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)

Chemokine receptors are not only able to bind chemokines but, together with CD4, they serve as an entry door for the human immunodeficiency virus type 1 (HIV-1). The signalling capacity of chemokine receptors, which is of fundamental importance for chemokine-induced chemotaxis, is not used by HIV-1 to enter a target cell, nor by chemokines or chemokine-derived ligands to inhibit viral entry. In addition, an ill-defined signal triggered by chemokines can, under some circumstances, lead to an increase in HIV-1 expression. We show here that, in infected cells, exposure to SDF-1 leads to an increased expression of a X4 strain of HIV-1. A similar increase can be induced by an N-terminal peptide of SDF-1 which had previously been shown to elicit an intracellular calcium response and to inhibit the entry of X4 strains of HIV-1. We demonstrate the involvement of extracellular signal-regulated kinases (ERK) in this phenomenon. SDF-1 activates ERK-1 and ERK-2 in Jurkat cells. In HeLa cells, ERK-2 only is activated by SDF-1 or by a SDF-derived peptide. This ERK activation can be blocked by pertussis toxin and by the MEK inhibitor U0126. Most importantly, SDF-1-dependent HIV-1 expression is abolished by pretreating the cells with pertussis toxin or with U0126. The consequences of this SDF-1-induced, ERK-dependent modulation of HIV-1 expression in infected cells may have a clinical relevance for eradicating latent viruses.
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PMID:SDF-1-induced activation of ERK enhances HIV-1 expression. 1102 34

We have previously shown that the CC-chemokine 1-309 (CCL1) protects mouse thymic lymphomas against corticoid-induced apoptosis. Here, we analyzed the signal transduction pathways involved in this activity on BW5147 lymphoma. Inhibition of the CCL1 activity by pertussis toxin suggested the involvement of a G protein-coupled chemokine receptor. The role of CCR8 was supported by the observation that vMIP-I, another CCR8-ligand identified from the genome of a T cell transforming herpes virus, shared CCL1 anti-apoptotic activity. In addition to CCR8, BW5147 cells also expressed the CXCR4 receptor but its ligand, SDF-1 (CXCL12) showed only a modest anti-apoptotic activity. Other chemokines acting on CCR2, CCR4 and CCR5 failed to protect against apoptosis and to induce BW5147 chemotaxis, suggesting that these receptors were not functionally expressed. By contrast, both CCL1 and vMIP-I up-regulated ERK1/2 MAPK phosphorylation in BW5147 cells. Further analysis demonstrated that CCL1 activates the MAPK pathway in CCR8-transfected CHO cells. The implication of this pathway was confirmed by the fact that PD98059, an inhibitor of MEK kinases, as well as a dominant negative isoform of the M-RAS protein specifically blocked the anti-apoptotic activity of CCL1.
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PMID:CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/ CCL1 and vMIP-I. 1264 48

We have studied the role of endothelins (ET-1, ET-2 and ET-3) and ET receptors (ET-RA and ET-RB) in the invasive capacity of breast tumor cells, which express ET-1 and ET-2 as well as ET-RA and ET-RB. Of five human breast tumor cell lines tested, all expressed mRNAs for ET-1, ET-2, and ET-RB. ET-RA mRNA was expressed by four of five tumor cell lines. Breast tumor cells migrated toward ET-1 and ET-2 but not toward ET-3. Chemotaxis involved signaling via both receptors, and a pertussis toxin-sensitive p42/p44 mitogen-activated protein kinase (MAPK)-mediated pathway that could be inhibited by MAPK kinase (MEK)1/2 antagonists. Chemotaxis toward ETs did not involve p38 or stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) and was not inhibited by hypoxia. Incubation of tumor cells with ET-2 also increased chemotaxis toward the chemokines CXCL12 and CCL21. As well as inducing chemotaxis of tumor cells, ET-1 and ET-2 increased tumor cell invasion through Matrigel. Furthermore, stimulation of macrophage/tumor cell cocultures with ETs led to increased matrix metalloproteinase (MMP)-2 and -9 production by macrophages and a marked increase in invasion of tumor cells. Antagonism of either ET-RA or ET-RB decreased the invasion seen in ET-stimulated cocultures, as did a broad-spectrum MMP inhibitor. Immunohistochemical staining of human breast tumor sections showed increased ET and ET receptor protein expression by tumor cells in invasive ductal carcinoma compared with normal breast tissue or ductal carcinoma in situ. Furthermore, tumor cell ET and receptor expression was stronger at the invasive margin of invasive ductal carcinomas, in the lymphovascular space, and in lymph node metastases. ET expression often colocalized with ET-RB expression in all neoplastic tissue indicating a possible autocrine action of ETs. We suggest that expression of ETs and their receptors by human breast tumors, particularly in conjunction with a high macrophage infiltrate, may have a role in the progression of breast cancer and the invasion of tumor cells.
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PMID:A role for endothelin-2 and its receptors in breast tumor cell invasion. 1505 99

