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)

Ovarian cancer metastasis involves the sloughing of epithelial cells from the ovary into the peritoneal cavity, where the cells can survive and proliferate in peritoneal ascites under anchorage-independent conditions. For normal epithelial cells and fibroblasts, cell adhesion to the extracellular matrix is required to prevent apoptosis and for proper activation and nuclear signaling of the ERK MAP kinase. The mechanisms of ERK regulation by adhesion have been determined by our lab and others. In this report, we elucidate a novel means of ERK regulation by cellular adhesion in ovarian cancer cells. We demonstrate that ERK and its activator MEK are robustly stimulated after cell detachment from a substratum in several ovarian cancer cell lines, but not a benign ovarian cell line, independent of serum and FAK or PAK activity. MEK and ERK activation was sustained for 48 h after detachment, while activation by serum or growth factors in adherent cells was transient. Re-attachment of suspended ovarian cells to fibronectin restored basal levels of MEK and ERK activity. ERK activity in suspended cells was dynamically controlled through an autocrine stimulatory pathway and prevalent phosphatase activity. Suspended cells demonstrated higher levels of ERK nuclear signaling to Elk1 compared to adherent cells. Inhibition of ERK activation with the MEK inhibitor U0126 had minor effects on adherent cell growth, but greatly decreased growth in soft agar. These data demonstrate a unique regulation of ERK by cellular adhesion and suggest a mechanism by which ERK may regulate anchorage-independent growth of metastatic ovarian cancer cells.
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PMID:ERK activation and nuclear signaling induced by the loss of cell/matrix adhesion stimulates anchorage-independent growth of ovarian cancer cells. 1872 93

Although Ras is a potent oncogene, its tumorigenicity depends on cellular context and cooperative events. Tumor suppressor PTEN is the most important negative regulator of the cell-survival signaling pathway initiated by phosphoinositide 3-OH kinase. Previously, we established various NIH/3T3 cells expressing H-Ras mutant proteins. This report shows that expression of PTEN is suppressed by the oncogenic H-Ras at its protein and transcript levels as well as by oncogenic K- and N-Ras. This activity of oncogenic Ras is mediated by Raf-1/Erk/MEK signaling pathway. In our previous reports, FAK Y(861) phosphorylation is higher in H-Ras transformed NIH/3T3 cells. In this report, level of FAK pY(861) was examined in Ras mutant cell lines. By generating wild-type PTEN, lipid phosphatase-deficient PTEN and activity-inert PTEN-inducible cell lines in the background of oncogenic H-Ras stable expression in NIH/3T3 cells, we show level of FAK pY(861) is decreased by protein phosphatase activity of PTEN.
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PMID:A cross-talk between oncogenic Ras and tumor suppressor PTEN through FAK Tyr861 phosphorylation in NIH/3T3 mouse embryonic fibroblasts. 1900 Jun 54

Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment.
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PMID:Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: An integrated molecular profiling approach. 1920 13

Increasing evidence is available showing the importance of the FAK (focal adhesion kinase) protein level in the migration and homeostasis of intestinal cells. TGFbeta (transforming growth factor beta) modulates FAK protein expression in a complex fashion not only by inducing the activation of p38 and Smad signaling resulting in increased fak promoter activity and increased FAK protein levels, but also by activating ERK (extracellular signal regulated kinases), p38, and the Smad pathway. We show that the blockade of ERK signaling by a specific MEK (MAPK kinase) inhibitor attenuates TGFbeta-induced FAK mRNA stability and reduces FAK protein levels in rat IEC-6 intestinal epithelial cells. The mTOR (mammalian target of rapamycin)-specific inhibitor rapamycin and small interfering RNAs for mTOR and p70(S6) kinase also block TGFbeta-induced FAK protein synthesis. Furthermore, we have found that a TGFbeta-induced increase in wound closures in monolayers of these cells is abolished in the presence ERK or mTOR inhibition. Thus, TGFbeta also modulates FAK protein levels in cultured rat IEC-6 intestinal epithelial cells via ERK activation, acting at the transcriptional level to complement Smad signaling and at on the translational level via the mTOR pathway downstream of ERK, which in turn promotes intestinal epithelial cell migration.
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PMID:Role of ERK/mTOR signaling in TGFbeta-modulated focal adhesion kinase mRNA stability and protein synthesis in cultured rat IEC-6 intestinal epithelial cells. 1934 Apr 59

