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)

The low density lipoprotein receptor-related protein (LRP) has been reported to regulate cellular migration. In this study, an antisense RNA expression strategy was used to reduce LRP to undetectable levels in HT 1080 fibrosarcoma cells. The LRP-deficient cells demonstrated increased levels of cell-surface uPAR, higher levels of uPA in conditioned medium, increased migration on vitronectin-coated surfaces, and increased invasion of Matrigel. LRP-deficient cells also demonstrated increased levels of phosphorylated extracellular signal-regulated kinase (ERK) in the absence of exogenous stimulants. Antibodies which block binding of endogenously produced uPA to uPAR reduced ERK phosphorylation and migration of LRP-deficient cells to the levels observed with control cells. Inhibitors of ERK activation, including PD098059 and dominant-negative MEK1, also decreased the migration of LRP-deficient but not control cells. By contrast, constitutively active MEK1 stimulated the migration of control but not LRP-deficient cells. Although Matrigel invasion by LRP-deficient cells was inhibited by the proteinase inhibitor, aprotinin, PD098059 in combination with aprotinin was necessary for an optimal effect. Expression of the VLDL receptor in LRP-deficient cells reversed the changes in cellular migration and invasion. These studies demonstrate that binding of endogenously produced uPA to uPAR may serve as a major determinant of basal levels of activated ERK and, by this mechanism, regulate cellular migration and invasion. By regulating the uPA/uPAR system, LRP may also regulate ERK activation, cellular migration, and invasion.
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PMID:Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and matrigel invasion. 1059 31

Vitronectin (VN) and pro-urokinase (pro-uPA) stimulated migration of rat smooth muscle cells in a dose-dependent and additive way, and induced motile-type changes in cell morphology together with a complete reorganization of the actin filaments and of the microtubules. All these effects were inhibited by pertussis toxin, or by antibodies directed against the urokinase receptor (uPAR) or against the VN receptor alpha(v)beta(3) suggesting that an association between the two receptors is required to mediate both signals. Investigation of the signaling pathways showed that increasing the intracellular cAMP resulted in a selective inhibition of VN-induced cell migration. On the other hand, PD 98059, an inhibitor of MEK, differentially inhibited the pro-uPA- but not the VN-induced cell migration. Phosphorylation and nuclear translocation of Erk by pro-uPA was directly observed. We conclude that the signaling pathways of pro-uPA and VN must be at least in part different.
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PMID:Urokinase/urokinase receptor and vitronectin/alpha(v)beta(3) integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways. 1136 Jan 87

Altered expression of alphav integrins plays a critical role in tumor growth, invasion, and metastasis. In this study, we show that normal human epithelial ovarian cell line, HOSE, and ovarian cancer cell lines, OVCA 429, OVCA 433, and OVHS-1, expressed alphav integrin and associated beta1, beta3, and beta5 subunits, but only ovarian cancer cell lines OVCA 429 and OVCA 433 expressed alphavbeta6 integrin. The expression of alphavbeta6 in OVCA 429 and OVCA 433 was far higher than alphavbeta3 and alphavbeta5 integrin and correlated with high p42/p44 mitogen activated protein kinase (MAPK) activity and high secretion of high molecular weight urokinase plasminogen activator (HMW-uPA), pro-metalloproteinase 2 and 9 (pro-MMP-9 and pro-MMP-2). In contrast to HOSE and OVHS 1, OVCA 433 and OVCA 429 exhibited approximately 2-fold more plasminogen-dependent [3H]-collagen type IV degradation. Plasminogen-dependent [3H]-collagen IV degradation was inhibited by inhibitor of uPA (amiloride) and MMP (phenanthroline) and by antibodies against uPA or MMP-9 or alphavbeta6 integrin, indicating the involvement of alphavbeta6 integrin, uPA and MMP-9 in the process. The alphavbeta6 correlated increase in HMW-uPA and pro-MMP secretion could be inhibited by tyrosine kinase inhibitor genistein or the MEK 1 inhibitor U0126, consistent with a role of active p42/44 MAPK in the elevation of uPA, MMP-9, and MMP-2 secretion. Under similar conditions, genistein and U0126 inhibited plasminogen-dependent [3H]-collagen type IV degradation. These data suggest that sustained elevation of p42/44 MAPK activity may be required for the co-expression of alphavbeta6 integrin, which in turn may regulate the malignant potential of ovarian cancer cells via proteolytic mechanisms.
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PMID:Association between alphavbeta6 integrin expression, elevated p42/44 kDa MAPK, and plasminogen-dependent matrix degradation in ovarian cancer. 1183 93

