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)

Hepatocyte growth factor/scatter factor (HGF/SF) is considered to be a mesenchymal-derived factor that acts via a dual system receptor, consisting of the MET receptor and proteoglycans present on adjacent epithelial cells. Surprisingly, HGS/SF stimulated the migration of rat mammary (Rama) 27 fibroblasts, although it failed to stimulate their proliferation. HGF/SF stimulated a transient activation of mitogen-activated protein kinases p44 and p42 (p42/44(MAPK)), with a maximum level of dual phosphorylation of p42/44(MAPK) occurring 10-15 min after the addition of the growth factor, which was followed by a rapid decrease to near basal levels after 20 min. Interestingly, a second phase of p42/44(MAPK) dual phosphorylation was observed at later times (3 h to 10 h). PD098059, a specific inhibitor of MEK-1, prevented the dual phosphorylation of p42/44(MAPK) and also the phosphorylation of p90(RSK) (ribosomal subunit S6 kinase), which mirrored the kinetics of p42/44(MAPK) phosphorylation. Moreover, PD098059 prevented the HGF/SF-induced migration of Rama 27 cells. HGF/SF also induced an early increase in the phosphorylation of protein kinase B/Akt. Akt phosphorylation was elevated 15 min after the addition of HGF/SF and then declined to basal levels by 30 min. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PtdIns3K), prevented the increase in Akt phosphorylation and abolished HGF/SF-induced migration of fibroblasts. PD098059 also inhibited the stimulation of Akt phosphorylation by HGF/SF and wortmannin similarly inhibited the stimulation of p42/44(MAPK) dual phosphorylation. These results suggest that HGF/SF-induced motility depends on both the transient dual phosphorylation of p42/44(MAPK) and the activation of PtdIns3K in Rama 27 fibroblasts and that these pathways are mutually dependent.
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PMID:Hepatocyte growth factor/scatter factor stimulates migration of rat mammary fibroblasts through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways. 1150 2

First published September 5, 2001; 10.1152/ajpcell.00077.2001.-Protective mechanisms for lysophosphatidic acid (LPA) against cell death caused by Clostridium difficile toxin, or tumor necrosis factor-alpha (TNF-alpha) plus D-galactosamine, were investigated in a murine hepatocyte cell line AML12 expressing Edg2 LPA receptor. In these models of hepatocellular injury, LPA prevented hepatocyte damage, suppressed apoptosis, and enhanced cell survival in a dose-dependent fashion. The protective effects of LPA were abolished by wortmannin and LY-294002, specific inhibitors of phosphatidylinositol 3-phosphate kinase (PI 3-kinase), and by PD-98059 and U-0126, inhibitors of MEK1/MEK2. In nontreated hepatocytes, LPA elicited a gradual and sustained increase in phosphorylation of Erk1/Erk2 over 180 min of stimulation and downstream phosphorylation of p90RSK and transcription factor Elk-1. In C. difficile toxin-treated cells, LPA-induced phosphorylation of Erk1/Erk2 was rapid but transient, while p90RSK and Elk-1 phosphorylation did not change significantly. LPA stimulated phosphorylation of Akt in a time-dependent manner in both intact and toxin-treated AML12 hepatocytes. Wortmannin and LY-294002 abolished phosphorylation of Akt, further supporting activation of PI 3-kinase/Akt as a signaling pathway, which mediates hepatocyte protection by LPA. Taken together, these results demonstrate that LPA prevents cell apoptosis induced by C. difficile toxin and TNF-alpha/D-galactosamine in the AML12 murine hepatocyte cell line. Cell protection by LPA involves activation of the mitogen-activated protein kinase Erk1/Erk2 cascade and PI 3-kinase-dependent phosphorylation of Akt.
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PMID:Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line. 1169 60

