Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following injury to the central nervous system, an astroglial scar forms that is thought to impede neuronal regeneration and recovery of function. It is our hypothesis that inflammatory cytokines act upon astrocytes to alter their biochemical and physical properties, which may in turn be responsible for failed neuronal regeneration. We have therefore examined the interactions of two cytokines with prominent actions following injury, interferon-gamma (IFN-gamma) and basic fibroblast growth factor (FGF2), in modulating the extracellular matrix and proliferation of astrocytes in culture. We also evaluated the effects of these cytokines on the ability of astrocytes to support the growth of neurites. IFN-gamma significantly inhibited the proliferation of rat cortical astrocytes both in serum-free and serum-containing media as measured by [3H]thymidine incorporation. Furthermore, IFN-gamma also antagonized FGF2-induced proliferation. In parallel, IFN-gamma reduced the levels of the ECM molecules tenascin, laminin, and fibronectin as evaluated by Western blot analysis and immunocytochemistry. Similarly, IFN-gamma also antagonized FGF2-induced tenascin formation. While IFN-gamma-pretreated astrocyte monolayers did not differ from control in their ability to support neurite outgrowth of cortical neurons, it antagonized the enhancement of neurite outgrowth on FGF2-treated monolayers. We demonstrate that IFN-gamma did not alter signal transduction through the FGF2 receptor down to the phosphorylation of mitogen-activated protein kinase, suggesting that the interaction is at the level of transcriptional regulation or that an alternate pathway is involved. These results support the hypothesis that inflammatory cytokines interact to modulate several facets of the gliotic response and such interactions may be important in creating the biochemical and physical properties of the glial scar.
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PMID:Inflammatory cytokines interact to modulate extracellular matrix and astrocytic support of neurite outgrowth. 941 38

Wounding corneal epithelium establishes a laterally oriented, DC electric field (EF). Corneal epithelial cells (CECs) cultured in similar physiological EFs migrate cathodally, but this requires serum growth factors. Migration depends also on the substrate. On fibronectin (FN) or laminin (LAM) substrates in EF, cells migrated faster and more directly cathodally. This also was serum dependent. Epidermal growth factor (EGF) restored cathodal-directed migration in serum-free medium. Therefore, the hypothesis that EGF is a serum constituent underlying both field-directed migration and enhanced migration on ECM molecules was tested. We used immunofluorescence, flow cytometry, and confocal microscopy and report that 1) EF exposure up-regulated the EGF receptor (EGFR); so also did growing cells on substrates of FN or LAM; and 2) EGFRs and actin accumulated in the cathodal-directed half of CECs, within 10 min in EF. The cathodal asymmetry of EGFR and actin staining was correlated, being most marked at the cell-substrate interface and showing similar patterns of asymmetry at various levels through a cell. At the cell-substrate interface, EGFRs and actin frequently colocalized as interdigitated, punctate spots resembling tank tracks. Cathodal accumulation of EGFR and actin did not occur in the absence of serum but were restored by adding ligand to serum-free medium. Inhibition of MAPK, one second messenger engaged by EGF, significantly reduced EF-directed cell migration. Transforming growth factor beta and fibroblast growth factor also restored cathodal-directed cell migration in serum-free medium. However, longer EF exposure was needed to show clear asymmetric distribution of the receptors for transforming growth factor beta and fibroblast growth factor. We propose that up-regulated expression and redistribution of EGFRs underlie cathodal-directed migration of CECs and directed migration induced by EF on FN and LAM.
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PMID:Electric field-directed cell motility involves up-regulated expression and asymmetric redistribution of the epidermal growth factor receptors and is enhanced by fibronectin and laminin. 1019 71

The dramatic increase in uterine growth during late pregnancy and the generation of labor contractions require dynamic remodeling of myometrial smooth muscle-ECM interactions. In many tissues, such interactions are provided by focal adhesions; however, there are no data as to the expression of focal adhesion proteins or of focal adhesion signaling in the myometrium. In this study, we show that tyrosine phosphorylation of myometrial FAK (FAK-P-Tyr) and of its downstream substrate, paxillin, exhibited a >10-fold increase during late pregnancy (days 15-22 of pregnancy) with each exhibiting a dramatic fall in P-Tyr on day 23 in association with the onset of labor. These changes in FAK-P-Tyr were paralleled by changes in FAK enzyme activity. Activated ERK1 and ERK2 expression remained relatively unchanged from day 15 to day 23, but decreased markedly 1 day post partum. Treatment of late pregnant rats with progesterone prevented the fall in FAK-P-Tyr/enzyme activity on day 23, and also blocked the onset of labor. These data suggest that progesterone (which decreases at term) modulates myometrial FAK activity/focal adhesion signaling and that these changes may underlie the tremendous remodeling that must occur in order for this muscle to develop optimal contractile activity during labor.
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PMID:Focal adhesion signaling in the rat myometrium is abruptly terminated with the onset of labor. 1061 48