The tumor suppressor PTEN possesses lipid and protein phosphatase activities. It has been well established that the lipid phosphatase activity is essential for its tumor-suppressive function via the phosphoinositide 3-kinase (PI3K) and Akt pathways. The precise role of the protein phosphatase activity is still unclear. In the current study, we demonstrate that overexpression of wild-type PTEN in the MCF-7 breast cancer line results in phosphatase activity-dependent decreases in the phosphorylation of ETS-2, which is a transcription factor whose DNA-binding ability is controlled by phosphorylation. Exposure of MCF-7 cells to insulin, insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF) can lead to the phosphorylation of ETS-2, Akt and ERK1/2. The MEK inhibitor PD590089 abrogates insulin-stimulated phosphorylation of ETS-2. In contrast, the PI3K inhibitor LY492002 has no effect on insulin-stimulated phosphorylation of ETS-2, despite the fact that it diminishes insulin-stimulated phosphorylation of Akt. Interestingly, overexpression of PTEN in MCF-7 leads to blockade of insulin-stimulated, but not EGF-stimulated, phosphorylation of ERK, accompanied by dramatic decreases in ETS-2 phosphorylation. We further show that the relationship of PTEN and ETS-2 has functional significance by demonstrating that PTEN abrogates activation of the uPA Ras-responsive enhancer, a target of ETS-2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. Our observations, therefore, suggest that PTEN blocks insulin-stimulated ETS-2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS-2 may be mediated through PTEN's protein phosphatase activity.
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PMID:PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. 1209 11

We investigated the chemotactic action of PDGF and urokinase on human airway smooth muscle (HASM) cells in culture. Cells were put in collagen-coated transwells with 8-micro m perforations, incubated for 4 h with test compounds, then fixed, stained, and counted as migrated nuclei by microscopy. Cells from all culture conditions showed some basal migration (migration in the absence of stimuli during the assay), but cells preincubated for 24 h in 10% FBS or 20 ng/ml PDGF showed higher basal migration than cells quiesced in 1% FBS. PDGF(BB), PDGF(AA), and PDGF(AB) were all chemotactic when added during the assay. PDGF chemotaxis was blocked by the phosphatidyl 3'-kinase inhibitor LY-294002, the MEK inhibitor U-0126, PGE(2), formoterol, pertussis toxin, and the Rho kinase inhibitor Y-27632. Urokinase alone had no stimulatory effect on migration of quiescent cells but caused a dose-dependent potentiation of chemotaxis toward PDGF. Urokinase also potentiated the elevated basal migration of cells pretreated in 10% FBS or PDGF. This potentiating effect of urokinase appears to be novel. We conclude that PDGF and similar cytokines may be important factors in airway remodeling by redistribution of smooth muscle cells during inflammation and that urokinase may be important in potentiating the response.
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PMID:Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells. 1257 95

Urokinase plasminogen activator receptor (uPAR) plays a major role in cancer invasion and metastasis and uPAR expression is correlated with a poor prognosis in various cancer types. Moreover, the expression of uPAR is increased under hypoxic conditions. Nitric oxide (NO) and its metabolites produced by inducible nitric oxide synthase (iNOS) are important products of hypoxic stress, and NO may activate or modulate extracellular signal regulated kinase (ERK). Here, we evaluated uPA, uPAR, and activated ERK levels under hypoxic conditions, and the modulatory effects of iNOS and NO in the MDA-MB-231 human breast cancer cell line. Cells were incubated in a hypoxic or normoxic incubator and treated with PD98059 (a MEK 1/2 inhibitor, which abrogates ERK phosphorylation) and aminoguanidine (a selective iNOS inhibitor). uPAR expression, ERK phosphorylation, and uPA activity were found to be increased under hypoxic conditions. Moreover, when cells were treated with PD98059 under hypoxic conditions, uPAR was downregulated, whereas aminoguanidine markedly increased ERK phosphorylation in a dose dependent manner. Furthermore, aminoguanidine increased uPAR expression and prevented the inhibition of uPAR expression by PD98059. These results demonstrated that uPAR is induced by hypoxia and that increased uPAR expression is mediated by ERK phosphorylation, which in turn is modulated by iNOS/NO in MDA-MB-231 cells. We conclude that iNOS/NO downregulates the expression of uPAR under hypoxic conditions via ERK pathway modulation.
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PMID:uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line. 1646 78

The interaction between prostate cancer cells and bone marrow stromal cells (BMSC) is critical for survival and proliferation of metastatic cancer cells in the bone microenvironment. In order to study molecular mechanisms of prostate cancer bone metastasis, we established a novel heterotypic co-culture system, in which the role of direct cell-cell contact between prostate cancer cells and BMSC in addition to soluble factors can be analyzed. Using both bi-compartmental (insert) system and heterotypic (contact) system, we identified gene expression profiles of interaction between prostate cancer and bone cells. Analysis of differential gene expressions in these two co-culture systems revealed three distinctive sets of genes: 1) genes that were modified only by soluble factors; 2) genes that were regulated by both soluble factors and physical contact; and 3) genes that were altered only by physical contact. The last group consisted of specific set of genes including collagen III, IV, X, XII, integrin alpha1, alpha2, MMP-2, MMP-9, uPA, biglycan, osteopontin and raf-1 in PC3, and collagen VIII, IX, BMP6, TGFbeta1, Smad6 and Twist in BMSC. Among genes that were modified by both soluble factors and physical contact, the gene expression was affected in the same direction (such as MKK4) or in the opposite direction (such as TGFbeta receptor 3). Overall, this suggests that heterotypic cell-cell contact may act as an independent factor affecting the progression of bone metastasis.
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PMID:Identification of a unique set of genes altered during cell-cell contact in an in vitro model of prostate cancer bone metastasis. 1659 70

