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

---

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

Glycogen synthase kinase-3 (GSK3) is inactivated in vitro by p70 S6 kinase or MAP kinase-activated protein kinase-1 beta (MAPKAP kinase-1 beta; also known as Rsk-2). Here we show that GSK3 isoforms are inhibited by 40% within minutes after stimulation of the rat skeletal-muscle cell line L6 with insulin-like growth factor-1 (IGF-1) or insulin. GSK3 was similarly inhibited in rabbit skeletal muscle after an intravenous injection of insulin. Inhibition resulted from increased phosphorylation of GSK3, probably at a serine/threonine residue(s), because it was reversed by incubation with protein phosphatase-2A. Rapamycin blocked the activation of p70 S6 kinase by IGF-1 in L6 cells, but had no effect on the inhibition of GSK3 or the activation of MAPKAP kinase-1 beta. In contrast, wortmannin, a potent inhibitor of PtdIns 3-kinase, prevented the inactivation of GSK3 and the activation of MAPKAP kinase-1 beta and p70 S6 kinase by IGF-1 or insulin. Wortmannin also blocked the activation of p74raf-1. MAP kinase kinase and p42 MAP kinase, but not the formation of GTP-Ras by IGF-1. The results suggest that the stimulation of glycogen synthase by insulin/IGF-1 in skeletal muscle involves the MAP-KAP kinase-1-catalysed inhibition of GSK3, as well as the previously described activation of the glycogen-associated form of protein phosphatase-1.
...
PMID:The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. 794 42

The hormonal regulation of insulin-like growth factor binding protein (IGFBP)-1 and -4 mRNA was compared in serum-free primary rat hepatocyte cultures. The combination of dexamethasone and glucagon (Dex/Gluc) strongly increased IGFBP-1 and IGFBP-4 mRNA levels. Insulin suppressed Dex/Gluc-stimulated IGFBP-1 but not IGFBP-4 mRNA levels. In contrast, the peroxovanadium compound, bisperoxovanadium 1,10-phenanthroline (bpV(phen)), completely abrogated Dex/Gluc induction of both IGFBP mRNA species. Wortmannin and rapamycin blocked the inhibitory effect of insulin but not that of bpV(phen) on Dex/Gluc-stimulated IGFBP mRNA. Thus, although phosphatidylinositol 3'-kinase and p70s6k are necessary for insulin-mediated transcriptional inhibition of the IGFBP-1 gene, a signaling pathway, independent of phosphatidyloinositol 3'-kinase and p70s6k, is activated by bpV(phen) and mediates IGFBP-1 as well as IGFBP-4 mRNA inhibition. Mitogen-activated protein (MAP) kinase activity induced by insulin was suppressed to below basal levels in the presence of Dex/Gluc, whereas in response to bpV(phen), MAP kinase activity was high and unaffected by Dex/Gluc, consistent with a role of MAP kinases in bpV(phen)-mediated inhibition of IGFBP mRNA. The specific MAP kinase kinase (MEK) inhibitor, PD98059, inhibited insulin but not bpV(phen)-stimulated MAP kinase activity, suggesting that MAP kinases can be activated in a MEK-independent fashion. Peroxovanadium compounds are strong inhibitors of tyrosine phosphatases, which may inhibit specific tyrosine/threonine phosphatases involved in the negative regulation of MAP kinases.
...
PMID:Phosphatidylinositol 3'-kinase and p70s6k are required for insulin but not bisperoxovanadium 1,10-phenanthroline (bpV(phen)) inhibition of insulin-like growth factor binding protein gene expression. Evidence for MEK-independent activation of mitogen-activated protein kinase by bpV(phen). 899 39

Evidence has accumulated that suggests that insulin-like growth factors (IGFs) exert a positive influence on myoblast differentiation. We have undertaken to study the signalling events required for differentiation resulting from type-1 IGF receptor stimulation in C2 myoblasts, where autocrine production of IGF-II was abolished by means of antisense RNA. Exposure of the cells to IGFs leads to a rapid and sustained activation of phosphatidyl-inositol 3-kinase followed by the expression of Myod, myogenin and differentiation. The fungal metabolite, wortmannin, inhibits both PI 3-kinase and muscle differentiation with an IC 50 in the nanomolar range. IGFs are also known to cause a rapid activation of MAP kinase. However, the synthetic inhibitor of MEK, PD098059, which prevents MAP kinase activation, does not affect myoblast differentiation. These results provide evidence that PI 3-kinase, but not MAP kinase, is required for insulin-like growth factor receptor-dependent differentiation of muscle cells.
...
PMID:Wortmannin inhibits IGF-dependent differentiation in the mouse myogenic cell line C2. 923 22

