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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vasoactive intestinal peptide (VIP) is known to regulate proliferation or differentiation in normal and tumoral cells. SH-SY5Y is a differentiated cell subclone derived from the SK-N-SH human neuroblastoma cell line and possess all the components for an autocrine action of VIP. In the present study, we investigated the morphological changes and intracellular signaling pathways occurring upon VIP treatment of SH-SY5Y cells. VIP induced an early remodeling of cell projections: a branched neurite network spread out and prominent varicosities developed along neurites. Although activated by VIP, the Ras/ERK pathway was not required for the remodeling process. In contrast, pull-down experiments revealed a strong Cdc42 activation by VIP while expression of a dominant-negative Cdc42 prevented the VIP-induced neurite changes, suggesting an important role for this small GTPase in the process. These data provide the first evidence for a regulation of the activity of Rho family GTPases by VIP and bring new insights in the signaling pathways implicated in neurite remodeling process induced by VIP in neuroblastoma cells.
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PMID:Vasoactive intestinal peptide-induced neurite remodeling in human neuroblastoma SH-SY5Y cells implicates the Cdc42 GTPase and is independent of Ras-ERK pathway. 1535 May 48

Previous studies have demonstrated in hepatocytes that deoxycholic acid (DCA) promotes inactivation of protein tyrosine phosphatases (PTPases) and activation of ERBB1 and the extracellular-regulated kinase (ERK) 1/2 pathway. The present studies have determined the biochemical mechanism(s) through which these events occur. DCA and taurodeoxycholic acid (TDCA) (100 micromol/L) caused activation of ERBB1, insulin receptor, and the ERK1/2 and AKT pathways in primary rodent hepatocytes. DCA- and TDCA-induced receptor and signaling pathway activations were blocked by the reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and Trolox (TX), as well as by cyclosporin A (CsA) and bongkrekic acid (BKA). DCA activated the ERK1/2 pathway in HuH7 human hepatoma cells that was blocked by the incubation of cells with an ERBB1 inhibitor, NAC, TX, CsA, or BKA. DCA did not activate the ERK1/2 pathway in mitochondria-defective HuH7 Rho 0 cells. In HuH7 cells and primary hepatocytes, DCA enhanced the production of ROS, an effect that was abolished in Rho 0 cells and by prior incubation of cells with CsA or BKA. In hepatocytes and HuH7 cells, DCA inhibited PTPase activity. Incubation of hepatocytes with either CsA or BKA prevented DCA-induced inhibition of PTPase activity. Loss of mitochondrial function in Rho 0 cells also abolished the inhibitory effects of DCA on PTPase activity. In conclusion, DCA and TDCA cause ROS generation in hepatocytes that is dependent on metabolically active mitochondria. The generation of ROS is essential for PTPase inactivation, receptor tyrosine kinase activation, and enhanced signaling down the ERK1/2 and AKT pathways.
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PMID:Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. 1538 21

Except functioning as lipid-lowering agents, HMG-CoA inhibitors, statins, are good tools to clarify the signaling role of small G proteins. In this study, we found in murine RAW264.7 macrophages, statins within 1-30 microM stimulated COX-2 gene transcription and PGE(2) formation, displaying potencies as lovastatin > fluvastatin > atorvastatin >> pravastatin. Transfection experiments with COX-2 promoter construct showed the necessity of C/EBPbeta and CRE promoter sites, but not NF-kappaB promoter site. Effects of statins on the activation of COX-2 promoter, induction of COX-2 protein, and PGE(2) production were all prevented by mevalonate and prenylated metabolites, FPP and GGPP. Consistent with the effect of statins, manumycin A, farnesyltransferase inhibitor, and geranylgeranyltransferase inhibitor increased PGE(2) production and COX-2 induction. Likewise, toxin B, an inhibitor of Rho family members, caused a prominent COX-2 induction. Results also indicated that tyrosine kinase, ERK, and p38 MAPK play essential roles in statin action. Taken together, these results not only demonstrate a unique action of statins in the upregulation of COX-2 expression in macrophages, but also suggest a negative role controlled by small G proteins in COX-2 gene regulation. Removal of this negative control by impairing G protein prenylation with statins leads to MAPKs activation and promotes COX-2 gene expression through the activation at CRE and C/EBPbeta sites.
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PMID:HMG-CoA reductase inhibitors induce COX-2 gene expression in murine macrophages: role of MAPK cascades and promoter elements for CREB and C/EBPbeta. 1553 Aug 65

The ternary complex factors (TCF) are a subfamily of ETS domain transcription factors that bind and activate serum response elements (SREs) in the promoters of target genes in a ternary complex with a second transcription factor, serum response factor (SRF). Here, we have identified the SRF gene as a target for the TCFs, thereby providing a positive feedback loop whereby TCF activation leads to the enhancement of the expression of its partner protein SRF. The binding of the TCF Elk-1 to the SRF promoter and subsequent regulation of SRF expression occurs in a ternary complex-dependent manner. Our data therefore reveal that SRF is an important target for the ERK and Rho signaling pathways that converge on a ternary TCF-SRF complex at the SRE on the SRF promoter.
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PMID:The ETS domain transcription factor Elk-1 regulates the expression of its partner protein, SRF. 1553 78

