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)

BCL6 is a potent transcriptional repressor that plays important roles in germinal center formation, T helper cell differentiation and lymphomagenesis and regulates expression of several chemokine genes in macrophages. In a further investigation of its role in macrophages, we show that BCL6 inactivation in primary bone marrow-derived macrophages leads to decreased polarization, motility and cell spreading accompanied by an increase in peripheral focal complexes, anchored F-actin bundles and cortical F-actin density. These changes were associated with excess RhoA activation. C3 transferase inhibition of RhoA activity reverted the adhesion structure phenotype, which was not affected by Rho kinase inhibitors, suggesting that other downstream effectors of Rho maintain this Bcl6(-/-) phenotype. Excess RhoA activation in BCL6-deficient macrophages is associated with a decrease in the p120RasGAP (RASA1)-mediated translocation of p190RhoGAP (GRLF1) to active RhoA at the plasma membrane and a reduction in cell surface expression of the CSF1R that has been reported to recruit RasGAP to the plasma membrane. Reconstitution of BCL6 expression in Bcl6(-/-) macrophages results in complete reversion of the morphological phenotype and a significant increase in cell surface CSF1R expression whereas overexpression of the CSF1R corrects the polarization and adhesion structure defects. These results demonstrate that BCL6 suppresses RhoA activity, largely through upregulation of surface CSF1R expression, to modulate cytoskeletal and adhesion structures and increase the motility of macrophages.
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PMID:BCL6 suppresses RhoA activity to alter macrophage morphology and motility. 1586 Jul 30

The present study shows that the incubation of human aortic smooth muscle cells (HASMC) and HepG2 cells with atorvastatin and mevastatin as HMG-CoA reductase inhibitors potentiated the interferon-gamma (INF-gamma)-induced group IIA phospholipase A(2) (sPLA(2)-IIA) expression in a dose- and time-dependent manner. The effect of statins on sPLA(2)-IIA expression was reduced by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inversely, inhibitors of the farnesyl transferase and geranylgeranyl transferase-I mimicked the effects of statins. Clostridium difficile toxin B (TcdB), Y-27632 and H-1152, functioning as inhibitors of Rho proteins and Rho-associated kinase, also augmented the sPLA(2)-IIA expression in combination with IFN-gamma. The same effects were observed when inhibitors of mitogen-activated/extracellular response protein kinase kinase (MEK), PD98059 or U0126 were used. Further, the Janus kinase-2 (Jak2)-specific inhibitor, AG-490 and inhibitors of nuclear factor-kappaB (NFkappaB) abrogated the sPLA(2)-IIA elevating effects of statins, TcdB and PD98059 in the presence of IFN-gamma. This cytokine alone increased the NFkappaB p65 and CAAT-enhancer-binding protein-beta (C/EBP-beta) activity in HASMC nuclear extract, but only C/EBP-beta was further augmented when the cells were incubated in addition to IFN-gamma with atorvastatin, H-1152, PD98059 or U0126. Moreover, after the incubation of cells with atorvastatin and IFN-gamma the stability of sPLA-(2)IIA mRNA significantly increased in comparison to those after incubation with IFN-gamma alone. In conclusion, the obtained data suggest that (i) the expression of sPLA(2)-IIA is negatively regulated by RhoA/Rho-associated kinase and MEK/ERK signaling pathways and (ii) statins, because of their ability to down-regulate these pathways, can potentiate the IFN-gamma-induced sPLA(2)-II expression at transcriptional and post-transcriptional levels.
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PMID:Statins potentiate the IFN-gamma-induced upregulation of group IIA phospholipase A2 in human aortic smooth muscle cells and HepG2 hepatoma cells. 1586 63