hGrb10alpha (previously named Grb-IR) is a Src-homology 2 domain-containing protein that binds with high affinity to the tyrosine-phosphorylated insulin receptor and insulin-like growth factor-1 receptor. At least two isoforms of human Grb10, (hGrb10alpha and hGrb10beta), which differ in the pleckstrin homology (PH) domain and the N-terminal sequence, have previously been identified in insulin target tissues such as human skeletal muscle and fat cells. Here we report the cloning of the third isoform of the hGrb10 family (hGrb10gamma) from human skeletal muscle and its localization to human chromosome 7. We have also determined the human chromosome localization of Grb7 to 17q21-q22 and Grb14 to chromosome 2. hGrb10gamma contains an intact PH domain and an N-terminal sequence that is present in hGrb10alpha but absent in hGrb10beta. RNase protection assays and Western blot analysis showed that hGrb10alpha and hGrb10gamma are differentially expressed in insulin target cells including skeletal muscle, liver, and adipocyte cells. hGrb10gamma is also expressed in HeLa cells and various breast cancer cell lines. The protein bound with high affinity to the insulin receptor in cells, and the interaction was dependent on the tyrosine phosphorylation of the receptor. hGrb10gamma also underwent insulin-stimulated membrane translocation and serine phosphorylation. hGrb10gamma phosphorylation was inhibited by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase, and wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. Taken together, our data suggest that hGrb10 isoforms are potential downstream signaling components of the insulin receptor tyrosine kinase and that the PH domain may play an important role in the involvement of these isoforms in signal transduction pathways initiated by insulin and other growth factors.
...
PMID:Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma. 936 Sep 86

Cardiac hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by a number of qualitative and quantitative changes in gene expression. Most forms of hypertrophy in vivo are compensatory or adaptative responses to increased workload resulting from various physiological and/or pathological etiologies. Until severe pathological alterations become apparent, myocytes show no drastic morphological changes. On the level of gene expression, upregulation of the so-called fetal genes, i.e., beta-myosin heavy chain, alpha-skeletal and alpha-smooth muscle actin, and atrial natriuretic factor (ANF) may be observed concomitant with a downregulation of alpha-myosin heavy chain and the Ca pump of sarcoplasmic reticulum. The use of primary cell culture systems for cardiomyocytes as an in vitro model for the hypertrophic reaction has identified a number of different stimuli as mediators of cardiac myocyte hypertrophy. The molecular dissection of the different intracellular signaling pathways involved herein has uncovered a number of branching points to cytosolic and nuclear targets and has identified many interactions between these pathways. The individual administration of these hypertrophic stimuli, i.e., hormones, cytokines, growth factors, vasoactive peptides, and catecholamines, to cultured cardiomyocytes, reveals that each stimulus induces a distinct phenotype as characterized by gene expression pattern and cellular morphology. Surprisingly, triiodothyronine (T3) and basic fibroblast growth factor (bFGF) effect a similar cellular phenotype although they use completely different intracellular pathways. This phenotype is characterized by drastic inhibition of myofibrillar growth and by upregulation of alpha-smooth muscle actin. On the other hand, insulin-like growth factor (IGF) I, a factor promoting muscle cell differentiation, and bFGF, an inhibitor of differentiation, cause completely different cardiomyocyte phenotypes although both are known to signal via receptor tyrosine kinases and have been shown to activate the Ras-Raf-MEK-MAP kinase pathway. However, both IGF-I and bFGF depend on T3 to bring about their typical responses, i.e., T3 is permissive for the action of these two growth factors on the expression of alpha-smooth muscle actin and cell morphology. Most of the hypertrophic stimuli are balanced under normal circumstances in vivo. When this balance is disturbed, however, a pathological heart phenotype may become dominant. Thus the knowledge of signaling pathways and cellular responses triggered by hypertrophic stimuli may be essential for the implementation of therapeutic strategies in the treatment of cardiac hypertrophy.
...
PMID:Various hypertrophic stimuli induce distinct phenotypes in cardiomyocytes. 942 23

In response to hypoxia, mammalian cells express multiple gene products [including erythropoietin (EPO) and vascular endothelial growth factor (VEGF)] that serve to increase O2 delivery, as well as glucose transporters and glycolytic enzymes (such as enolase 1) that allow metabolic adaptation to decreased O2 availability. Increased transcription of the genes encoding these proteins in hypoxic cells is mediated by hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. Expression of HIF-1 and downstream genes can also be induced by exposure of cells to divalent metals (such as CoCl2) or iron chelators [such as desferrioxamine (DFO)]. We report here that the organomercurial compound mersalyl induced expression of VEGF and enolase 1 mRNA, as well as HIF-1 activity, in cultured cells. Expression of reporter genes containing hypoxia response elements from the EPO and VEGF genes was also induced by mersalyl treatment. However, mersalyl inhibited endogenous EPO mRNA expression induced by hypoxia, CoCl2, or DFO. In cells lacking expression of the insulin-like growth factor-1 receptor, mersalyl did not induce HIF-1 activity or VEGF mRNA expression, whereas induction by hypoxia, CoCl2, or DFO was unaffected. The mitogen-activated protein kinase kinase inhibitor PD098059 markedly reduced induction of HIF-1 by mersalyl but not by hypoxia. These results indicate that mersalyl induces expression of HIF-1 and a subset of hypoxia-inducible genes by a mechanism, involving the insulin-like growth factor-1 receptor and mitogen-activated protein kinase activity, that is distinct from mechanisms of induction by hypoxia, CoCl2, or DFO.
...
PMID:Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity. 980 9