The acquired capabilities of resistance to apoptotic cell death and tissue invasion are considered to be obligate steps in tumor progression. The binding of the serine protease urokinase (uPA) to its receptor (uPAR) plays a central role in the molecular events coordinating tumor cell adhesion, migration, and invasion. Here we investigate whether uPAR signaling may also prevent apoptosis following loss of anchorage (anoikis) or DNA damage. If nontransformed human retinal pigment epithelial cells are pre-exposed to uPA or to its noncatalytic amino-terminal region (residues 1-135), they exhibit a markedly reduced susceptibility to anoikis as well as to UV-induced apoptosis. This anti-apoptotic effect is retained by a uPA-derived synthetic peptide corresponding to the receptor binding domain and is inhibited by anti-uPAR polyclonal antibodies. Furthermore, the stable reduction of uPA or uPAR expression by RNA interference leads to an increased susceptibility to UV-, cisplatin-, and detachment-induced apoptosis. In particular, the level of uPAR expression positively correlates with cell resistance to anoikis. The protective ability of uPA is prevented by UO126, LY294002, by an MAPK targeting small interference RNA, and by a dominant negative Akt variant. Accordingly, incubation of retinal pigment epithelial cells with uPA elicits a time-dependent enhancement of MAPK and phosphatidylinositol 3-kinase activities as well as the transcriptional activation of Bcl-xL anti-apoptotic factor. Vice versa, the silencing of Bcl-xL expression prevents uPA protection from anoikis. In conclusion, the data show that ligand engagement of uPAR promotes cell survival by activating Bcl-xL transcription through the MEK/ERK- and phosphatidylinositol 3-kinase/Akt-dependent pathways.
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PMID:Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. 1663 75

It is well recognized that the majority of cancer related deaths is caused by metastatic diseases. Therefore, there is an urgent need for the development of therapeutic intervention specifically targeted to the metastatic process. In the last decade, significant progress has been made in this research field, and many new concepts have emerged that shed light on the molecular mechanism of metastasis cascade which is often portrayed as a succession of six distinct steps; localized invasion, intravasation, translocation, extravasation, micrometastasis and colonization. Successful metastasis is dependent on the balance and complex interplay of both the metastasis promoters and suppressors in each step. Therefore, the basic strategy of our interventions is aimed at either blocking the promoters or potentiating the suppressors in this disease process. Toward this goal, various kinds of antibodies and small molecules have been designed. These include agents that block the ligand-recepter interaction of metastasis promoters (HGF/c-Met), antagonize the metastasis-promoting enzymes (AMF, uPA and MMP) and inhibit the transcriptional activity of metastasis promoter (beta-Catenin). On the other hand, the intriguing roles of metastasis suppressors and their signal pathways have been extensively studied and various attempts have been made to potentiate these factors. Small molecules have been developed to restore the expression or mimic the function of metastasis-suppressor genes such as NM23, E-cadherin, Kiss-1, MKK4 and NDRG1, and some of them are under clinical trials. This review summarizes our current understanding of the molecular pathway of tumor metastasis and discusses strategies and recent development of anti-metastatic drugs.
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PMID:Drug development against metastasis-related genes and their pathways: a rationale for cancer therapy. 1869 17

Elevated concentrations of IL-6 (interleukin-6) and sIL-6r (soluble IL-6 receptor) in the synovial fluid and serum of patients with arthritis have been implicated in joint cartilage destruction. This study examined the effects of IL-6 and sIL-6r on the expression of MMPs (matrix metalloproteinases), TIMPs (tissue inhibitor of metalloproteinases), the plasminogen activation system including tPA (tissue-type PA), uPA (urokinase-type PA) and PAI-1 (PA inhibitor type 1) using chondrocytes derived from normal human femur cartilage. The cells were cultured with or without 50 ng/ml IL-6 and/or 30 ng/ml sIL-6r in the presence or absence of the JAK3 (Janus kinase 3) inhibitor WHI-P131 or the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular signal protein kinase) kinase] inhibitor PD98059 for up to 28 days. The expression of MMPs, TIMPs, uPA, tPA and PAI-1 was investigated at the mRNA and protein levels. MMP protein expression and pSTAT3 (phosphorylation of signal transducer and activator of transcription 3) and pERK (phosphorylation of ERK) were also measured. Treatment with both IL-6 and sIL-6r markedly increased the expression of MMP-1, MMP-13, TIMP-1 and PAI-1, while significantly decreasing the expression of tPA and uPA and stimulating pSTAT3 and pERK. Adding WHI-P131 or PD98059 decreased IL-6 and sIL-6r enhancement of MMP-1, -3 and -13. The results suggest that IL-6 and sIL-6r stimulate the production of MMPs and their inhibitor via JAK-STAT and ERK-MAPK signalling in chondrocytes.
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PMID:IL-6 and soluble IL-6 receptor stimulate the production of MMPs and their inhibitors via JAK-STAT and ERK-MAPK signalling in human chondrocytes. 2208 78


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