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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor/scatter factor (HGF) and the angiogenesis factors platelet-derived growth factors (PDGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) are found in elevated concentrations in serum or tumor tissue of patients with head and neck squamous cell carcinomas (HNSCC), suggesting these factors may be coregulated. A cDNA microarray analysis for HGF-inducible genes revealed that HGF also modulates PDGFA expression, a gene recently shown to be inducible by the transcription factor, early growth response-1 (Egr-1). In the present study, we investigated the potential role of HGF-induced Egr-1 in expression of PDGF, VEGF, and IL-8. HGF induced expression of all three factors and Egr-1 expression and DNA-binding activity. The analysis of promoter sequences showed putative Egr-1 binding sites in the PDGFA or VEGF but not in the IL-8 promoter, and HGF-induced Egr-1-binding activity was confirmed by chromatin immunoprecipitation (ChIP) assay. The maximal basal and HGF-induced promoter activity for the PDGFA gene existed within -630 bp of the promoter region, and overexpression of Egr-1 significantly increased such activity. Consistent with this, expression of PDGFA and VEGF but not IL-8 showed corresponding differences with Egr-1 expression in HNSCC tumor specimens and were strongly suppressed by transfection of Egr-1-antisense or small interference RNA (siRNA) oligonucleotides. HGF-induced expression of Egr-1, PDGFA, and VEGF was suppressed by pharmacologic and siRNA inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and protein kinase C (PKC) pathways. We conclude that the HGF-induced activation of transcription factor Egr-1 by MEK1/2- and PKC-dependent mechanisms differentially contributes to expression of PDGF and VEGF, which are important angiogenesis factors and targets for HNSCC therapy.
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PMID:Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma. 1610 54

Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent alpha4beta1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL.
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PMID:Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma. 1618 74

Biological responses of hepatocyte growth factor (HGF) are mediated by the Met receptor tyrosine kinase. Although HGF is a potent mitogen for a variety of cells, the signals required for cell-cycle progression by the Met/HGF receptor are poorly defined. In this study, we have used the Xenopus oocyte system to define the role of various Met proximal-binding partners and downstream signaling pathways in cell-cycle regulation. We show that cell-cycle progression and activation of MAPK and JNK mediated by the oncogenic Met receptor, Tpr-Met, are dependent on its kinase activity and the presence of the twin phosphotyrosine (Y482 & Y489) residues in its C-terminus, but that the recruitment of Grb2 and Shc adaptor proteins is dispensable, implicating other signaling molecules. However, using Met receptor oncoproteins engineered to recruit specific signaling proteins, we demonstrate that recruitment of Grb2 or Shc adaptor proteins is sufficient to induce cell-cycle progression and activation of MAPK and JNK, while the binding of phospholipase-Cgamma or phosphatidylinositol 3-kinase alone fails to elicit these responses. Using various means to block phosphatidylinositol 3-kinase, phospholipase-Cgamma, MEK, JNK, Mos, and Raf1 activity, we show that unlike the fibroblast growth factor receptor, MEK-dependent and independent signaling contribute to Met receptor-mediated cell-cycle progression, but phospholipase-Cgamma or JNK activity and Mos synthesis are not critical. Notably, we demonstrate that Raf1 and phosphatidylinositol 3-kinase signaling are required for cell-cycle progression initiated by the Met receptor, a protein frequently deregulated in human tumors.
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PMID:Oncogenic Met receptor induces cell-cycle progression in Xenopus oocytes independent of direct Grb2 and Shc binding or Mos synthesis, but requires phosphatidylinositol 3-kinase and Raf signaling. 1633 88

Hepatocyte growth factor (HGF), also known as scatter factor (SF), and its receptor, the c-Met tyrosine kinase, play roles in cancer invasion and metastasis in a wide variety of tumor cells. Clinical observations suggest that HGF can promote metastasis of hepatoma cells while stimulating tumor invasiveness. We use HGF as an invasive inducer of human hepatoma HepG2 cells to investigate the effect of flavonoids on anti-invasion. In our preliminary study, we investigated the effect of flavonoids including luteolin, quercetin, baicalein, genistein, taxifolin and catechin on HGF-mediated migration and invasion of HepG2 cells. We found that luteolin presented the most potent potential on anti-migration and anti-invasion by Boyden chamber assay. Furthermore, luteolin inhibited HGF-induced cell scattering and cytoskeleton change such as filopodia and lamellipodia was determined by both phase-contrast and fluorescence microscopy studies. In addition, Western blotting and immunoprecipitation were performed to confirm luteolin suppressed the phosphorylation of c-Met, the membrane receptor of HGF, as well as ERK1/2 and Akt, but not JNK1/2, which is activated by HGF. Our investigation demonstrated that luteolin similar to PD98059, which acts as a specific inhibitor of MEK, an up stream kinase regulating ERK1/2, and wortmannin, a PI3K inhibitor, inhibited the invasiveness induced by HGF. In conclusion, the luteolin inhibited HGF-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways.
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PMID:Inhibitory effect of luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways. 1645 70