The Ste20-like kinase, SLK, is involved in the control of cell motility through its effects on actin reorganization and focal adhesion turnover. Here we investigated the role of SLK in chemotaxis downstream of the tyrosine kinase receptor, HER2/ErbB2/Neu, which is frequently overexpressed in human breast cancers. Our results show that SLK is required for the efficient cell migration of human and mouse mammary epithelial cell lines in the presence of the Neu activator, heregulin, as a chemoattractant. SLK activity is stimulated by heregulin treatment or by overexpression of activated Neu. Phosphorylation of tyrosine 1201 or tyrosines 1226/7 on Neu is a key event for SLK activation and cell migration, and cancer cell invasion mediated by these tyrosines is inhibited by kinase-inactive SLK. Signaling pathway inhibitors show that Neu-mediated SLK activation is dependent on MEK, PI3K, PLCgamma and Shc signaling. Furthermore, heregulin-stimulated SLK activity requires signals from the focal adhesion proteins, FAK and src. Finally, phospho-FAK analysis shows that SLK is required for Neu-dependent focal adhesion turnover. Together, these studies define an interaction between Neu and SLK signaling in the regulation of cancer cell motility.
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PMID:The Ste20-like kinase SLK is required for ErbB2-driven breast cancer cell motility. 1952 80

Activated Ras has been found in many types of cancer. However, the mechanism underlying Ras-promoted tumor metastasis remains unclear. We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade. ERK phosphorylates FAK S910 and recruits PIN1 and PTP-PEST, which colocalize with FAK at the lamellipodia of migrating cells. PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis. These findings uncover the importance of sequential modification of FAK-by serine phosphorylation, isomerization, and tyrosine dephosphorylation--in the regulation of FAK activity and, thereby, in Ras-related tumor metastasis.
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PMID:FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. 1964 11

Specific transcription factors regulate the totipotent and pluripotent capability of embryonic stem cells. Amongst these regulatory transcription factors in embryonic stem cells, Oct4 and Nanog are master factors that also have unique characteristic ability of cell-specific pluripotency and self-renewal. The expression of Nanog in fibroblasts confirms increased cell proliferation and transformation of foci-forming phenotype indicative of its oncogenic potential. The expression of Oct4, interestingly, leads to transformation of non-tumorgenic mouse into tumorigenic mouse. Our current investigation ascertains that the resultant increase in DNA synthesis and cell proliferation is the consequence of transforming the phenotype into foci formation. We used a manually curetted ProteoChip to carry out the signaling protein microarray analysis, which revealed up-regulated expression of various proteins including FAK1, MEK1 and Raf1. Some of the proteins explain the mechanism by which Oct4 and Nanog transform the phenotype. In NIH3T3 cells expressed with mouse Oct4 (mOct4), mouse Nanog (mNanog) separately as well as together, the specific knockdown of mFAK1 inhibited morphological transformation of the cells, and their invasion activity. The mFAK1 overexpression leads to morphological transformation as shown with mOct4 and mNanog. Additionally, we showed that the ERK1/2 pathway is involved in the up-regulation of c-myc and cyclin D1 expression mediated by mFAK1. Our results signify that the combinatorial signaling protein-array using biomolecular approach may possibly provide us with a new tool to understand cellular homeostasis.
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PMID:Protein chip analysis of pluripotency-associated proteins in NIH3T3 fibroblast. 1970 7

The natural product sesamin has been known to act as a potent antioxidant and prevent endothelial dysfunction. We here found that sesamin increased in vitro angiogenic processes, such as endothelial cell proliferation, migration, and tube formation, as well as neovascularization in an animal model. This compound elicited the activation of multiple angiogenic signal modulators, such as ERK, Akt, endothelial nitric oxide synthase (eNOS), NO production, FAK, and p38 MAPK, but not Src. The MEK inhibitor PD98059 and the PI3K inhibitor Wortmannin specifically inhibited sesamin-induced activation of the ERK and Akt/eNOS pathways. These inhibitors reduced angiogenic events, with high specificity for MEK/ERK-dependent cell proliferation and migration and PI3K/Akt-mediated tube formation. Moreover, inhibition of p38 MAPK effectively inhibited sesamin-induced cell migration. The angiogenic activity of sesamin was not associated with VEGF expression. Furthermore, this compound did not induce vascular permeability and upregulated ICAM-1 and VCAM-1 expression, which are hallmarks of vascular inflammation. These results suggest that sesamin stimulates angiogenesis in vitro and in vivo through the activation of MEK/ERK-, PI3K/Akt/eNOS-, p125(FAK)-, and p38 MAPK-dependent pathways, without increasing vascular inflammation, and may be used for treating ischemic diseases and tissue regeneration.
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PMID:Angiogenic activity of sesamin through the activation of multiple signal pathways. 1991 68