Insulin regulates the expression of several hepatic genes. Although the general definition of insulin signaling has progressed dramatically, the elucidation of the complete signaling pathway from insulin receptor to transcription factors involved in the regulation of a specific gene remains to be established. In fact, recent works suggest that multiple divergent insulin signaling pathways regulate the expression of distinct genes. 5-Aminolevulinate synthase (ALAS) is a mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. It has been reported that insulin caused the rapid inhibition of housekeeping ALAS transcription, but the mechanism involved in this repression has not been explored. The present study investigates the role of phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein kinase pathways in insulin signaling relevant to ALAS inhibition. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in rat hepatocytes and HepG2 cells. Wortmannin and LY294002, PI3-kinase inhibitors, as well as lovastatin and PD152440, Ras farnesylation inhibitors, and MEK inhibitor PD98059 abolished the insulin repression of ALAS transcription. The inhibitor of mTOR/p70(S6K) rapamycin had no effect whatsoever upon hormone action. The overexpression of vectors encoding constitutively active Ras, MEK, or p90(RSK) mimicked the inhibitory action of insulin. Conversely, negative mutants of PKB, Ras, or MEK impaired insulin inhibition of ALAS promoter activity. Furthermore, inhibition of one of the pathways blocks the inhibitory effect produced by the activation of the other. Our findings suggest that factors involved in two signaling pathways that are often considered to be functionally separate during insulin action, the Ras/ERK/p90(RSK) pathway and the PI3K/PKB pathway, are jointly required for insulin-mediated inhibition of ALAS gene expression in rat hepatocytes and human hepatoma cells.
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PMID:Phosphatidylinositol 3-kinase and Ras/mitogen-activated protein kinase signaling pathways are required for the regulation of 5-aminolevulinate synthase gene expression by insulin. 1171 32

The lens possesses comprehensive mitogen-activated signal transduction pathways (MAPK), which include the mitogen response pathway (Raf-MEK-ERK cascade), the stress-response pathways (p38 and SAPK/JNK cascades) and also the survival pathway (PI-3K-Akt). To understand the cross-cascade intercommunication among signal transduction pathways in the lens, we used specific protein kinase inhibitors and cultured the lenses under unstimulated, basic fibroblast growth factor (bFGF)- or galactose-treated conditions. Inhibitors included genistein (tyrosine kinases inhibitor), U0126 (MEK inhibitor), SB203580 or SB202190 (p38 inhibitor), FTS (Ras inhibitor), wortmannin (PI-3K inhibitor) or phorbol ester (protein kinase C down-regulator following long-term exposure). The results showed that genistein inhibited the activations of the members of the MAPK superfamily and the activation of PI-3K. FTS suppressed the activation of Raf and PI-3K but stimulated the other members of MAPKs. MEK inhibitor restrained the activations of ERK, SAPK/JNK (under bFGF-stimulated condition) and p38 (under galactose-stimulated condition) while p38 inhibitor suppressed ERK but stimulated SAPK/JNK. Both MEK and p38 inhibitors stimulated PI-3K. Wortmannin had a strong inhibitory effect on Raf but little effect on its downstream target proteins. Down-regulating PKC suppressed Raf and PI-3K but stimulated ERK. Taken together, these data suggest that all the stimuli responses are mediated through phosphorylation and that the signaling among the mitogenic and stress response pathways is integrated through 'cross-talk' to process the most appropriate response. The survival signaling pathway appears to communicate well with the mitogenic and stress response pathways. In addition to Ras, both Raf and MEK emerge to be the diverging or regulatory points for signal integration, amplification, suppression or compensatory action in the lens.
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PMID:Studies of the mitogen-activated protein kinases and phosphatidylinositol-3 kinase in the lens. 2. The intercommunications. 1213 63

The signaling pathways involved in mussel immune defence were investigated utilizing a model of killing of Escherichia coli by Mytilus galloprovincialis hemocytes in a co-culture setting. In particular, the role played by different mitogen activated protein kinases (MAPKs) and by the production of eicosanoids were investigated utilising specific cell permeant, pharmacological enzyme inhibitors. Hemocyte pretreatment with the p38 MAPK inhibitor SB203580 significantly reduced bacterial killing, whereas PD98059 (an inhibitor of ERK--extracellularly regulated kinase--MAPK activation) had no significant effect. Wortmannin also inhibited bacterial killing, indicating a crucial role for PI3-kinase activation in the immune response. Killing of E. coli was also reduced by inhibitors of both PLA2 and cyclooxygenase activities, indicating that eicosanoid production is involved in mediating the response to bacterial challenge. The results demonstrate that bacterial killing by mussel hemocytes is particularly sensitive to inhibitors of the key steps involved in the transduction of bacterial signals into the host cell. Moreover, these data indicate that the hemocyte bactericidal activity can be suitably utilized not only for identifying the signaling pathways involved in the response to bacterial infection, but also as a potential investigative-toxicology model to test drugs and contaminants for their effect on the overall mussel immune defence.
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PMID:Bacterial killing by Mytilus hemocyte monolayers as a model for investigating the signaling pathways involved in mussel immune defence. 1240 15