Stromal cell-derived factor (SDF1) and its cognate receptor CXCR4 have been shown to play a central role in the development of the cerebellum, hippocampus, and neocortex. However, little is known about the functions of SDF1/CXCR4 in early spinal cord progenitor cell differentiation. Here, we show that a functional SDF1alpha/CXCR4 signaling pathway is present in developing spinal cord cells (a spliced variant of SDF1). RT-PCR analysis of SDF1alpha and CXCR4 showed that they were present in E10.5 neural tube and their expression increased as neuroepithelial cells differentiated into more committed spinal cord progenitors. Stimulation of the more differentiated progenitors (E14.5) with SDF1alpha resulted in rapid activation of the extracellular signal-regulated kinase (ERK)1/2. This SDF1alpha-induced ERK activity was dose dependent and could be inhibited by pre-treatment of the cells with either pertussis toxin, an inactivator of G-protein-coupled receptors, or PD98059, a MEK1 inhibitor. Concomitant with ERK activation, SDF1alpha also activated the downstream transcription factor Ets, a substrate for ERK phosphorylation. Further, downstream activation of genes associated with cell survival, differentiation and migration was assessed using a G-protein-coupled receptor pathway-focused microarray. We found that 23 genes, including PDK1, Egr-1, Grm5, and E-selectin, were up-regulated by SDF1alpha. Furthermore, SDF1alpha induced chemotaxis in both neural and glial progenitors in in vitro migration assays. Pre-treatment of the cells with either pertussis toxin or PD98059 completely inhibited SDF1alpha-induced chemotaxis. Thus, our data suggest that SDF1alpha may function through a CXCR4/ERK/Ets-linked signalling pathway in spinal cord neural development to modulate migration of progenitor cells.
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PMID:Functional SDF1 alpha/CXCR4 signaling in the developing spinal cord. 1581 68

The establishment of metastatic bone lesions in prostate cancer (CaP) is a process partially dependent on angiogenesis. Previously we demonstrated that the stromal-derived factor-1 (SDF-1 or CXCL12)/CXCR4 chemokine axis is critical for CaP cell metastasis. In this investigation, cell lines were established in which CXCR4 expression was knocked down using siRNA technology. When CaP cells were co-transplanted with human vascular endothelial cells into SCID mice, significantly fewer human blood vessels were observed paralleling the reductions in CXCR4 levels. Likewise, the invasive behaviors of the CaP cells were inhibited in vitro. From these functional observations we explored angiogenic and signaling mechanisms generated following SDF-1 binding to CXCR4. Differential activation of the MEK/ERK and PI3K/AKT pathways that result in differential secretion IL-6, IL-8, TIMP-2 and VEGF were seen contingent on the cell type examined; VEGF and TIMP-2 expression in PC3 cells are dependent on AKT activation and ERK activation in LNCaP and LNCaP C4-2B cells leads to IL-6 or IL-8 secretion. At the same time, expression of angiostatin levels were inversely related to CXCR4 levels, and inhibited by SDF-1 stimulation. These data link the SDF-1/CXCR4 pathway to changes in angiogenic cytokines by different signaling mechanisms and, suggest that the delicate equilibrium between proangiogenic and antiangiogenic factors may be achieved by different signal transduction pathways to regulate the angiogenic phenotype of prostate cancers. Taken together, our results provide new information regarding expression of functional CXCR4 receptor-an essential role and potential mechanism of angiogenesis upon SDF-1 stimulation.
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PMID:Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. 1600 85

