Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of alpha(1)- and beta(2)-adrenergic agonists on hepatocyte growth factor (HGF)-stimulated mitogen-activated protein kinase (MAPK) isoforms in primary cultures of adult rat hepatocytes. Hepatocytes were isolated and cultured with HGF (5 ng/ml) and/or alpha- and beta-adrenergic agonists. Phosphorylated MAPK isoforms (p42 and p44 MAPK) were detected by Western blotting analysis using anti-phospho-MAPK antibody. The results show that HGF increased phosphorylation of p42 MAPK by 2.2-fold within 3 min. The HGF-induced MAPK activation was abolished by AG1478 treatment (10(-7) M). The MEK (MAPK kinase) inhibitor PD98059 (10(-6) M) completely inhibited the HGF-dependent increase in MAPK activity. Phenylephrine (10(-6) M) and metaproterenol (10(-6) M) alone had no effect in the absence of HGF, but significantly increased p42 MAPK induction by HGF. Moreover, the cell-permeable cAMP analog, 8-bromo cAMP (10(-7) M), and phorbol 12-myristate 13 acetate (10(-7) M) potentiated HGF-induced MAPK phosphorylation. The effects of these analogs were antagonized by the protein kinase A (PKA) inhibitor H-89 (10(-7) M) and the protein kinase C (PKC) inhibitor sphingosine (10(-6) M), respectively. These results suggest that direct or indirect activation of both PKA and PKC represent a positive regulatory mechanism for stimulating MAPK induction by HGF.
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PMID:Activation of mitogen-activated protein kinase by hepatocyte growth factor is stimulated by both alpha1- and beta2-adrenergic agonists in primary cultures of adult rat hepatocytes. 1740 28

The c-MET receptor can be overexpressed, amplified, or mutated in solid tumours including small cell lung cancer (SCLC). In c-MET-overexpressing SCLC cell line NCI-H69, hepatocyte growth factor (HGF) dramatically induced c-MET phosphorylation at phosphoepitopes pY1230/1234/1235 (catalytic tyrosine kinase), pY1003 (juxtamembrane), and also of paxillin at pY31 (CRKL-binding site). We utilised a global proteomics phosphoantibody array approach to identify further c-MET/HGF signal transduction intermediates in SCLC. Strong HGF induction of specific phosphorylation sites in phosphoproteins involved in c-MET/HGF signal transduction was detected, namely adducin-alpha [S724], adducin-gamma [S662], CREB [S133], ERK1 [T185/Y187], ERK1/2 [T202/Y204], ERK2 [T185/Y187], MAPKK (MEK) 1/2 [S221/S225], MAPKK (MEK) 3/6 [S189/S207], RB [S612], RB1 [S780], JNK [T183/Y185], STAT3 [S727], focal adhesion kinase (FAK) [Y576/S722/S910], p38alpha-MAPK [T180/Y182], and AKT1[S473] and [T308]. Conversely, inhibition of phosphorylation by HGF in protein kinase C (PKC), protein kinase R (PKR), and also CDK1 was identified. Phosphoantibody-based immunohistochemical analysis of SCLC tumour tissue and microarray established the role of c-MET in SCLC biology. This supports a role of c-MET activation in tumour invasive front in the tumour progression and invasion involving FAK and AKT downstream. The c-MET serves as an attractive therapeutic target in SCLC, as shown through small interfering RNA (siRNA) and selective prototype c-MET inhibitor SU11274, inhibiting the phosphorylation of c-MET itself and its downstream molecules such as AKT, S6 kinase, and ERK1/2. Investigation of mechanisms of invasion and, ultimately, metastasis in SCLC would be very useful with these signal transduction molecules.
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PMID:Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion. 1766 9

The activation or the inhibition of melanocyte-specific receptors offers novel means of augmenting normal melanocyte function, skin color, and photoprotection, or treating melanocytic disorders, namely at this time, metastatic melanoma. Melanocyte-specific receptors include melanocortin-1 (MCR1) and melatonin receptors. Other receptors that play an important role in melanoma progression are G-protein couple receptors such as Frizzled 5 and receptor tyrosine kinases such as c-Kit and hepatocyte growth factor (HGF) receptor. These receptors activate two crucial cell-signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT, integral to melanoma cell survival, and can serve as targets for therapy of disseminated melanoma. Activation of death receptors is another pathway that can be exploited with targeted therapeutics to control advanced melanoma. This article reviews the current understanding of melanocyte receptors, their agonists and inhibitors, and their potential to treat the melanocytic pathology.
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PMID:Melanocyte receptors: clinical implications and therapeutic relevance. 1790 13