Transforming growth factor beta (TGF-beta) inhibits proliferation and promotes cell migration. In TGF-beta-treated MCF10A mammary epithelial cells overexpressing HER2 and by chromatin immunoprecipitation, we identified novel Smad targets including protein tyrosine phosphatase receptor type kappa (PTPRK). TGF-beta up-regulated PTPRK mRNA and RPTPkappa (receptor type protein tyrosine phosphatase kappa, the protein product encoded by the PTPRK gene) protein in tumor and nontumor mammary cells; HER2 overexpression down-regulated its expression. RNA interference (RNAi) of PTPRK accelerated cell cycle progression, enhanced response to epidermal growth factor (EGF), and abrogated TGF-beta-mediated antimitogenesis. Endogenous RPTPkappa associated with EGF receptor and HER2, resulting in suppression of basal and ErbB ligand-induced proliferation and receptor phosphorylation. In MCF10A/HER2 cells, TGF-beta enhanced cell motility, FAK phosphorylation, F-actin assembly, and focal adhesion formation and inhibited RhoA activity. These responses were abolished when RPTPkappa was eliminated by RNA interference (RNAi). In cells expressing RPTPkappa RNAi, phosphorylation of Src at Tyr527 was increased and (activating) phosphorylation of Src at Tyr416 was reduced. These data suggest that (i) RPTPkappa positively regulates Src; (ii) HER2 signaling and TGF-beta-induced RPTPkappa converge at Src, providing an adequate input for activation of FAK and increased cell motility and adhesion; and (iii) RPTPkappa is required for both the antiproliferative and the promigratory effects of TGF-beta.
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PMID:Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function. 1589 72

There is evidence for a functionally important extracellular calcium-sensing receptor in osteoblasts, but there is disagreement regarding its identity. Candidates are CASR and a putative novel calcium-sensing receptor, called Ob.CASR. To further characterize Ob.CASR and to distinguish it from CASR, we examined the extracellular cation-sensing response in MC3T3-E1 osteoblasts and in osteoblasts derived from CASR null mice. We found that extracellular cations activate ERK and serum response element (SRE)-luciferase reporter activity in osteoblasts lacking CASR. Amino acids, but not the calcimimetic NPS-R568, an allosteric modulator of CASR, also stimulate Ob.CASR-dependent SRE-luciferase activation in MC3T3-E1 osteoblasts. In addition, we found that the dominant negative Galphaq(305-359) construct inhibited cation-stimulated ERK activation, consistent with Ob.CASR coupling to Galphaq-dependent pathways. Ob.CASR is also a target for classical GPCR desensitization mechanisms, since beta-arrestins, which bind to and uncouple GRK phosphorylated GPCRs, attenuated cation-stimulated SRE-luciferase activity in CASR deficient osteoblasts. Finally, we found that Ob.CASR and CASR couple to SRE through distinct signaling pathways. Ob.CASR does not activate RhoA and C3 toxin fails to block Ob.CASR-induced SRE-luciferase activity. Mutational analysis of the serum response factor (SRF) and ternary complex factor (TCF) elements in SRE demonstrates that Ob.CASR predominantly activates TCF-dependent mechanisms, whereas CASR activates SRE-luciferase mainly through a RhoA and SRF-dependent mechanism. The ability of Ob.CASR to sense cations and amino acids and function like a G-protein coupled receptor suggests that it may belong to the family of receptors characterized by an evolutionarily conserved amino acid sensing motif (ANF) linked to an intramembranous 7 transmembrane loop region (7TM).
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PMID:Osteoblast calcium-sensing receptor has characteristics of ANF/7TM receptors. 1596 13

Rho GTPases are overexpressed in human tumors and are involved in a variety of cellular processes such as organization of the actin cytoskeleton, cell-cell contact and malignant transformation. EGFR activation plays a key role in the acquisition of motile properties in carcinoma cells, and it has been proposed that downregulation of FAK activity is one of its most relevant consequences. In the present study, using mammary MCF-7 cells, we demonstrated that overexpression of the active form of the small GTPase RhoA induced the activation of EGFR by a phenomenon that depends on the activity of a metalloproteinase (MMP), which presumably cleaves a membrane-bound EGFR ligand. The EGFR tyrosine phosphorylation correlates with ERK1,2 activation and the stimulation of urokinase production. An aggressive mammary cell line (MDA-MB-231) that overexpresses both RhoA and EGFR in their active forms also displayed an MMP-dependent activation mechanism of EGFR. RhoA-GTP-transfected cells showed a cortical array of F-actin, rounded morphology, reduced spreading potential and a dephosphorylation of FAK that was released by integrin-dependent fibronectin adhesion and a specific EGFR tyrosine kinase inhibitor. Our results suggest that the MMP-dependent EGFR activation observed in V14 RhoA cells represents the starting point of a signaling route that promotes cell motility by activation of ERK1,2 and further enhancement of proteases production.
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PMID:Overexpression of RhoA-GTP induces activation of the Epidermal Growth Factor Receptor, dephosphorylation of focal adhesion kinase and increased motility in breast cancer cells. 1596 82