We used GH4C1 cells as a model to study the effects of the chemokine stromal cell-derived factor 1 (SDF1) in pituitary functions. In these cells, SDF1alpha induced proliferation and growth hormone secretion, suggesting a possible regulatory role for this chemokine at pituitary level. We evaluated the intracellular signaling involved in these effects: SDF1alpha increased cytosolic [Ca(2+)] and activated Pyk2, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and large-conductance Ca(2+)-activated K(+) channels (BK(Ca)) channels. To correlate these intracellular effectors with the proliferative and secretory effects, we inhibited their activity using BAPTA-AM (Ca(2+) chelator), 2'-amino-3'-methoxyflavone (PD98059; a mitogen-activated protein kinase kinase inhibitor), salicylate (Pyk2 inhibitor), and tetraethyl ammonium (K(+) channel blocker). All of these compounds reverted SDF1alpha-induced proliferation, suggesting the involvement of multiple intracellular pathways. Conversely, only BAPTA-AM reverted growth hormone secretion. To identify a possible cross-talk and a molecular ordering among these pathways, we tested these antagonists on SDF1alpha-dependent activation of ERK1/2, Pyk2, and BK(Ca) channels. From these experiments, we observed that the inhibition of [Ca(2+)](i) increase or BK(Ca) channel activity did not affect ERK1/2 activation by SDF1alpha; Pyk2 activation was purely Ca(2+)-dependent, not involving ERK1/2 or BK(Ca) channels; and BK(Ca) channel activity was antagonized by Pyk2 but not by ERK1/2 inhibitors. These data suggest that an SDF1alpha-dependent increase of [Ca(2+)](i) activates Pyk2, which in turn regulates BK(Ca) channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion, we demonstrate that SDF1alpha causes both proliferation and growth hormone release from pituitary adenoma cells, suggesting that the activation of CXCR4 may represent a novel regulatory mechanism for growth hormone secretion and pituitary cell proliferation, which may contribute to pituitary adenoma development.
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PMID:Chemokine stromal cell-derived factor 1alpha induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals. 1625 74

The present work focused on the study of the secretory activity of pre-B acute lymphoblastic leukaemia (ALL) cells harvested from bone marrow (BM) and peripheral blood (PB) in 16 children. The basal and cytokine (SDF-1, GM-CSF, bFGF, VEGF)-stimulated secretions of gelatinases 2 and 9 (MMPs-2 and -9) and expression of their genes were monitored by zymography and RT-PCR, respectively. A wide heterogeneity was found in the secretory capacities of these cells. The basal secretion of MMP-9 was more frequently observed than that of MMP-2 in both cell types. The cytokines VEGF and bFGF were found to induce predominant stimulatory effects on the MMP-2 secretion. In contrast, GM-CSF was shown to exert a more pronounced activation of the MMP-9 production. Experiments using inhibitors of metabolic pathways (U0126, LY294002 and SN50) revealed that the secretion of MMP-9 was mediated through PI3/MEK1 kinases. The MMP-2 secretion appeared to be however, stimulated through a different metabolic pathway. The microfluorimetric approach showed that the basal and stimulated secretions of MMPs-2 and -9 depended on the extracellular calcium pool. The cytokines VEGF and bFGF represent potent factors increasing the intracellular calcium concentration with similar kinetics. In contrast, GM-CSF was found to activate a verapamil-sensitive efflux of indo-1 from cytosol suggesting that this cytokine could be responsible for the activation of xenobiotic membrane transporters. Experiments using the trypan blue exclusion test demonstrated that bFGF, in contrast to VEGF and GM-CSF, markedly augmented pre-B ALL cell survival. Further investigations into a possible correlation between the plasma concentrations of MMP-2 and -9, VEGF, bFGF and GM-CSF, and the poor evolution of pre-B ALL in children could have valuable diagnostic implications.
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PMID:Spontaneous and cytokine-evoked production of matrix metalloproteinases by bone marrow and peripheral blood pre-B cells in childhood acute lymphoblastic leukaemia. 1626 64