Low-energy laser irradiation (LELI) drives quiescent skeletal muscle satellite cells into the cell cycle and enhances their proliferation, thereby promoting skeletal muscle regeneration. Ongoing protein synthesis is a prerequisite for these processes. Here, we studied the signaling pathways involved in the LELI regulation of protein synthesis. High levels of labeled [35S]methionine incorporation were detected in LELI cells as early as 20 min after irradiation, suggesting translation of pre-existing mRNAs. Induced levels of protein synthesis were detected up until 8 h after LELI implying a role for LELI in de novo protein synthesis. Elevated levels of cyclin D1, associated with augmented phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and its inhibitory binding protein PHAS-I, suggested the involvement of LELI in the initiation steps of protein translation. In the presence of the MEK inhibitor, PD98059, eIF4E phosphorylation was abolished and levels of cyclin D1 were dramatically reduced. The LELI-induced PHAS-I phosphorylation was abolished after preincubation with the PI3K inhibitor, Wortmannin. Concomitantly, LELI enhanced Akt phosphorylation, which was attenuated in the presence of Wortmannin. Taken together, these results suggest that LELI induces protein translation via the PI3K/Akt and Ras/Raf/ERK pathways.
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PMID:Low-energy laser irradiation enhances de novo protein synthesis via its effects on translation-regulatory proteins in skeletal muscle myoblasts. 1258 57

Estrogens affect the functioning of several non-reproductive tissues, the immune system in particular. In mammalian immunocytes, 17beta-estradiol (E2) has both dose- and cell-type specific effects and the responses to E2 seem to be mediated by rapid, non-genomic mechanisms; these may be initiated at either membrane or cytosolic locations, and can result in both direct local effects, such as modification of ion fluxes, and regulation of gene transcription secondary to activation of different kinase cascades, including mitogen activated protein kinases (MAPKs). In this work, the short-term effects of E(2) and the possible mechanisms of estrogen-mediated cell signaling were investigated in the hemocytes, the immune cells of the bivalve mollusc, the mussel Mytilus galloprovincialis Lam. The results show that E2 (25nM) caused a rapid and significant increase in hemocyte cytosolic [Ca2+]; lower concentrations (5 nM) showed a smaller, not significant effect. Both E2 concentrations affected the phosphorylation state of the components of tyrosine kinase-mediated signal transduction MAPK- and STAT- (signal transducers and activators of transcription) like proteins within 5-15 min from E2 addition. A greater effect and clearer time course were observed with 25 nM E2: in particular, E2 induced a transient increase in p-ERK2 MAPK and a persistent increase in p-p38 MAPK. Moreover, both STAT3 and STAT5 were tyrosine phosphorylated in response to E2. E2 (5 nM) induced both morphological (as evaluated by SEM) and functional changes (such as extracellular release of hydrolytic enzymes, lysosomal membrane destabilisation, and stimulation of the bactericidal activity) within 10-30 min from addition. Lysosomal membrane destabilisation induced by both E2 concentrations was abolished by hemocyte preincubation with the p38 MAPK inhibitor SB203580, and significantly reduced by PD98059 and Wortmannin (inhibitors of ERK MAPK and PI3-K, respectively), this suggesting that rapid activation of kinase cascades is involved in mediating the effects of E2 in mussel hemocytes. The antiestrogen Tamoxifen prevented or strongly reduced most, but not all, the effects of E2. Western blotting with heterologous anti-ERalpha-anti-ERbeta-antibodies revealed the presence of immunoreactive ERalpha- and ERbeta-like proteins in hemocyte protein extracts. Overall, our data support the hypothesis that the rapid effects and mechanisms of action of 17beta-estradiol are extremely conserved and that they may play a crucial role in endocrine-immune interactions in invertebrates.
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PMID:Rapid effects of 17beta-estradiol on cell signaling and function of Mytilus hemocytes. 1498 Jul 97

Insulin-like growth factor-1 (IGF-1) has been described as an important factor in proliferation, cell survival and migration of multiple myeloma (MM) cells. Angiogenesis correlates with development and prognosis of the MM disease. Vascular endothelial growth factor (VEGF) is one of the prominent factors involved in this process. The different functions of IGF-1 were investigated in the 5TMM mouse model with emphasis on proliferation, migration and VEGF secretion, and the signalling pathways involved. Western Blot analysis revealed that ERK1/2 and Akt (PKB) were activated after IGF-1 stimulation. The activation of ERK1/2 was reduced by the PI3K inhibitor Wortmannin, implying that the PI3K pathway is involved in its activation. Insulin-like growth factor-1 induced an increase in DNA synthesis in MM cells, which was mediated by a PI3K/Akt-MEK/ERK pathway. Insulin-like growth factor-1 enhanced F-actin assembly and this process was only PI3K mediated. Stimulation by IGF-1 of VEGF production was reduced by PD98059, indicating that only the MEK-ERK pathway is involved in IGF-1-stimulated VEGF production. In conclusion, IGF-1 mediates its multiple effects on MM cells through different signal transduction pathways. In the future, we can study the potential in vivo effects of IGF-1 inhibition on tumour growth and angiogenesis in MM.
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PMID:Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model. 1499 10