Growth factors accelerate G0 to S progression in the cell cycle, however, the roles of growth factors in other cell cycle phases are largely unknown. Here, we show that treatment of HeLa cells with hepatocyte growth factor (HGF) at G2 phase induced the G2/M transition delay as evidenced by FACS analysis as well as by mitotic index and time-lapse analyses. Growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF) also induced G2/M transition delay like HGF. HGF treatment at G2 phase causes a delayed activation of cyclin B1-associated kinase and a diminished nuclear translocation of cyclin B1. Either U0126, a MAPK kinase (MEK) inhibitor, or kinase-dead mutant of ribosomal S6 kinase (RSK) abolished the delay. Additionally, knockdown of RSK1, but not RSK2, with siRNA abrogated the delay, indicating that the extracellular-regulated protein kinase (ERK)-RSK1 mediates the HGF-induced delay. We further found that the delay in G2/M transition of cells expressing oncogenic HGF receptor, M1268T, was abolished by RSK1 knockdown. Intriguingly, we observed that HGF induced chromosomal segregation defects, and depletion of RSK1, but not RSK2, aggravated these chromosomal aberrations. Taken together, the ERK-RSK1 activation by growth factors delays G2/M transition and this might be required to maintain genomic integrity during growth factor stimulation.
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PMID:The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations. 1845 Apr 23

Hepatocyte growth factor (HGF) is one of the survival factors with a potent ability to promote cell survival by inhibiting apoptosis. However, the mechanism by which HGF inhibits apoptosis is not completely understood. To explore the genes associated with stomach cancer cell survival by HGF, we used cDNA microarray technology and selected 26 genes up- or downregulated in NUGC-3 cells during HGF treatment. Among them, BAD was confirmed to be upregulated at the RNA and protein levels by HGF treatment. We investigated the effect of BAD induced by HGF on cell survival. HGF treatment inhibited apoptosis induced by BAD overexpression and enhanced BAD phosphorylation. Pretreatment of NUGC-3 cells with PI3K inhibitors, LY 294002, decreased HGF-induced BAD phosphorylation on Ser136 whereas an MEK inhibitor, PD 98059, decreased BAD phosphorylation on Ser112. In conclusion, increases in BAD levels as well as BAD phosphoryation by HGF might contribute to HGF-mediated cell survival in NUGC-3 cells.
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PMID:Hepatocyte growth factor promotes cell survival by phosphorylation of BAD in gastric cancer cells. 1848 12

Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates in tumors, where it may induce invasion, angiogenesis, and chemoresistance. We have studied the mechanisms by which SF and its receptor (c-Met) protect cells against the DNA-damaging agent adriamycin (ADR) as a model for chemoresistance of SF/c-Met-overexpressing tumors. Previous studies identified a phosphatidylinositol 3-kinase/c-Akt/Pak1/NF-kappaB cell survival pathway in DU-145 prostate cancer and Madin-Darby canine kidney epithelial cells. Here we studied Src signaling pathways involved in SF cell protection. Src enhanced basal and SF stimulated NF-kappaB activity and SF protection against ADR, in a manner dependent upon its kinase and Src homology 3 domains; and endogenous Src was required for SF stimulation of NF-kappaB activity and cell protection. The ability of Src to enhance SF stimulation of NF-kappaB activity was due, in part, to its ability to stimulate Akt and IkappaB kinase activity; and Src-mediated stimulation of NF-kappaB was due, in part, to a Rac1/MKK3/6/p38 pathway and was Akt-dependent. SF caused the activation of Src and the Rac1 effector Pak1. Furthermore, SF induced activating phosphorylations of MKK3, MKK6, and p38 within the c-Met signalsome in an Src-dependent manner. The NF-kappaB-inducing kinase was found to act downstream of TAK1 (transforming growth factor-beta-activated kinase 1) as a mediator of SF- and Src-stimulated NF-kappaB activity. Finally, the Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-kappaB-inducing kinase pathways exhibited cross-talk at the level of MKK3. These findings delineate some novel signaling pathways for SF-mediated resistance to ADR.
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PMID:Role of Src signal transduction pathways in scatter factor-mediated cellular protection. 1904 46

Tumor cells are known to produce larger amounts of reactive oxygen species (ROS) than normal cells. Although numerous reports have indicated the importance of ROS in urokinase plasminogen activator (uPA) production, the precise mechanisms remain controversial. In our study, we investigated the effect of ROS on uPA generation in human hepatoma cells, HepG2 and Hep 3B. We determined the effects of hepatocyte growth factor (HGF) on the regulation of ROS, which resulted in suppression of ROS production, as measured with the fluorescent probe, 2'-7'-dichlorofluorescein diacetate. The role of HGF in modulating ROS production, particularly that regulated by Rac-1, was determined. HGF suppressed the increment in Rac-1-regulated ROS in both cell lines. Treatment with 200 micrometer of H(2)O(2) showed a 1.6-2.1 fold increment in HGF, but a little increment occurred at 500 micrometer of H(2)O(2). It looks no dose dependent manner. Combined treatment with H(2)O(2) and HGF, resulted in a slightly increased production of HGF compared to no treatment (control). Also, H(2)O(2) upregulated uPA expression in both hepatoma cell lines. To identify the downstream pathways regulated by ROS, we treated cells with PD 98059, an MEK inhibitor, and SB 203580, a p38 inhibitor, after treatment with H(2)O(2), and showed negative control between ERK and p38 kinase activities for uPA regulation. We found that HGF modulate Rac-1-regulated ROS production through activation of Akt and ROS regulates uPA production via MAP kinase, which provides a novel clue to clarify the mechanism underlying hepatoma progression.
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PMID:Reactive oxygen species regulate the generation of urokinase plasminogen activator in human hepatoma cells via MAPK pathways after treatment with hepatocyte growth factor. 1929 37