Molecular markers like IgV(H) mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and the signaling function of CD38 in CLL. This study shows that ZAP-70(+) CLL B cells respond in vitro more readily than ZAP-70(-) CLL and normal B cells to chemokine migratory signals through enhanced surface CCR7 expression (P = .009; P < .001) and increased responsiveness to its ligands CCL19 and CCL21, demonstrated by F-actin polymerization (P < .05) and cellular migration (P < .01). In addition, ZAP-70(+) CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1-alpha, a survival factor produced by stromal cells) compared with ZAP-70(-) cells (P = .004). Following coculture with nurse-like cells, the survival of ZAP-70(+) but not ZAP-70(-) CLL cells is significantly enhanced by the addition of CXCL12 (P < .05), an effect that is partially blocked by the MEK inhibitor PD98059. These advantageous migratory and survival responses may promote easier access to and greater proliferation in pseudo-germinal centers and explain in part the more progressive nature of ZAP-70(+) disease.
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PMID:ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). 1633 69

Stromal cell-derived factor (SDF-1), by activating its cognate receptor CXCR4, plays multiple roles in cell migration, proliferation and survival in the development of the central nervous system. Recently, we have shown that functional SDF1alpha/CXCR4 signaling mediates chemotaxis through extracellular signal-regulated kinase (ERK) activation in the developing spinal cord. Here, we report that SDF1alpha/CXCR4 signaling activates beta-catenin/TCF transcriptional activity in embryonic rat spinal cord neural progenitors. Stimulation of neural progenitors with SDF1alpha resulted in cytoplasmic beta-catenin accumulation in 30 min, and lasted for approximately 240 min, while Wnt3a, a positive control, stabilized cytoplasmic beta-catenin in 120 min. Dose-response studies indicated that the beta-catenin stabilization effect could be detected in cells exposed to fM concentrations of SDF1alpha. This SDF1alpha-induced beta-catenin stabilization effect was inhibited by pretreatment of the cells with either pertussis toxin (PTX), an inactivator of G protein-coupled receptors, or PD98059, a MEK1 inhibitor. Concomitant with beta-catenin accumulation in the cytoplasm, SDF1alpha enhanced nuclear translocation of beta-catenin and its binding to nuclear transcription factor T cell-specific transcription factor/lymphoid enhancer-binding factor (TCF/LEF). Furthermore, SDF1alpha increased expression of genes such as Ccnd1, 2, 3, and c-Myc known as targets of the Wnt/beta-catenin/TCF pathway. The increased expression of Ccnd1 and c-Myc by SDF1alpha was further confirmed by immunoblot analysis. Our data suggest that SDF1alpha/CXCR4 signaling may interact with the Wnt/beta-catenin/TCF pathway to regulate the development of the central nervous system.
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PMID:SDF1alpha/CXCR4 signaling stimulates beta-catenin transcriptional activity in rat neural progenitors. 1646 39

Intracellular signaling mechanisms regulating SDF-1-induced chemotaxis of hematopoietic cells have remained elusive. Here we demonstrate that overexpression of the adaptor molecule CrkL enhances SDF-1-induced chemotaxis of hematopoietic BaF3 and 32Dcl3 cells. Overexpression of CrkL also enhanced SDF-1-induced activation of the Raf-1/MEK/Erk signaling pathway as well as that of the small GTPases Ras, Rap1, and Rac, while a dominant negative mutant of Ras or Rac suppressed CrkL-enhanced Erk activation. SDF-1 stimulation induced tyrosine phosphorylation of CrkL, which was inhibited by the Src family kinase inhibitor PP1 or by dominant negative mutants of Lyn, thus indicating that Lyn mediated SDF-1-induced phosphorylation of CrkL. However, inhibition of the Lyn kinase activity failed to affect SDF-1-induced activation of the small GTPases and Erk. On the other hand, SDF-1-induced activation of the Erk signaling pathway as well as chemotaxis was inhibited by overexpression of a CrkL mutant lacking the N-terminal SH3 domain, which mediates interaction with various signaling molecules including guanine nucleotide exchange factors for the Ras and Rho family GTPases. SDF-1-induced chemotaxis was also inhibited by the dominant negative Ras or Rac mutant as well as by the MEK inhibitor PD98059. These results indicate that CrkL mediates SDF-1-induced activation of the Raf-1/MEK/Erk signaling pathway through Ras as well as Rac in hematopoietic cells and, thereby, plays important roles in the induction of chemotactic response.
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PMID:CrkL plays a role in SDF-1-induced activation of the Raf-1/MEK/Erk pathway through Ras and Rac to mediate chemotactic signaling in hematopoietic cells. 1678 Nov 19


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