Cyclooxygenase 2 (COX-2) is an immediate early gene induced by a variety of stimuli and its expression is stimulated by individual activation of Ras or Rho GTPases. Here we investigate the role of coordinate activation of Ras and Rho GTPases in the induction of COX-2. Individual expression of constitutively active Ras, RhoA, or Rac1 was capable of stimulating COX-2 expression in NIH3T3 cells, but co-expression of constitutively active RhoA with either constitutively active Ras or Rac1 was required for full stimulation of COX-2 expression. Serum growth factors differentially activated Ras, RhoA, and Rac1, which correlated with the activation of Raf-1, ERK, and c-Jun as well as with induction of COX-2. Inhibition of Ras significantly blocked the activation of Raf-1, ERK, and c-Jun and the stimulation of COX-2 expression in response to serum. In contrast, inhibition of Rho family GTPases partially blocked serum induction of ERK activation but had little effects on COX-2 expression. Both inhibitors of MEK (PD098059) and JNK (SP600125) inhibited serum induction of COX-2. PD98059 only inhibited constitutively active Ras-induced COX-2 expression, while SP600125 significantly inhibited both constitutively active Ras- and RhoA-induced COX-2 expression. Together, our data suggest that constitutively active oncogenic Ras and Rho coordinately stimulate COX-2 expression whereas transient activation of Ras but not RhoA or Rac1 mediates the induction of COX-2 in response to serum. Furthermore, ERK and JNK activation are both required for serum- and oncogenic Ras-mediated COX-2 expression whereas only JNK activation is required for oncogenic RhoA-mediated stimulation of COX-2 expression.
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PMID:Differential regulation of cyclooxygenase 2 expression by small GTPases Ras, Rac1, and RhoA. 1608 58

Integrin-mediated cell adhesion induces activation of the EGF receptor tyrosine kinase independently of the soluble growth factor ligand. EGFR activation is instrumental for subsequent activation of additional signaling pathways in adherent cells, including the Ras-MAP kinase pathway and the phosphatidylinositol 3-kinase/Akt pathway. We demonstrate here that integrin-dependent EGFR activation is also essential for adhesion-induced formation of actin stress fibers, focal adhesion localization and tyrosine phosphorylation of the adapter protein paxillin, as well as transcriptional activation of the serum response factor. All these events are known to be mediated by the small GTPase RhoA. EGFR activity was not found to regulate the activity status of RhoA, however. Instead, we found that EGFR activity is required for integrin-induced phosphorylation of cofilin. Cofilin is an actin-binding protein, which, when unphosphorylated, stimulates depolymerization and severing of actin filaments. Thus, in the absence of the kinase activity of the EGFR, cofilin remains dephosphorylated and depolymerizes actin filaments, rendering cells unable to respond to RhoA signaling. These studies demonstrate adhesion-dependent regulation of cofilin phosphorylation, and identify a novel role for EGFR in integrin signaling.
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PMID:EGF receptor activity is essential for adhesion-induced stress fiber formation and cofilin phosphorylation. 1612 57

