secretion, ruffling, spreading, and cytokine production. Previous evidence that the pan-prenylation inhibitor lovastatin blocks Ag-stimulated Ca2+ influx, secretion, and membrane/cytoskeletal responses implicated isoprenylated proteins in the Fc epsilonRI-coupled signaling cascade but could not distinguish between contributions of C15 (farnesylated) and C20 (geranylgeranylated) species. Here we establish concentrations of lovastatin and the farnesyl-specific inhibitor BZA-5B that inhibit the farnesylation and Ag-induced activation of Ras species in RBL-2H3 cells (H-Ras, K-RasA, and K-RasB). These inhibitors have little effect on tyrosine kinase activation, which initiates Fc epsilonRI signaling. Although Ras is disabled, only lovastatin substantially blocks Raf-1 activation, and neither inhibitor affects mitogen-activated protein kinase kinase/extracellular signal regulated kinase kinase (MEK) or ERK1/ERK2 activation. Thus, the pathway to Fc epsilonRI-mediated MEK/ERK and ERK activation can apparently bypass Ras and Raf-1. Predictably, only lovastatin inhibits Ag-induced ruffling, spreading, and secretion, previously linked to geranylgeranylated Rho and Rab family members. Additionally, only lovastatin inhibits phospholipase Cgamma-mediated inositol (1,4,5) trisphosphate production, sustained Ca2+ influx, and Ca2+-dependent IL-4 production, suggesting novel roles for geranylgeranylated (lovastatin-sensitive, BZA-5B-insensitive) proteins in Fc epsilonRI signal propagation. Remarkably, BZA-5B concentrations too low to inactivate Ras reduce the lag time to Ag-induced Ca2+ stores release and enhance secretion. These results link a non-Ras farnesylated protein(s) to the negative regulation of Ca2+ release from intracellular stores and secretion. We identified no clear role for Ras in Fc epsilonRI-coupled signaling but suggest its involvement in mast cell growth regulation based on the inhibition of cell proliferation by both BZA-5B and lovastatin.
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PMID:MEK and ERK activation in ras-disabled RBL-2H3 mast cells and novel roles for geranylgeranylated and farnesylated proteins in Fc epsilonRI-mediated signaling. 986 3

Heterotrimeric G protein beta gamma subunit (Gbeta gamma) mediates signals to two types of stress-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase, in mammalian cells. To investigate the signaling mechanism whereby Gbeta gamma regulates the activity of JNK, we transfected kinase-deficient mutants of two JNK kinases, mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7), into human embryonal kidney 293 cells. Gbeta gamma-induced JNK activation was blocked by kinase-deficient MKK4 and to a lesser extent by kinase-deficient MKK7. Moreover, Gbeta gamma increased MKK4 activity by 6-fold and MKK7 activity by 2-fold. MKK4 activation by Gbeta gamma was blocked by dominant-negative Rho and Cdc42, whereas MKK7 activation was blocked by dominant-negative Rac. In addition, Gbeta gamma-mediated MKK4 activation, but not MKK7 activation, was inhibited completely by specific tyrosine kinase inhibitors PP2 and PP1. These results indicate that Gbeta gamma induces JNK activation mainly through MKK4 activation dependent on Rho, Cdc42, and tyrosine kinase, and to a lesser extent through MKK7 activation dependent on Rac.
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PMID:Differential regulation of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7) by signaling from G protein beta gamma subunit in human embryonal kidney 293 cells. 989 Sep 51

Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimensional collagen. Collagen-related induction of MMP-13 expression was dependent on tyrosine kinase activity, as it was abolished by treatment of fibroblasts with tyrosine kinase inhibitors genistein and herbimycin A. Contact of fibroblasts to three-dimensional collagen resulted in simultaneous activation of mitogen-activated protein kinases (MAPKs) in three distinct subgroups: extracellular signal-regulated kinase (ERK)1 and ERK2, Jun N-terminal kinase/stress-activated protein kinase, and p38. Induction of MMP-13 expression was inhibited by treatment of fibroblasts with a specific p38 inhibitor, SB 203580, whereas blocking the ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by PD 98059, a selective inhibitor of MEK1,2 activation potently augmented MMP-13 expression. Furthermore, specific activation of ERK1,2 pathway by 12-O-tetradecanoylphorbol-13-acetate markedly suppressed MMP-13 expression in dermal fibroblasts in collagen gel. These results show that collagen-dependent induction of MMP-13 in dermal fibroblasts requires p38 activity, and is inhibited by activation of ERK1,2. Therefore, the balance between the activity of ERK1,2 and p38 MAPK pathways appears to be crucial in regulation of MMP-13 expression in dermal fibroblasts, suggesting that p38 MAPK may serve as a target for selective inhibition of collagen degradation, e.g. in chronic dermal ulcers.
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PMID:Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. 989 Oct 15

Receptors for interleukins, colony stimulating factors, and hormones have a homology in their extracellular regions, characterized by the conserved cysteine residues and the tryptophan-serine-x-tryptophan-serine motif, thus, they are classified to the type 1 cytokine receptor superfamily. Janus tyrosine kinase (JAKs) have been found to be involved in the signal transduction through type I cytokine receptors. JAKs associate with the membrane proximal region in the cytoplasmic domain having box1 and box2, which are conserved among the family, and upon the stimulation JAKs can be aggregated following the receptor dimerization and activated probably by transphosphorylation. JAKs then phosphorylate the receptor and various signal transducing molecules, including STATs (signal transducer and activator of transcriptions) and other SH2-containing adapter molecules. STATs were initially identified as transcription factors containing a SH2 domain and regulating interferons-inducible genes. STATs can be tyrosine phosphorylated by JAKs and form dimer (either hetero- or homo-dimers) to enter the nucleus, resulting in the expression of a set of genes. On the other hand, adapter molecules such as Shc, GRB2, and SHP-2 have been shown to link the cytokine receptors to Ras, followed by the activation of the Raf-MEK-MAP kinase pathway, leading to the activation of various transcription factors in the nucleus. These two signals are generated by different ways upon the stimulation of the receptors and they elicit a variety of biological functions in various cell types. In this review, we will discuss the mechanism by which cytokines activate JAKs, STATs, and a variety of adapter molecules. We further discuss the roles of each signal transduction pathways in the expression of biological activities of cytokines.
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PMID:Signal transduction through cytokine receptors. 991 44

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


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