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)

Little is known regarding hepatic insulin-like growth factor-1 IGF-I signaling with aging despite the observation that other tissues demonstrate resistance to IGF-I with aging and declines in liver mass accompany aging. Our aim was to determine if the IGF-I-induced signaling process changes with aging. Young (5 months) and old (24 months) C57BL/6 mice hepatic tissues and blood samples were taken 20 min after an intraperitoneal injection of desIGF-I. Age had no significant effect on plasma glucose, insulin and total IGF-I levels. IRS-1 protein was significantly decreased (33%) with aging. Basal phosphorylation of IRS-1, PKB and ERK were unaffected whereas basal phosphorylation of CREB and FKHR were significantly increased (37 and 33%, respectively) with aging. desIGF-I caused a significant decrease in plasma glucose concentrations in both young (53%) and old (44%) mice. desIGF-I administration significantly increased the phosphorylation of IRS-1 in both young (104%) and old (89%) hepatic tissues. Similarly, the phosphorylation of PKB was dramatically enhanced in both young (527%) and old (350%) hepatic tissues after desIGF-I stimulation. By contrast, desIGF-I administration had no significant effects on the phosphorylation of ERK and phosphorylation of transcription factors CREB and FKHR in both young and old hepatic tissues. These data suggest that aging dose not impair IGF-I signaling in hepatic tissues.
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PMID:Effects of aging on hepatic IGF-I signaling. 1185 24

Transformation by ras oncogenes induces the deregulation of intracellular signalling cascades that are critical elements in cell growth control. Ras proteins are molecular switches with the ability to interact and activate several effector molecules. Among those, Raf-1 kinase, PI3K and Ral-GDS are the best characterised. Raf activates the mitogenic MEK/ERK kinases pathway, while PI3K regulates the PKB/Akt cascade, involved in the control of proliferation, metabolism and apoptotic responses. Finally, Ral-GDS belongs to a family of guanine nucleotide exchange factors that activate Ral GTPases. While Raf and PI3K have emerged as critical elements in regulating cell growth and apoptosis, little is known about the role of the Ral-GDS family. We have previously reported that Ras proteins are critical elements in the regulation of phospholipase D (PLD), a proposed target for the Ral-GDS/RalA pathway. Physiological regulation of PLD by growth factors requires the simultaneous activation of the endogenous, wild-type Ras proteins, and a PKC-dependent mechanism. Transformation by ras oncogenes induces drastic alterations in PLD activity and the usual response to external stimuli, through a PKC-independent mechanism. Here we provide further evidence on the mechanisms by which oncogenic Ras proteins induces the deregulation of PLD and here we try to identify the specific effectors involved. A complex system for PLD regulation is unravelled which implies the existence of two positive regulatory pathways, mediated by Ral-GDS and PI3K, and two negative feedback mechanisms mediated by Raf and Ral-GDS. These results strongly support participation of PLD in Ras-mediated signalling. Furthermore, we provide evidence that oncogenic Ras proteins constitutively activate PLD by mechanisms different to those used by normal Ras proteins.
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PMID:Modulation of phospholipase D by Ras proteins mediated by its effectors Ral-GDS, PI3K and Raf-1. 1216 89

