Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urocortin (Ucn), is a peptide related to hypothalamic corticotrophin-releasing factor (CRF) and binds with a high affinity to the CRF-R2 beta receptor which is expressed in the heart. Ucn promotes cardiac myocyte survival against hypoxia reoxygenation (HR) injury and this involves activation of the mitogen activated protein kinase pathway (MEK1/2 p42/44 MAPK). In this study we report that Ucn stimulates the phosphorylation of protein kinase B (PKB/Akt) via phosphatidylinositol (PI) 3-OH kinase (PI-3 kinase). To investigate the signalling pathways that mediate the anti-apoptotic and cell survival effect of Ucn in hypoxia reoxygenation (HR), gene based inhibitors of MEK1/2, PI-3 kinase and Akt were over-expressed in rat neonatal cardiac myocytes and cell survival effects against HR were assessed. The dominant negative mutants of the MEK1/2, PI-3 kinase and Akt inhibited Ucn mediated cardioprotection in HR and active PI-3 kinase was itself cardioprotective. In addition, chemical inhibitors of the PI-3 kinase pathway, wortmannin and LY294002 inhibit Ucn mediated cardioprotection in HR in both neonatal and adult cardiac myocytes. Hence the PI-3 kinase/Akt pathway is required in addition to MEK1/2 to mediate Ucn cardioprotection in HR. To our knowledge this is the first report of the activation of the PI-3 kinase/Akt pathway by a member of the CRF family of peptides.
 ...
PMID:Activation of protein kinase B/Akt by urocortin is essential for its ability to protect cardiac cells against hypoxia/reoxygenation-induced cell death. 1199 36

beta-Arrestin-1 mediates agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCRs) and is also essential for GPCR mitogenic signaling. In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by beta-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation. Here, we report that treatment of cells for 12 h with insulin (100 ng/ml) induces an approximately 50% decrease in cellular beta-arrestin-1 content due to ubiquitination of beta-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in beta-arrestin-1 content was blocked by inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with wortmannin and PD98059, respectively. We also found a marked decrease in the association of beta-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, beta-arrestin-1-downregulated cells, there was complete inhibition of lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase phosphorylation. This was associated with a decrease in beta-arrestin-1 association with the beta2-AR as well as a decrease in beta-arrestin-1-Src and Src-beta2-AR association. Ectopic expression of wild-type beta-arrestin-1 in insulin-treated cells in which endogenous beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. In conclusion, we found the following. (i) Chronic insulin treatment leads to enhanced beta-arrestin-1 degradation. (ii) This downregulation of endogenous beta-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type beta-arrestin-1. (iii) Finally, these results describe a novel mechanism for heterologous desensitization, whereby insulin treatment can impair GPCR signaling, and highlight the importance of beta-arrestin-1 as a target molecule for this desensitization mechanism.
 ...
PMID:Insulin induces heterologous desensitization of G-protein-coupled receptor and insulin-like growth factor I signaling by downregulating beta-arrestin-1. 1216 19

At a low-oxygen tension, cells increase the expression of several genes (such as erythropoietin, the vascular endothelial growth factor, and glycolytic enzymes) in order to adapt to hypoxic stress. A common transactivator, named the hypoxia-inducible factor 1 (HIF-1) activates these genes. HIF-1 is a heterodimeric transactivator that is composed of alpha and beta subunits. HIF-1 activity is primarily determined by the hypoxia-induced stabilization of the alpha subunit, whereas the HIF-1beta subunit is expressed constitutively. Our previous observation implied that the MEK-1/p42/p44 MAPK pathway is involved in the hypoxia-induced transactivation ability, but not in the stabilization and DNA binding of HIF-1alpha. In this paper, we dissected the transactivation domain of HIF-1alpha in more detail, and tested the correlation between specific domains of HIF-1alpha and specific signaling pathways. We designed several fusion proteins that contain deletion mutants of HIF-1alpha that is linked to the DNA binding domain of the yeast protein Gal4. By using the Gal4-driven reporter system, we tested the transactivation activities of the Gal4/HIF-1alpha fusion proteins in Hep3B cells. Our findings suggest that tyrosine kinases, the MEK-1/p42/p44 MAPK pathway, but not the PI-3 kinase/Akt pathway, are involved in the hypoxia-induced transactivation of HIF-1alpha. We have shown that the functional transactivation activities are located at both 522-649 and 650-822 amino acids of HIF-1alpha. Treatment of PD98059, a MEK-1 inhibitor, blocked the hypoxia-induced transactivation abilities of both the 522-649 and 650-822 amino acids of the C-terminal half of HIF-1alpha. This implies that the MEK-1/p42/p44 MAPK signaling pathway cannot distinguish between the two hypoxia-induced transactivation domains.
 ...
PMID:Two transactivation domains of hypoxia-inducible factor-1alpha regulated by the MEK-1/p42/p44 MAPK pathway. 1224 58