Activation of the insulin-like growth factor (IGF) autocrine loop is required for myogenic differentiation and results in sustained activation of extracellular signal-regulated kinases-1 and -2 (ERK-1 and -2). We show here that insulin receptor substrate-1 (IRS-1) phosphorylation on tyrosine and serine residues and association with phosphatidylinositol 3-kinase (PI 3-kinase) are also associated with IGF-dependent myogenic differentiation. Down-regulation of IRS-1 is linked to its serine phosphorylation dependent on PI 3-kinase activity and appears required for differentiation to occur, as IRS-1 is not modified and continues to accumulate in a nondifferentiating myoblast cell line. Furthermore, inhibition of PI 3-kinase activity with LY294002 blocks differentiation, as demonstrated by inhibition of myogenin and myosin heavy chain expression and ERK activation. Blocking the Raf/MEK/ERK cascade with PD98059 does not block myogenic differentiation; however, myotubes do not survive. Thus, PI 3-kinase, in association with IRS-1, is involved in an ERK-independent signaling pathway in myoblasts required for IGF-dependent myogenic differentiation and in inducing sustained activation of ERKs necessary for later stages of differentiation.
...
PMID:Insulin receptor substrate-1 and phosphatidylinositol 3-kinase regulate extracellular signal-regulated kinase-dependent and -independent signaling pathways during myogenic differentiation. 984 61

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.
...
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

Invasion is an essential cellular response that plays an important role in a number of physiological and pathological processes. Matrix metalloproteinase (MMP) production and cell movement are diverse cellular responses integral to the process of invasion. The complexity of the invasive process suggests the necessity of coordinate activation of more than one signaling pathway in order to activate specific factors responsible for regulating these cellular responses. In this report, we demonstrate that cell movement and MMP-9 production are both directly dependent on the activation of endogenous ERK signaling in hepatocyte growth factor (HGF)-or epidermal growth factor (EGF)-stimulated human epidermal keratinocytes. The kinetic profiles of endogenous MEK and ERK activity suggest that prolonged activation of these signal transducers is an underlying mechanism involved in stimulating cell motility and MMP-9 production. In support of this finding, a transient MEK/ERK signal elicited by keratinocyte growth factor (KGF) or insulin-like growth factor-1 (IGF-1) fails to stimulate these invasion-related responses. Specific inhibition of MEK leads to suppression of ERK activation, marked reduction in steady-state levels of c-Fos, and inhibition of cell movement and MMP-9 production. This occurs despite continued activation of JNK and c-Jun signaling in the presence of MEK-specific inhibition. In contrast, when JNK activity is specifically inhibited in HGF-stimulated cells, AP-1 activity is suppressed but cell motility is not affected. This evidence suggests that while ERK and JNK activity are necessary for AP-1 activation, ERK but not JNK is sufficient in stimulating cell motility.
...
PMID:Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes. 1039 97

Endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs) Edg-1, Edg-3, and Edg-5 bind sphingosine 1-phosphate (S1P), and Edg-2 and Edg-4 Rs bind lysophosphatidic acid (LPA). LPA and S1P initiate ras- and rho-dependent signaling of cellular growth. Cultured lines of human breast cancer cells (BCCs) express Edg-3 > Edg-4 > Edg-5 > or = Edg-2, without detectable Edg-1, by both assessment of mRNA and Western blots with rabbit and monoclonal mouse anti-Edg R antibodies. BCC proliferation was stimulated significantly by 10(-9) M to 10(-6) M LPA and S1P. Luciferase constructs containing the serum response element (SRE) of growth-related gene promoters reported mean activation of BCCs by LPA and S1P of up to 85-fold. LPA and S1P stimulated BCC secretion of type II insulin-like growth factor (IGF-II) by 2-7-fold, to levels at which exogenous IGF-II stimulated increased proliferation and SRE activation of BCCs. All BCC responses to LPA and S1P were suppressed similarly by pertussis toxin, mitogen-activated protein kinase kinase inhibitors, and C3 exoenzyme inactivation of rho, suggesting mediation by Edg Rs. Monoclonal anti-IGF-II and anti-IGFR1 antibodies suppressed proliferation and SRE reports of BCCs to LPA and S1P by means of up to 65%. Edg Rs thus transduce LPA and S1P enhancement of BCC growth, both directly through SRE and indirectly by enhancing the contribution of IGF-II.
...
PMID:Dual mechanisms for lysophospholipid induction of proliferation of human breast carcinoma cells. 1049 33


1 2 3 4 5 6 7 8 9 10 Next >>

---