The parkinsonian neurotoxin methylpyridinium (MPP(+)) mimics the neuropathology of Parkinson's disease (PD) and likely kills neurons by inhibiting complex I of the electron transport chain and increasing oxidative stress. We examined the time course of activation/inactivation of multiple pro- and anti-apoptotic signaling pathways in MPP(+)-induced apoptotic death of SH-SY5Y neuroblastoma cells. We found an early increase and later decrease of transcriptional activity of the generally anti-apoptotic nuclear factor kappa-beta (NF-kappa B) and early increases in activating phosphorylation of the anti-apoptotic upstream kinase protein kinase B (PKB, also known as AKT). Sequestration-inducing phosphorylation of pro-apoptotic BAD protein increased early then declined. A small biphasic increase in the generally pro-apoptotic p38 kinase activity paralleled the biphasic rise in NF-kappa B-mediated transcription. Inhibition of p38 kinase with 5 micro M SB203540, inhibition of MEK-ERK with 50 micro M U0126, or inhibition of phosphatidylinositol-3-kinase (PI3K) with 10 micro M LY294002 reduced cell viability by 4, 18 or 37%, respectively, after 24 h. All three kinase inhibitors increased cell death in response to 24 h of MPP(+), with the greatest effect shown by LY294002. Nerve growth factor (NGF) caused an early increase in activating phosphorylation of PKB/AKT and MEK-ERK and increased cell survival during MPP(+) exposure. We found that acute MPP(+) exposure activates multiple interacting death- and survival-promoting pathways. Survival-promoting MEK-ERK and PI3K pathways contribute to viability during MPP(+) exposure, both are activated by NGF, and loss of PI3K-mediated signaling and NF-kappa B-mediated transcription may commit cells irreversibly to apoptosis in this model. It remains unknown to what extent these signaling pathways modulate dopamine neuronal death in PD.
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PMID:Methylpyridinium (MPP(+))- and nerve growth factor-induced changes in pro- and anti-apoptotic signaling pathways in SH-SY5Y neuroblastoma cells. 1236 9

The action mechanisms of several chemopreventive agents derived from herbal medicine and edible plants have become attractive issues in cancer research. Tea is the most widely consumed beverage worldwide. Recently, the cancer chemopreventive actions of tea have been intensively investigated. It have been demonstrated that the active principles of tea were attributed to their tea polyphenols. Recently, tremendous progress has been made in elucidating the molecular mechanisms of cancer chemoprevention by tea and tea polyphenols. The suppression of various tumor biomarkers including growth factor receptor tyrosine kinases, cytokine receptor kinases, PI3K, phosphatases, ras, raf, MAPK cascades, N x FB, I x B kinase, PKA, PKB, PKC, c-jun, c-fos, c-myc, cdks, cyclins, and related transducing proteins by tea polyphenols has been studied in our laboratory and others. The I x B kinase (IKK) activity in LPS-activated murine macrophages (RAW 264.7 cells) was found to be inhibited by various tea polyphenols including (-) epigallocatechin-3-gallate (EGCG), theaflavin (TF-1), theaflavin-3-gallate (TF-2) and theaflavin-3,3'-digallate (TF-3). TF-3 inhibited IKK activity in activated macrophages more strongly than did the other tea polyphenols. TF-3 inhibited both IKK1 and IKK2 activity and prevented the degradation of I x B x and I x B x in activated macrophage cells. The results suggested that the inhibition of IKK activity by TF-3 and other tea polyphenols could occur by a direct effect on IKKs or on upstream events in the signal transduction pathway. TF-3 and other tea polyphenols blocked phosphorylation of IB from the cytosolic fraction, inhibited NFB activity and inhibited increases in inducible nitric oxide synthase levels in activated macrophage. TF-3 and other tea polyphenols also inhibited strongly the activities of xanthine oxidase, cyclooxygenase, EGF-receptor tyrosine kinase and protein kinase C. These results suggest that TF-3 and other tea polyphenols may exert their cancer chemoprevention through suppressing tumor promotion and inflammation by blocking signal transduction. The mechanisms of this inhibition may be due to the blockade of the mitogenic and differentiating signals through modulating EGFR function, MAPK cascades, NFkappaB activation as well as c-myc, c-jun and c-fos expression.
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PMID:Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. 1243 85