Hepatocyte growth factor (HGF) promotes the proliferation of adult myoblasts and inhibits their differentiation, whereas insulin-like growth factor I (IGF-I) enhances both processes. Recent studies indicate that activation of the phosphoinositide 3'-kinase (PI3K) pathway promotes myoblast differentiation, whereas activation of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) promotes proliferation and inhibits their differentiation. This simple model is confounded by the fact that both HGF and IGF-I have been shown to activate both pathways. In this study, we have compared the ability of HGF and IGF-I to activate PI3K and MAPK/ERK in i28 myogenic cells. We find that, although the two stimuli result in comparable recruitment of the p85alpha subunit of PI3K into complexes with tyrosine-phosphorylated proteins, the p85beta regulatory subunit and p110alpha catalytic subunit of PI3K are preferentially recruited into these complexes in response to IGF-I. In agreement with this observation, IGF-I is much more potent than HGF in stimulating phosphorylation of Akt/PKB, a protein kinase downstream of PI3K. In contrast, MAPK/ERK phosphorylation was higher in response to HGF and lasted longer, relative to IGF-I. Moreover, the specific PI3K inhibitor, Wortmannin, abolished MAPK/ERK and Elk-1 phosphorylation in HGF-treated cells, suggesting the requirement of PI3K in mediating the HGF-induced MAPK pathway. UO126, a specific MAPK pathway inhibitor, had no effect on PI3K activity or Akt phosphorylation, implying that at least in muscle cells, the MAPK/ERK pathway is not required for HGF-induced PI3K activation. These results provide a biochemical rationale for the previous observations that HGF and IGF-I have opposite effects on myogenic cells, consistent with studies linking PI3K activation to differentiation and MAPK/ERK activation to proliferation in these cells. Moreover, the finding that PI3K activity is required for HGF-induced MAPK activation suggests its additional role in proliferation, rather than exclusively in the differentiation of adult myoblasts.
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PMID:Differential regulation of the phosphoinositide 3-kinase and MAP kinase pathways by hepatocyte growth factor vs. insulin-like growth factor-I in myogenic cells. 1519 38

Adequate extravillous trophoblast (EVT) invasion is an essential step for placental formation. The aim of this study was to examine the possible role of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling in epidermal growth factor (EGF)-induced EVT migration and to determine if the 70 kDa ribosomal S6 kinase (p70S6K) is involved in this process. In this study, EGF significantly stimulated HTR8/SVneo cell migration and the phosphorylation of AKT, ERK1/2 and p70S6K in a concentration-dependent manner. The MAPK inhibitor U0126 decreased cell migration and ERK phosphorylation, but it did not influence p70S6K phosphorylation in response to EGF. In the presence of PI3K inhibitors (Wortmannin), EGF-stimulated trophoblast migration and phosphorylation of AKT and P70S6K (Thr(389) and Thr(421)/Ser(424)) were decreased, while EGF-induced ERK phosphorylation was not affected. Expression of an activated AKT (Myr-AKT2) increased basal phospho-p70S6K (Thr(389) and Thr(421)/Ser(424)) content, but failed to stimulate cell migration. However, it induced cell migration in the presence of EGF and Wortmannin, in which both AKT and MAPK pathways were activated. In addition, there was a concentration-dependent inhibition of cell migration and p70S6K phosphorylation (Thr(389) and Thr(421)/Ser(424)) in the presence of Rapamycin, a specific inhibitor of the mammalian target of rapamycin (mTOR, a downstream of AKT). Taken together, our data suggest that EGF-induced trophoblast migration involves the coordinated regulation of both PI3K/AKT and MAPK signalling pathways. mTOR/p70S6K is important in PI3K- but not MAPK-mediated trophoblast migration in response to EGF.
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PMID:Both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signalling are required in epidermal growth factor-induced human trophoblast migration. 1523 5


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