CD47 is an integrin-associated penta-transmembrane protein that possesses an immunoglobulin-like domain in its extracellular region. We have now investigated the role of CD47 in the regulation of epithelial cell spreading and migration. CD47 is colocalized with E-cadherin at cell-cell adhesion sites of epithelial cells. A Ca2+ switch experiment showed that CD47 was endocytosed and then relocalized to cell-cell adhesion sites in a similar manner to E-cadherin. Such polarized localization of CD47 required the multiple spanning region of this protein. Forced expression of CD47 induced cell spreading with marked lamellipodium formation and resulted in both partial disruption of cell-cell adhesion and enhancement of the hepatocyte growth factor-stimulated scattering of Madin-Darby canine kidney cells. The CD47-induced cell spreading was blocked by inhibition of Src and mitogen-activated protein kinase kinase. Thus, these results suggest that CD47 participates in the regulation of cell-cell adhesion and cell migration through reorganization of the actin cytoskeleton in epithelial cells. This function of CD47 is mediated by the activation of Src and mitogen-activated protein kinase kinase.
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PMID:CD47 regulation of epithelial cell spreading and migration, and its signal transduction. 1677 78

We investigated the survival signals of epidermal growth factor (EGF) in human gastric adenocarcinoma cell line TMK-1. Treatment of TMK-1 cells with adriamycin (ADR) caused apoptosis and apoptosis-related reactions such as the release of cytochrome c from mitochondria and the activation of caspase 9. However, EGF treatment greatly reduced the ADR-induced apoptosis as well as these reactions. We previously reported that hepatocyte growth factor transmitted protective signals against ADR-induced apoptosis by causing activation of the phosphatidylinositol-3'-OH kinase (PtdIns3-K)/Akt signaling pathway in human epithelial cell line MKN74 [Takeuchi K & Ito F (2004) J Biol Chem279, 892-900]. However, PtdIns3-K/Akt signaling did not mediate the antiapoptotic action of EGF in TMK-1 cells. EGF increased the expression of the Bcl-X(L) protein, an antiapoptotic member of the Bcl-2 family, but not that of other anti (Bcl-2) or proapoptotic (Bad and Bax) protein members. Expression of the c-Fos and c-Jun, components of activator protein 1 (AP1), which are known to regulate bcl-X(L) gene transcription, were increased in response to EGF. Pretreatment of the cells with PD98059, an inhibitor of MAP kinase kinase, inhibited the EGF-induced c-Fos and c-Jun expression, AP1 DNA binding, Bcl-X(L) expression, and the resistance against ADR-induced apoptosis, suggesting that EGF transmitted the antiapoptotic signal in such a way that it activated AP1 via a MAP kinase signaling pathway. TMK-1 cells stably transfected with TAM67, c-Jun dominant-negative mutant, did not display EGF-induced Bcl-X(L) expression or resistance against ADR-induced apoptosis. These results indicate that AP1-mediated upregulation of Bcl-X(L) expression is critical for protection of TMK-1 cells against ADR-induced apoptosis.
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PMID:Role of transcription factor activator protein 1 (AP1) in epidermal growth factor-mediated protection against apoptosis induced by a DNA-damaging agent. 1691 23

Hepatocyte growth factor (HGF) influences several components of the angiogenic response, including endothelial cell migration. While recent studies indicate a crucial role of HGF in brain angiogenesis, the signaling pathways that regulate brain endothelial cell migration by HGF remain uncharacterized. Herein, we report that HGF stimulated human brain microvascular endothelial cell (HBMEC) migration in a dose- and time-dependent manner. Challenge of HBMECs with HGF activated the c-jun amino-terminal kinase (JNK), increased phosphorylation of the proline-rich tyrosine kinase 2 (Pyk-2) at Tyr(402) and activated c-Src. Inhibition of JNK by SP600125 or expression of a dominant negative JNK1 construct abrogated the migratory response of HBMECs to HGF. Treatment of HBMECs with the Src inhibitor PP2 markedly decreased HGF-stimulated JNK activation and migration to HGF. Moreover, expression of a mutant Pyk-2 construct prevented HGF-induced Pyk-2 phosphorylation at Tyr(402) and stimulation of HBMEC migration. Next, we examined activation of the extracellular signal regulated kinase (ERK) pathway. Stimulation of HBMECs by HGF led to rapid activation of ERK1/2, phosphorylation of Raf-1 at Ser(338) and Tyr(340/341) and MEK1/2 at Ser(222). Moreover, inhibition of ERK activation by UO126 and PD98059 markedly decreased HGF-stimulated HBMEC migration. HGF also activated AKT, while inhibition of AKT by LY294002 induced a modest decrease of HGF-induced HBMEC migration. These results highlight a model whereby JNK and ERK play a critical role in regulation of brain endothelial cell migration by HGF.
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PMID:c-jun amino-terminal kinase and mitogen activated protein kinase 1/2 mediate hepatocyte growth factor-induced migration of brain endothelial cells. 1705 84

Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates within tumors in vivo and protects tumor cells against cytotoxicity and apoptosis due to DNA damaging agents in vitro. Previous studies have established that SF-mediated cell protection involves antiapoptotic signaling from its receptor (c-Met) to PI3 kinase --> c-Akt --> Pak1 (p21-activated kinase -1) --> NF-kappaB (nuclear factor-kappa B). Here, we found that Ras proteins (H-Ras and R-Ras) enhance SF-mediated activation of NF-kappaB and protection of DU-145 and MDCK (Madin-Darby canine kidney) cells against the topoisomerase IIalpha inhibitor adriamycin. Studies of Ras effector loop mutants and their downstream effectors suggest that Ras/PI3 kinase and Ras/Raf1 pathways contribute to SF stimulation of NF-kappaB signaling and cell protection. Further studies revealed that Raf1 positively regulates the ability of SF to stimulate NF-kappaB activity and cell protection. The ability of Raf1 to stimulate NF-kappaB activity was not due to the classical Raf1 --> MEK1/2 --> ERK1/2 pathway. However, we found that a MEK3/6 --> p38 pathway contributes to SF-mediated activation of NF-kappaB. In contrast, RalA, a target of the Ras/RalGDS pathway negatively regulated the ability of SF to stimulate NF-kappaB activity and cell protection. Ras, Raf1 and RalA modulate SF stimulation of NF-kappaB activity, in part, by regulating IkappaB kinase (IKK)-beta kinase activity. These findings suggest that Ras/Raf1/RalA pathways may converge to modulate NF-kappaB activation and SF-mediated survival signaling at the IKK complex and/or a kinase upstream of this complex.
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PMID:Ras effector pathways modulate scatter factor-stimulated NF-kappaB signaling and protection against DNA damage. 1729 51

The nuclear receptor constitutive active/androstane receptor (CAR) is sequestered in the cytoplasm of liver cells before its activation by therapeutic drugs and xenobiotics such as phenobarbital (PB) and 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in mouse liver, the regulatory mechanism of which remains poorly understood. Given the finding that epidermal growth factor repressed PB activation of CAR-mediated transcription (Mol Pharmacol 65:172-180, 2004), here we investigated the regulatory role of hepatocyte growth factor (HGF)-mediated signal in sequestering CAR in the cytoplasm of mouse primary hepatocytes. HGF treatment effectively repressed the induction of endogenous CYP2b10 gene by PB and TCPOBOP in mouse primary hepatocytes. On the other hand, inhibition by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) of an HGF downstream kinase mitogen-activated protein kinase kinase (MEK) induced the Cyp2b10 gene and up-regulated the CAR-regulated promoter activity in the absence of TCPOBOP. HGF treatment increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in the cytosol, thus decreasing the TCPOBOP-induced nuclear accumulation of CAR. In contrast, U0126 dephosphorylated ERK1/2 and increased nuclear CAR accumulation in the absence of TCPOBOP. These results are consistent with the conclusion that the HGF-dependent phosphorylation of ERK1/2 is the endogenous signal that sequesters CAR in the cytoplasm of mouse primary hepatocytes.
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PMID:Extracellular signal-regulated kinase is an endogenous signal retaining the nuclear constitutive active/androstane receptor (CAR) in the cytoplasm of mouse primary hepatocytes. 1731 19

The effect of growth factors on the cell cycle progression, except G1/S transition, is poorly understood. Herein, we examined the effect of hepatocyte growth factor (HGF) treated at S phase on the cell cycle progression of HeLa cells. Interestingly, the treatment resulted in G2 delay, evidenced by flow cytometric and mitotic index analyses. The delay corresponded with the delay of degradation of cyclin A and cyclin B, and the delay of decrease of Cdk1/cyclin B and Cdk2/cyclin A kinase activities. As for the signaling responsible, sustained activation of ERK, but neither of p38MAPK nor of JNK, was observed after HGF treatment at S phase. Furthermore, U0126, an inhibitor of MEK1, and DN-MEK partially abrogated the G2 delay, indicating that activation of MEK-ERK pathway is involved. Taken together, HGF treatment of HeLa cells at S phase induces G2 delay partially through sustained activation of ERK signaling.
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PMID:Hepatocyte growth factor at S phase induces G2 delay through sustained ERK activation. 1734 75


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