Replicative senescence is characterized by numerous phenotypic alterations including loss of proliferative capacity and numerous changes in gene expression such as impaired serum inducibility of the immediate early gene c-fos and increased expression of collagenase. Transcription of c-fos in response to mitogens depends on the activation of a multiprotein complex formed on the c-fos serum response element (SRE), which includes the transcription factors serum response factor (SRF) and ternary complex factor (TCF). TCF is activated after phosphorylation by the Extracellular signals Regulated Kinase 1 and 2 (ERK1/2), two kinases of the Raf/MEK/ERK signaling pathway. We have previously demonstrated that collagenase expression is under positive regulation by the transcription factor FKHRL1 and that this transcription factor is under negative regulation by the phosphatidylinositol 3-kinase(PI3K)/Akt(PKB) pathway. Although total activity of ERK and Akt was similar in total cell lysates from early and late passage fibroblasts our data indicate that in senescent cells neither ERK nor Akt are able to phosphorylate efficiently their nuclear targets. Our findings suggest that although they can be fully activated in the cytosol of both early and late passage cells, the Raf/MEK/ERK and the PI3K/Akt pathways, which are essential for cellular proliferation, are down regulated in the nuclei of senescent cells.
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PMID:Role of the Raf/MEK/ERK and the PI3K/Akt(PKB) pathways in fibroblast senescence. 1247 Aug 26

A large and diverse spectrum of oncogenes has been implicated as a contributor to angiogenesis in solid tumors based, in part, on its ability to induce proangiogenic growth factors such as vascular endothelial growth factor (VEGF), and the fact that various anti-oncogenic signaling inhibitor drugs have been shown to reverse such proangiogenic effects both in vitro and in vivo. Because leukemias are now also considered to be angiogenesis-dependent malignancies, we asked whether a similar paradigm might exist for the BCR-ABL oncogene and the Bcr-Abl targeting drug, STI-571 (imatinib mesylate), in the context of chronic myelogenous leukemia (CML) cells. We found that levels of VEGF expression in BCR-ABL-positive K562 cells were reduced in vitro by treatment with STI-571 in a dose-dependent fashion. Transfection of BCR-ABL into murine myeloid 32D and human megakaryocyte MO7e hematopoietic cells resulted in enhanced VEGF expression, which could be further elevated by the exposure to cytokines such as interleukin 3 and granulocyte macrophage colony-stimulating factor. We also found that conditioned media taken from 32D-p210-transfected cells could stimulate human umbilical vein endothelial cells by increasing phosphorylation of VEGF-R2/KDR and the downstream serine/threonine kinase PKB/Akt, an important regulator of endothelial cell survival. Moreover, amplification of BCR-ABL in STI-571-resistant cells was associated with elevated VEGF expression levels which could be reversed by treatment with higher concentrations of STI-571. Taken together, our results implicate BCR-ABL as a possible regulator of CML angiogenesis and raise the possibility that STI-571 could mediate some of its anti-CML properties in vivo through an angiogenesis-dependent mechanism.
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PMID:Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. 1249 55

Galectin-8, a member of the galectin family of mammalian lectins, is a secreted protein that promotes cell adhesion and migration upon binding to a subset of integrins through sugar-protein interactions. Ligation of integrins by galectin-8 triggers a distinct pattern of cytoskeletal organization, including formation of F-actin-containing microspikes. This is associated with activation of integrin-mediated signaling cascades (ERK and phosphatidylinositol 3 kinase (PI3K)) that are much more robust and are of longer duration than those induced upon cell adhesion to fibronectin. Indeed, formation of microspikes is enhanced 40% in cells that overexpress protein kinase B, the downstream effector of PI3K. Inhibition of PI3K activity induced by wortmannin partially inhibits cell adhesion and spreading while largely inhibiting microspike formation in cells adherent to galectin-8. Furthermore, the inhibitory effects of wortmannin are markedly accentuated in cells overexpressing PKB or p70S6K (CHO(PKB) and CHO(p70S6K) cells), whose adhesion and spreading on galectin-8 (but not on fibronectin) is inhibited approximately 25-35% in the presence of wortmannin. The above results suggest that galectin-8 is an extracellular matrix protein that triggers a unique repertoire of integrin-mediated signals, which leads to a distinctive cytoskeletal organization and microspike formation. They further suggest that downstream effectors of PI3K, including PKB and p70 S6 kinase, in part mediate cell adhesion, spreading, and microspike formation induced by galectin-8.
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PMID:Sustained induction of ERK, protein kinase B, and p70 S6 kinase regulates cell spreading and formation of F-actin microspikes upon ligation of integrins by galectin-8, a mammalian lectin. 2975 18