The potential role of hepatocyte growth factor (HGF) in the regulation of angiogenesis factors in hepatoma cells is not widely appreciated. We investigated the role of HGF-induced activation of a transcription factor, Egr-1, in the expression of pro-angiogenic factors. Genes associated with angiogenesis induced by HGF were screened by using cDNA microarray technology in hepatocellular carcinoma cell lines, HepG2 and Hep3B. Expression levels of Egr-1, vascular endothelial growth factor (VEGF), and interleukin (IL)-8 were further confirmed by real time RT-PCR and Western blot analysis. Roles of Egr-1 in the levels of HGF-induced up-regulations of VEGF and IL-8 were measured by knockdown of Egr-1 with Egr-1 shRNA and chromatin immunoprecipitation assay. The levels of Egr-1, VEGF and IL-8 were up-regulated in cells treated with HGF. HGF-induced up-regulations of Egr-1, VEGF, and IL-8 were inhibited by the pretreatment with an MEK inhibitor, PD098059. HGF-induced up-regulation of VEGF and IL-8 were repressed by Egr-1 knockdown. HGF enhanced the binding activity of Egr-1 to the VEGF promoter in control cells, but not in the Egr-1-shRNA cells. No constitutive and inducible Egr-1 binding activities to the IL-8 promoter were observed in control and Egr-1-shRNA cells. Egr-1 knockdown reduced the luciferase activities increased by HGF not in the IL-8 promoter, but in the VEGF promoter. Egr-1 might play an important role in the up-regulation of VEGF and IL-8 induced by HGF and contribute to HGF-mediated angiogenesis, which might be promising targets for hepatocellular carcinoma therapy.
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PMID:Hepatocyte growth factor induced up-regulations of VEGF through Egr-1 in hepatocellular carcinoma cells. 1952 16

We previously showed cell-cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch-wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase-2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch-wound healing in a concentration-dependent manner. The HGF receptor, c-Met, was rapidly phosphorylated in the nemosis-stimulated keratinocytes. Nemosis-induced in vitro scratch-wound healing was inhibited by an HGF-neutralizing antibody as well as the small molecule c-Met inhibitor, SU11274. HGF-induced in vitro scratch-wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen-activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF-induced keratinocyte in vitro scratch-wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch-wound healing, and that in this effect signaling via HGF/c-Met is involved.
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PMID:Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway. 1961 22

Evidence points towards a pivotal role for cyclooxygenase (COX)-2 in promoting colorectal tumorigenesis through increasing prostaglandin E(2) (PGE(2)) levels. PGE(2) signalling is closely associated with the survival, proliferation and invasion of colorectal cancer cells. Recently, a reduction in PGE(2) inactivation, a process mediated by the nicotinamide adenine dinucleotide (NAD+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), has also been shown to promote tumoral PGE(2) accumulation. The hepatocyte growth factor (HGF) receptor, Met, is frequently over-expressed in colorectal tumours and promotes cancer growth, metastasis and resistance to therapy, although the mechanisms for this have not been fully elucidated. Here, we report that HGF/Met signalling can promote PGE(2) biogenesis in colorectal cancer cells via COX-2 up-regulation and 15-PGDH down-regulation at the protein and messenger RNA level. Pharmacological inhibition of MEK and PI3K suggested that both extracellular signal-regulated kinase (ERK) and AKT signalling are required for COX-2 protein up-regulation and 15-PGDH down-regulation downstream of Met. Notably, inhibition of Met with the small molecule inhibitor SU11274 reduced COX-2 expression and increased 15-PGDH expression in high Met-expressing cells. We also show that hypoxia potentiated HGF-driven COX-2 expression and enhanced PGE(2) release. Furthermore, inhibition of COX-2 impeded the growth-promoting effects of HGF, suggesting that the COX-2/PGE(2) pathway is an important mediator of HGF/Met signalling. These data reveal a critical role for HGF/Met signalling in promoting PGE(2) biogenesis in colorectal cancer cells. Targeting the crosstalk between these two important pathways may be useful for therapeutic treatment of colorectal cancer.
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PMID:HGF/Met signalling promotes PGE(2) biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells. 1963 28


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