Cancer metastasis involves multiple processes which may complicate clinical management and even lead to death. Matrix metalloproteinases (MMPs) play an important role in cancer cell invasion, metastasis and angiogenesis, depending on whether agents can inhibit MMPs which could lead to inhibition of the migration and invasion of cancer cells. Curcumin, the active constituent of the dietary spice turmeric, has potential for the prevention and therapy of cancer. However, there is no study to address the effects of curcumin on migration and invasion of mouse-rat hybrid retina ganglion cells (N18). This is the first study to explore the anti-migration and -invasion of curcumin in mouse-rat hybrid retina ganglion cells (N18) in vitro. Curcumin exerted a dose- and time-dependent inhibitory effect on the invasion and migration of N18 cells in vitro. Results from Western blotting showed that curcumin inhibited the protein levels of PKC, FAK, NF-kappaB p65 and Rho A leading to the inhibition of ERK1/2, MKK7, COX-2 and ROCK1, respectively, finally causing the inhibition of MMP-2 and -9 for the inhibition of migration and invasion of N18 cells. Moreover, this action was involved in the inhibition of gene expression of MMP-2 and -7, FAK, ROCK1 and Rho A. Overall, the above data show that the anticancer effect of curcumin also exists for the inhibition of migration and invasion in N18 cells, and that curcumin may be a powerful candidate for developing preventive agents for cancer metastasis.
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PMID:Curcumin blocks migration and invasion of mouse-rat hybrid retina ganglion cells (N18) through the inhibition of MMP-2, -9, FAK, Rho A and Rock-1 gene expression. 2012 4

Farnesyltransferase (FTase) inhibitors induce growth arrest and apoptosis in various human cancer cells by inhibiting the post-translational activation of Ras. FTase inhibitors also function to suppress the release of vascular endothelial growth factor (VEGF) from tumor cells by inhibiting Ras activation; however, the effects of FTase inhibitors on VEGF-induced angiogenesis in endothelial cells have not been studied. We have investigated the antiangiogenic effect and molecular mechanism of 4-((1-((1-((4-bromophenyl)methyl)-1H-imidazol-5-yl)methyl)-4-(1-napthalenyl)-1H-pyrrol-3-yl)carbonyl)-(9C1)-morpholine (LB42708), a selective nonpeptidic FTase inhibitor, using in vitro and in vivo assay systems. LB42708 inhibited VEGF-induced Ras activation and subsequently suppressed angiogenesis in vitro and in vivo by blocking the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric-oxide synthase pathways in endothelial cells without altering FAK/Src activation. In addition, this inhibitor suppressed VEGF-induced endothelial cell cycle progression at the G(1) phase by suppressing cyclin D1 expression and retinoblastoma phosphorylation as well as up-regulating the cyclin-dependent kinase inhibitors p21 and p27. Knockdown of Ras by short interfering RNA revealed similar inhibitory effects on VEGF-induced angiogenic signal events compared with LB42708. Moreover, the inhibitory effects of LB42708 were significantly higher than those of 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336), a well known FTase inhibitor. LB42708 suppressed tumor growth and tumor angiogenesis in both xenograft tumor models of Ras-mutated HCT116 cells and its wild-type Caco-2 cells, indicating its potential application in the treatment of both Ras-mutated and wild type tumors. These data indicate that the antitumor effect of LB42708 can be associated with direct inhibition of VEGF-induced tumor angiogenesis by blocking Ras-dependent MAPK and PI3K/Akt signal pathways in tumor-associated endothelial cells.
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PMID:The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways. 2040 54


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