Within epithelial tissue, cells are held together by specialized lateral junctions. At particular stages of development and in pathological processes such as metastasis, cells break down the intercellular junctions, separate from the epithelial sheet and migrate individually. Despite the importance of these processes, little is understood about the regulatory mechanisms of active cell separation. In view of the effects of insulin-like growth factor I (IGF-I) on mammary gland development and cancer, we developed a model using MCF-7 human breast cancer cells in which the process of cell separation can be induced by IGF-I. The separation was enhanced in MCF-7 cells overexpressing the IGF-IR and blocked in the cells expressing a dead-kinase mutant of this receptor. Activation of the IGF-IR resulted in a rapid formation of motile actin microspikes at the regions of cell-cell contacts, disorganization of mature adherens junctions and the onset of cell migration. In cell separation, the signaling between the IGF-IR kinase and actin required phosphatidylinositol 3 (PI 3)-kinase-generated phospholipids but not MAP kinases and was mediated by alpha-actinin. The activity of MEK1/2 kinases was needed for consecutive cell migration. This work also defined a new function for alpha-actinin. Upon IGF-IR activation, green fluorescence protein (GFP)-labeled alpha-actinin concentrated at the base of actin microspikes. Deletion of the N-terminal actin-binding domain of alpha-actinin prevented this redistribution, indicating that this domain is necessary. Detection of the C-terminal tail of alpha-actinin reduced the number of microspikes, showing that alpha-actinin has a role in the development of microspikes and is not passively reorganized with filamentous actin. We suggest that the signaling pathway from the IGF-IR kinase through the PI-3 kinase to alpha-actinin participates in the rapid organization of actin into microspikes at the cell-cell junctions and leads to active cell separation, whereas signaling through ERK1/2 MAP kinases controls cell migration following cell separation.
 ...
PMID:Functional role of alpha-actinin, PI 3-kinase and MEK1/2 in insulin-like growth factor I receptor kinase regulated motility of human breast carcinoma cells. 1235 18

Insulin-like growth factor 1 receptor (IGF-1R) expression is augmented on T cells upon ligation of CD28, and this promotes IGF-1-mediated protection from Fas-induced cell death for up to 6 days. To determine the mechanism of action of IGF-1R in T-cell expansion, we investigated the signalling pathways activated by IGF-1 in T cells and in Jurkat cells. We found that IGF-1 transiently induces Akt, jun N-terminal kinases (JNK), and c-Jun phosphorylation in activated T cells, with JNK and c-Jun phosphorylation occurring faster than Akt phosphorylation. To mimic IGF-1R expression levels in CD28-stimulated Jurkat cells these cells were stably transfected to over-express the IGF-1R. Jurkat/IGF-1R cells exhibited enhanced constitutive Akt phosphorylation compared with mock-transfected controls, but IGF-1 induced transient phosphorylation of MKK4, JNKs, and c-Jun. Inhibition of PI-3 kinase activity and Akt phosphorylation with LY294002 totally suppressed IGF-1-mediated protection from Fas killing in activated T cells, but only partially suppressed IGF-1-mediated protection in Jurkat/IGF-1R cells. However, either dicumarol in T cells or a dominant negative JNK1 (APF) in Jurkat/IGF-1R cells greatly suppressed IGF-1-mediated protection from Fas killing. Together, these data demonstrate that IGF-1-mediated activation of JNKs and PI-3 kinase contributes to normal T-cell survival, whereas the JNK pathway may be more important in Jurkat leukaemia cells.
 ...
PMID:Insulin-like growth factor-1 activates Akt and Jun N-terminal kinases (JNKs) in promoting the survival of T lymphocytes. 1246 Jan 91