Pasteurella multocida toxin (PMT) is a potent mitogen, which is known to activate phospholipase Cbeta by stimulating the alpha-subunit of the heterotrimeric G protein G(q). PMT also activates RhoA and RhoA-dependent pathways. Using YM-254890, a specific inhibitor of G(q/11), we studied whether activation of RhoA involves G proteins other than G(q/11). YM-254890 inhibited PMT or muscarinic M3-receptor-mediated stimulation of phospholipase Cbeta at similar concentrations in HEK293m3 cells. In these cells, PMT-induced RhoA activation and enhancement of RhoA-dependent luciferase activity were partially inhibited by YM-254890. In Galpha(q/11)-deficient fibroblasts, PMT induced activation of RhoA, increase in RhoA-dependent luciferase activity, and increase in ERK phosphorylation. None of these effects were influenced by YM-254890. However, RhoA activation by PMT was inhibited by RGS2, RGS16, lscRGS, and dominant negative G(13)(GA), indicating involvement of Galpha(12/13) in the PMT effect on RhoA. In Galpha(12/13) gene-deficient cells, PMT-induced stimulation of RhoA, luciferase activity, and ERK phosphorylation were blocked by YM-254890, indicating the involvement of G(q). Infection with a virus harboring the gene of Galpha(13) reconstituted the increase in RhoA-dependent luciferase activity by PMT even in the presence of YM-254890. The data show that YM-254890 is able to block PMT activation of Galpha(q) and indicate that, in addition to Galpha(q), the Galpha(12/13) G proteins are targets of PMT.
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PMID:Pasteurella multocida toxin-induced activation of RhoA is mediated via two families of G{alpha} proteins, G{alpha}q and G{alpha}12/13. 1614 Dec 14

In order to display the full metastatic phenotype, the cancer cell must acquire the ability to migrate. In breast cancer, we have previously shown that insulin-like growth factor I (IGF-I) enhances cell motility in the highly metastatic MDA-231BO cell line by activating the type I IGF receptor (IGF1R). This motility response requires activation of IRS-2 and integrin ligation. In order to identify the key molecules downstream of IRS-2, we examined several signaling pathways known to be involved in cell motility. Focal adhesion kinase (FAK) was not activated by IGF-I, but IGF-I caused redistribution of FAK away from focal adhesion plaques. IGF-I treatment of MDA-231BO cells activated RhoA and inhibition of Rho-kinase (ROCK) inhibited the IGF-mediated motility response. The mitogen activated protein kinase (MAPK), p38, was also activated by IGF-I and inhibition of p38 by SB203580 blocked IGF-I induced cell motility. ROCK inhibition with Y-27632 also inhibited p38 phosphorylation suggesting that p38 lies downstream of ROCK. Both Erk1,2 and phosphatidyl-3 kinase (PI3K) were required for IGF-I stimulated cell motility, but only PI3K appeared to be directly downstream of IGF-I. Thus, IGF-I activation of its receptor coordinates multiple signaling pathways required for cell motility. Defining the key molecules downstream of the type I IGF receptor may provide a basis for optimizing therapies directed at this target.
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PMID:Multiple signaling pathways are activated during insulin-like growth factor-I (IGF-I) stimulated breast cancer cell migration. 1618 36

To determine signaling pathways responsible for modulation of COX-2 expression in nontransformed and transformed epithelial cells, we studied a rat intestinal epithelial (RIE) cell line expressing constitutively active Ras and RhoA. Expression of COX-2 protein was higher in RIE-RhoA(63L) (four-fold) and RIE-Ras(12V) (seven-fold) cells than in parental cells. Prior work suggests that Ras hyperactivity induces the expression of transforming growth factor (TGF)beta and increases epidermal growth factor (EGF)-related peptide signaling-possible mechanisms for increased COX-2 expression. Expression of COX-2 was stimulated by TGFbeta and TGFalpha in RIE and RIE-Rho(63L) cells, but not further stimulated in RIE-Ras(12V) cells. PD153035, an inhibitor of EGF receptor tyrosine kinase, and PD98059, an inhibitor of Erk, attenuated COX-2 expression in RIE and RIE-RhoA(63L). However, the high levels of COX-2 expression in RIE-Ras(12V) cells were not inhibited by either compound. Titration with a pan-neutralizing anti-TGFbeta antibody did not decrease COX-2 in RIE-Ras(12V) cells, even with concurrent EGFR inhibition. Thus, stimulation of the EGF receptor is important in the modulation of COX-2 expression in nontransformed RIE and RIE-RhoA(63L) cells. In Ras-transformed cells, signaling by additional Ras effector pathways, perhaps the RhoA pathway, must be invoked. Identification of these pathways is critical for therapeutic manipulation of COX-2 expression.
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PMID:Differential regulation of cyclooxygenase-2 in nontransformed and ras-transformed intestinal epithelial cells. 1620 78


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