A variety of genetic alterations and gene expression changes are involved in the pathogenesis of bladder tumor. To explore these changes, oligonucleotide array analysis was performed on RNA obtained from carcinogen-induced mouse bladder tumors and normal mouse bladder epithelia using Affymetrix (Santa Clara, CA) MGU74Av2 GeneChips. Analysis yielded 1164 known genes that were changed in the tumors. Certain of the upregulated genes included EGFR-Ras signaling genes, transcription factors, cell cycle-related genes, and intracellular signaling cascade genes. However, downregulated genes include mitogen-activated protein kinases, cell cycle checkpoint genes, Rab subfamily genes, Rho subfamily genes, and SH2 and SH3 domains-related genes. These genes are involved in a broad range of different pathways including control of cell proliferation, differentiation, cell cycle, signal transduction, and apoptosis. Using the pathway visualization tool GenMAPP, we found that several genes, including TbR-I, STAT1, Smad1, Smad2, Jun, NFkappaB, and so on, in the TGF-beta signaling pathway and p115 RhoGEF, RhoGDI3, MEKK4A/MEKK4B, PI3KA, and JNK in the G13 signaling pathway were differentially expressed in the tumors. In summary, we have determined the expression profiles of genes differentially expressed during mouse bladder tumorigenesis. Our results suggest that activation of the EGFR-Ras pathway, uncontrolled cell cycle, aberrant transcription factors, and G13 and TGF-beta pathways are involved, and the cross-talk between these pathways seems to play important roles in mouse bladder tumorigenesis.
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PMID:Altered gene expression profile in mouse bladder cancers induced by hydroxybutyl(butyl)nitrosamine. 1554 66

Although Vav can act as a guanine nucleotide exchange factor for RhoA, Rac1, and Cdc42, its transforming activity has been ascribed primarily to its ability to activate Rac1. However, because activated Vav, but not Rac-specific guanine nucleotide exchange factors, exhibits very potent focus-forming transforming activity when assayed in NIH 3T3 cells, Vav transforming activity must also involve activation of Rac-independent pathways. In this study, we determined the involvement of other Rho family proteins and their signaling pathways in Vav transformation. We found that RhoA, Rac1, and Cdc42 functions are all required for Vav transforming activity. Furthermore, we determined that Vav activation of nuclear factor-kappaB and the Jun NH2-terminal kinase mitogen-activated protein kinase (MAPK) is necessary for full transformation by Vav, whereas p38 MAPK does not seem to play an important role. We also determined that Vav is a weak activator of Elk-1 via a Ras- and MAPK/extracellular signal-regulated kinase kinase-dependent pathway, and this activity was essential for Vav transformation. Thus, we conclude that full Vav transforming activation is mediated by the activation of multiple small GTPases and their subsequent activation of signaling pathways that regulate changes in gene expression. Because Vav is activated by the epidermal growth factor receptor and other tyrosine kinases involved in cancer development, defining the role of aberrant Vav signaling may identify activities of receptor tyrosine kinases important for human oncogenesis.
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PMID:Vav transformation requires activation of multiple GTPases and regulation of gene expression. 1563 59

In this study, we have examined the interaction of hyaluronan (HA)-CD44 with IQGAP1 (one of the binding partners for the Rho GTPase Cdc42) in SK-OV-3.ipl human ovarian tumor cells. Immunological and biochemical analyses indicated that IQGAP1 (molecular mass of approximately 190 kDa) is expressed in SK-OV-3.ipl cells and that IQGAP1 interacts directly with Cdc42 in a GTP-dependent manner. Both IQGAP1 and Cdc42 were physically linked to CD44 in SK-OV-3.ipl cells following HA stimulation. Furthermore, the HA-CD44-induced Cdc42-IQGAP1 complex regulated cytoskeletal function via a close association with F-actin that led to ovarian tumor cell migration. In addition, the binding of HA to CD44 promoted the association of ERK2 with the IQGAP1 molecule, which stimulated both ERK2 phosphorylation and kinase activity. The activated ERK2 then increased the phosphorylation of both Elk-1 and estrogen receptor-alpha (ER alpha), resulting in Elk-1- and estrogen-responsive element-mediated transcriptional up-regulation. Down-regulation of IQGAP1 (by treating cells with IQGAP1-specific small interfering RNAs) not only blocked IQGAP1 association with CD44, Cdc42, F-actin, and ERK2 but also abrogated HA-CD44-induced cytoskeletal function, ERK2 signaling (e.g. ERK2 phosphorylation/activity, ERK2-mediated Elk-1/ER alpha phosphorylation, and Elk-1/ER alpha-specific transcriptional activation), and tumor cell migration. Taken together, these findings indicate that HA-CD44 interaction with IQGAP1 serves as a signal integrator by modulating Cdc42 cytoskeletal function, mediating Elk-1-specific transcriptional activation, and coordinating "cross-talk" between a membrane receptor (CD44) and a nuclear hormone receptor (ER alpha) signaling pathway during ovarian cancer progression.
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PMID:Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression. 1565 47