Activation of G-protein coupled muscarinic acetylcholine receptors and MAPKs/ERK-1/2 has been found to inhibit neural cell apoptosis and promote neural cell survival. Bcl-2 protein family also plays an important role in regulating neural cell apoptosis and survival. However, signaling pathways coupling muscarinic receptors to Bcl-2 family remains to be elucidated. In the present study, it was found that carbachol not only activated MEK/ERK-1/2 signaling pathways, but also increased the expression levels of Bcl-2 and phospho-Bad proteins in human neuroblastoma SH-SY5Y cells. These effects were blocked by a muscarinic receptor antagonist (atropine) and a MEK inhibitor(PD98059) and were significantly attenuated by a Src family kinases inhibitor(PP1) and a PKC inhibitor (bisindolymaleimide-I), but were not influenced by a G(i/o)-uncoupling reagent (pertussin toxin) and a PI-3 kinase inhibitor (wortmannin). Furthermore, carbachol also stimulated Bcl-2 promoter-driven luciferase gene expression in transfected SH-SY5Y cells. Co-transfection of Ras or Raf dominant negative mutants with the pBcl-2-Luc plasmid abolished carbachol s effects. These data suggested that muscarinic acetylcholine receptors regulated the expression of Bcl-2 protein family by Ras-ERK-1/2 signaling pathway involving the pertussin toxin-insensitive G-proteins, PKC and Src.
 ...
PMID:[G-protein-coupled muscarinic acetylcholine receptor activation up-regulates Bcl-2 and phospho-bad via Ras-ERK-1/2 signaling pathway]. 1251 26

Keloids are proliferative dermal growths representing a pathological wound-healing response. We report high proliferation rates in normal (NF) and keloid-derived fibroblasts (KF) cocultured with keloid-derived keratinocytes (KK). IGF binding protein (IGFBP)-3 mRNA and secreted IGFBP-3 in conditioned media were increased in NF cocultured with KK compared with NF but markedly reduced in KF cocultured with KK or normal keratinocytes (NK). IGFBP-2 and IGFBP-4 mRNA levels were elevated, whereas IGFBP-5 mRNA was decreased in KF cocultured with KK or NK. Significant increases in IGFBP-2 and -4 mRNA in KF cocultured with KK did not correlate with protein secretion. Downstream IGF signaling cascade components, phospho-Raf, phospho-MEK1/2, phospho-MAPK, PI-3 kinase, phospho-Akt, and phospho-Elk-1, were elevated in KF cocultured with KK. Addition of recombinant human IGFBP-3 or antibodies against IGF-I or IGF-IR significantly inhibited proliferation of KF. The bioavailability of IGF-I may be related to the levels of IGFBP-3 produced, which in turn influences KF proliferation, suggesting that modulation of IGF-I, IGF-IR, and IGFBP-3, individually or in combination, may represent novel approaches to the treatment of keloids.
 ...
PMID:Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid-derived keratinocytes in vitro. 1262 Aug 90