CC139 fibroblasts are one of several model systems in which the Raf --> MEK --> ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however, the precise mechanism for this protective effect is not known. Serum withdrawal from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid, de novo accumulation of Bim(EL), a proapoptotic 'BH3-only' member of the Bcl-2 protein family. Bim(EL) expression was an early event, occurring several hours prior to caspase activation. In contrast to studies in neurons, activation of the JNK --> c-Jun pathway was neither necessary nor sufficient to induce Bim(EL) expression. Selective inhibition of either the ERK pathway (with U0126) or the PI3K pathway (with LY294002) caused an increase in the expression of Bim(EL). Furthermore, selective activation of the ERK1/2 pathway by deltaRaf-1:ER* substantially reduced Bim(EL) expression, abolished conformational changes in Bax and blocked the appearance of apoptotic cells. The ability of deltaRaf-1:ER* to repress Bim(EL) expression required the ERK pathway but was independent of the PI3K --> PDK --> PKB pathway. Thus, serum withdrawal-induced expression of Bim(EL) occurs independently of the JNK --> c-Jun pathway and can be repressed by the ERK pathway independently of the PI3K pathway. This may contribute to Raf- and Ras-induced cell survival at low serum concentrations.
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PMID:Activation of ERK1/2 by deltaRaf-1:ER* represses Bim expression independently of the JNK or PI3K pathways. 1261 53

The network of enzymes that contribute to the signal transduction of extracellular factors in pancreatic cancer is ever increasing. The classical Raf-MEK-ERK signaling cascade plays a crucial role in the regulation of apoptosis, proliferation, and metastasis of pancreatic cancer. Phosphatidylinositide-3-kinase also contributes to growth and prevents apoptosis in pancreatic cancer cells, acting in part via its downstream targets, PKB/AKT and the FRAP/p70s6k signaling complex. Recently, members of the PKC family of serine threonine kinases have emerged as novel modulators of transformation and cell cycle progression of pancreatic cancers. The novel PKD family of serine threonine kinases has just been detected in pancreatic cancer and awaits its functional characterization in these tumors.
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PMID:Novel protein kinases in pancreatic cell growth and cancer. 1262 11

Cholecystokinin (CCK) acting through its G protein-coupled receptor is now known to activate a variety of intracellular signaling mechanisms and thereby regulate a complex array of cellular functions in pancreatic acinar cells. The best studied mechanism is the coupling through heterotrimeric G proteins of the Gq family to activate a phospholipase C leading to an increase in inositol trisphosphate and release of intracellular Ca2+. This pathway along with protein kinase C activation in response to the increase in diacylglycerol stimulates the secretion of digestive enzymes by the process of exocytosis. CCK also activates signaling pathways in acini more related to other processes. The three mitogen activated protein kinase cascades leading to ERKs, JNKs and p38 MAPK are all activated by CCK. CCK activates the ERK cascade by PKC activation of Raf which in turn activates MEK and ERKs. JNKs are activated by a distinct mechanism which requires higher concentrations of CCK. Both ERKs and JNKs are presumed to regulate gene expression. CCK activation of p38 MAPK also plays a role in regulating the actin cytoskeleton through phosphorylation of the small heat shock protein HSP27. The PI3K-PKB-mTOR pathway is activated by CCK and plays a major role in regulating protein synthesis at the translational level. This includes both activation of p70 S6K leading to phosphorylation of ribosomal protein S6 and the phosphorylation of the binding protein for initiation factor 4E leading to formation of the mRNA cap binding complex. Other signaling pathways activated by CCK receptors include NF-kappaB and a variety of tyrosine kinases. Further work is needed to understand how CCK receptors activate most of the above pathways and to better understand the biological events regulated by these diverse signaling pathways.
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PMID:Cholecystokinin activates a variety of intracellular signal transduction mechanisms in rodent pancreatic acinar cells. 1268 72


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