Increased matrix metalloproteinase-9 (MMP-9) expression is associated with intimal hyperplasia in saphenous vein (SV) bypass grafts. Recent evidence suggests that HMG-CoA reductase inhibitors (statins) can prevent the progression of vein graft failure. Here we investigated whether statins inhibited MMP-9 secretion from cultured human SV smooth muscle cells (SMC) and examined the underlying mechanisms. SV-SMC from different patients were exposed to phorbol ester (TPA) or PDGF-BB plus interleukin-1alpha (IL-1). MMP-9 secretion and mRNA expression were analyzed using gelatin zymography and RT-PCR, respectively. Specific signal transduction pathways were investigated by immunoblotting and pharmacological inhibition. Simvastatin reduced TPA- and PDGF/IL-1-induced MMP-9 secretion and mRNA levels, effects reversed by geranylgeranyl pyrophosphate and mimicked by inhibiting Rho geranylgeranylation or Rho-kinase (ROCK). MMP-9 secretion induced by PDGF/IL-1 was mediated via the ERK, p38 MAPK, and NFkappaB pathways, whereas that induced by TPA was mediated specifically via the ERK pathway. Simvastatin failed to inhibit activation of these signaling pathways. Moreover, simvastatin did not affect MMP-9 mRNA stability. Together these data suggest that simvastatin reduces MMP-9 secretion from human SV-SMC by inhibiting the RhoA/ROCK pathway and decreasing MMP-9 mRNA levels independently of effects on signaling pathways required for MMP-9 gene expression.
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PMID:Simvastatin inhibits MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP-9 mRNA levels. 1572 60

Raf kinases relay signals inducing proliferation, differentiation, and survival. The Raf-1 isoform has been extensively studied as the upstream kinase linking Ras activation to the MEK/ERK module. Recently, however, genetic experiments have shown that Raf-1 plays an essential role in counteracting apoptosis, and that it does so independently of its ability to activate MEK. By conditional gene ablation, we now show that Raf-1 is required for normal wound healing in vivo and for the migration of keratinocytes and fibroblasts in vitro. Raf-1-deficient cells show a symmetric, contracted appearance, characterized by cortical actin bundles and by a disordered vimentin cytoskeleton. These defects are due to the hyperactivity and incorrect localization of the Rho-effector Rok-alpha to the plasma membrane. Raf-1 physically associates with Rok-alpha in wild-type (WT) cells, and reintroduction of either WT or kinase-dead Raf-1 in knockout fibroblasts rescues their defects in shape and migration. Thus, Raf-1 plays an essential, kinase-independent function as a spatial regulator of Rho downstream signaling during migration.
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PMID:Raf-1 regulates Rho signaling and cell migration. 1575 27

Stimulation of muscarinic M3 and M2 receptors on gastrointestinal smooth muscle elicits contraction via activation of G proteins that are coupled to a diverse set of downstream signaling pathways and effector proteins. Many studies suggest a canonical excitation-contraction coupling pathway that includes activation of phospholipases, production of inositol 1,4,5-trisphosphate and diacylglycerol, release of calcium from the sarcoplasmic reticulum, activation of L-type calcium channels, and activation of nonselective cation channels. These events lead to elevated intracellular calcium concentration, which activates myosin light chain kinase to phosphorylate and activate myosin II thus causing contraction. In addition, muscarinic receptors are coupled to signaling pathways that modulate the effect of activator calcium. The Rho/Rho kinase pathway inhibits myosin light chain phosphatase, one of the key steps in sensitization of the contractile proteins to calcium. Phosphatidylinositol 3-kinases and Src family tyrosine kinases are also activated by muscarinic agonists. Src family tyrosine kinases regulate L-type calcium and nonselective cation channels. Src activation also leads to activation of ERK and p38 MAPKs. ERK MAPKs phosphorylate caldesmon, an actin filament binding protein. P38 MAPKs activate phospholipases and MAPKAP kinase 2/3, which phosphorylate HSP27. HSP27 may regulate cross-bridge function, actin filament formation, and actin filament attachment to the cell membrane. In addition to the well-known role of M3 muscarinic receptors to regulate myoplasmic calcium levels, the integrated effect of muscarinic activation probably also includes signaling pathways that modulate phospholipases, cyclic nucleotides, contractile protein function, and cytoskeletal protein function.
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PMID:Signal-transduction pathways that regulate visceral smooth muscle function. III. Coupling of muscarinic receptors to signaling kinases and effector proteins in gastrointestinal smooth muscles. 1582 32


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