In this study, we identified whether mitogen-activated protein kinases (MAPKs) mediate the effects of angiopoietin-1 (Ang-1) on endothelial cell apoptosis. Exposure of human umbilical vein endothelial cells to Ang-1 (300 ng/ml) evoked within 15-30 min a 15-fold and a 5-fold increase in phosphorylation of ERK1/2 and p38 MAPKs, respectively. Inhibitors of the PI-3 kinase pathway attenuated Ang-1-induced ERK1/2 phosphorylation at a level up-stream from Raf and MEK1/2, but these inhibitors augmented Ang-1-induced p38 phosphorylation. When serum and growth supplements were withdrawn, the percentage of endothelial apoptosis tripled over 24 h compared with control cells. The presence of Ang-1 (300 ng/ml) significantly attenuated endothelial cell apoptosis and inhibited caspase-9, -7, and -3 activation. These antiapoptotic effects were augmented when a p38 inhibitor was combined with Ang-1, whereas inhibition of ERK1/2 eliminated the antiapoptotic properties of Ang-1. We conclude that both anti- (ERK1/2) and pro- (p38) apoptotic members of MAPKs are simultaneously activated by Ang-1 in endothelial cells and that activation of ERK1/2 by Ang-1 is mediated through the PI-3 kinase pathway. The strong antiapoptotic effects of the ERK and the PI-3 kinase pathways mask the proapoptotic function of p38 MAPKs resulting in net attenuation of apoptosis by Ang-1.
 ...
PMID:Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein kinases. 1282 93

Because ErbB-2 receptor is involved in hormone-independency for growth and metastasis of prostate cancer cells, the aim was to investigate the effects of quercetin on ErbB-2 and ErbB-3 expression and its critical components such as MAP kinase and PI-3 kinase. Hemocytometric counts and [3H]-thymidine incorporation were used to determine the effects of quercetin, EGF and TGF-alpha on cell proliferation and DNA synthesis in PC-3 and LnCap cells. Changes in ErbB-2, ErbB-3 and components of MAPK and PI-3K pathways were analyzed by Western blot analysis. Treatment of PC-3 and LnCap cells with quercetin resulted in a dose-dependent growth inhibition. The rate of DNA synthesis was decreased by 40, 55 and 65% on treatment with 14.5, 29.0 and 58.0 microM of quercetin, respectively. Concomitantly, these treatments led to a dose-dependent decrease in ErbB-2, ErbB-3 and their basal autophosphorylation levels as compared to controls. Cyclin D1 expression and basal phosphorylation of c-Raf, MAPK, Elk-1 and Akt-1 in PC-3 cells was also inhibited by quercetin treatment. Co-treating PC-3 cells with quercetin significantly attenuated EGF- and TGF-alpha-induced growth and phosphorylation of ErbB-2, ErbB-3, c-Raf, MAPK kinase 1/2 (MEK1/2), MAPK, Elk-1 and Akt-1. Since ErbB receptor is important for growth, metastasis and drug resistance, inhibition of ErbB-2 and ErbB-3 by pharmacological doses of quercetin may provide a new approach for treatment of prostate cancers.
 ...
PMID:Inhibition of ErbB-2 and ErbB-3 expression by quercetin prevents transforming growth factor alpha (TGF-alpha)- and epidermal growth factor (EGF)-induced human PC-3 prostate cancer cell proliferation. 1288 23

Nischarin, a cytosolic protein that binds the alpha5beta1 integrin, plays an important role in fibroblast migration, and in regulation of the actin cytoskeleton. The effect of Nischarin on Rac induced migration and invasion by breast and colon epithelial cell lines has been determined. In these cells, Rac potently induced migration, as well as invasion of matrix; both of these events were strongly inhibited by overexpression of Nischarin. To understand the mechanism of Nischarin's inhibitory role in Rac induced cell migration, several effector domain mutants of Rac1 were employed. Nischarin was able to inhibit migration induced by Rac effector mutants that can activate PAK and JNK, but not migration stimulated by other Rac mutants. Further, Nischarin inhibited PAK induced cell migration, while not affecting migration induced by MEKK1, a Rac effector in the JNK pathway. In addition, Nischarin failed to inhibit migration induced by MEK1, a downstream effector in the Ras-Raf-MEK-Erk signaling cascade. Furthermore, Nischarin does not affect Rac mediated JNK and PI3K activities. However, Rac induced migration and invasion were effectively blocked by pharmacological inhibitors of PI-3 kinase and MEK. These results suggest that several pathways contribute to cell migration, but that Nischarin selectively inhibits Rac driven signaling cascades that affect migration through PAK.
 ...
PMID:Nischarin inhibits Rac induced migration and invasion of epithelial cells by affecting signaling cascades involving PAK. 1291 32


<< Previous 1 2 3 4 5 6 Next >>