Cell adhesion promotes cellular proliferation through the regulation of gene expression, including the immediate early genes. However, the precise role of cell adhesion in the regulation of the c-Myc proto-oncogene is not clear, and the adhesion-dependent signaling pathway(s) regulating the expression of c-Myc has yet to be defined. We now show that integrin signaling directly regulates the expression of c-Myc in the mammary epithelial cell line 184A1N4 (A1N4). Adhesion of quiescent A1N4 cells to fibronectin, and to collagen types IV or I, induces the expression of c-Myc in an ECM concentration-dependent fashion. Cytoskeletal rearrangement, and integrin engagement and integrin clustering are required for the induction of c-Myc by fibronectin. Furthermore, beta1 integrin function-blocking antibodies prevent the adhesion-dependent induction of c-Myc. Adhesion of A1N4 cells results in the activation both of c-Src and of the Erk 1/2 mitogen-activated protein kinase (MAPK), each of which precedes the induction of c-Myc. Pharmacological inhibitors specific for either the c-Src family of kinases or for MEK1 block the adhesion-dependent induction of c-Myc. These observations indicate that beta1 integrins regulate the expression of c-Myc through the activation of the Src family of tyrosine kinases and the MAK kinase pathway.
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PMID:Regulation of the expression of c-Myc by beta1 integrins in epithelial cells. 1131 9

During restenosis following arterial injury, vascular smooth muscle cells (VSMCs) form a neointimal layer in arteries by changing from a differentiated, contractile phenotype to a dedifferentiated, migratory, and proliferative phenotype. Several growth factors, cytokines, and extracellular matrix components released following injury have been implicated in these phenotypic changes. We have recently detected the expression of laminin-5, an ECM protein found predominantly in epithelial tissues, in the arterial vasculature. Here we report that ln-5 expression by VSMC is upregulated by platelet-derived growth factor (PDGF-BB), epidermal growth factor, basic fibroblast growth factor, and transforming growth factor-beta1. Adhesion to ln-5 specifically enhances PDGF-BB-stimulated VSMC proliferation and migration. PD98059, a specific inhibitor of the ERK1/2 members of the Mitogen Activated Protein kinase family, increases both VSMC adhesion to ln-5 and blocks PDGF-BB-stimulated VSMC migration on ln-5. These results suggest that adhesion to ln-5 mediates a PDGF-BB-stimulated VSMC response to vascular injury via an ERK1/2 signaling pathway.
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PMID:ERK1/2 mediates PDGF-BB stimulated vascular smooth muscle cell proliferation and migration on laminin-5. 1205 59

Activation of the Ras-MAPK signal transduction pathway is necessary for biological responses both to growth factors and ECM. Here, we provide evidence that phosphorylation of S298 of MAPK kinase 1 (MEK1) by p21-activated kinase (PAK) is a site of convergence for integrin and growth factor signaling. We find that adhesion to fibronectin induces PAK1-dependent phosphorylation of MEK1 on S298 and that this phosphorylation is necessary for efficient activation of MEK1 and subsequent MAPK activation. The rapid and efficient activation of MEK and phosphorylation on S298 induced by cell adhesion to fibronectin is influenced by FAK and Src signaling and is paralleled by localization of phospho-S298 MEK1 and phospho-MAPK staining in peripheral membrane-proximal adhesion structures. We propose that FAK/Src-dependent, PAK1-mediated phosphorylation of MEK1 on S298 is central to the organization and localization of active Raf-MEK1-MAPK signaling complexes, and that formation of such complexes contributes to the adhesion dependence of growth factor signaling to MAPK.
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PMID:PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. 1287 77

ESX is an epithelial-restricted member of a large family of transcription factors known as the Ets family. ESX expression has been shown to be correlated with Her2/neu proto-oncogene amplification in highly aggressive breast cancers and induced by Her2/neu in breast cell lines, but its role in tumorigenesis is unknown. Previously, we have shown that ESX enhances breast cell survival in colony-formation assays. In order to determine whether ESX can act as a transforming gene, we stably transfected MCF-12A human mammary epithelial cells with the ESX expression vector, pCGN2-HA-ESX. The MCF-12A cell line is immortalized, but nontransformed, and importantly, these cells fail to express endogenous ESX protein. We used pCGN2-HA-Ets-2 and pSVRas expression vectors as positive controls for transformation. Like HA-Ets-2 and V12-Ras, stable expression of ESX induced EGF-independent proliferation, serum-independent MAPK phosphorylation and growth in soft agar. Additionally, stable ESX expression conferred increased cell adhesion, motility and invasion in two-dimensional and transwell filter assays, and an epithelial to mesenchymal morphological transition. In three-dimensional cultures, parental and vector control (pCGN2) cells formed highly organized duct-like structures with evidence of cell polarity, ECM adhesion-dependent proliferation and cell survival, and lack of cellular invasion into surrounding matrix. Remarkably, the ESX stable cells formed solid, disorganized structures, with lack of cell polarity, loss of adhesion junctions and cytokeratin staining and loss of dependence on ECM adhesion for cell proliferation and survival. In addition, ESX cells invaded the surrounding matrix, indicative of a transformed and metastatic phenotype. Taken together, these data show that ESX expression alone confers a transformed and in vitro metastatic phenotype to otherwise normal MCF-12A cells.
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PMID:ESX induces transformation and functional epithelial to mesenchymal transition in MCF-12A mammary epithelial cells. 1476 72

Amines such as agmatine, putrescine, spermidine and spermine have been reported to be involved in a variety of physiological and biochemical phenomena. However, it is not known whether they are also involved in the homeostasis of intracellular fibronectin content via upregulation of protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and transforming growth factor-beta1 (TGF-beta1). To determine this, we have studied the effect of multiple amines on fibronectin, TGF-beta1, ERK, and PKC levels in mesangial cells under high glucose conditions. All the amines tested (at 0.1-1 mM) affected neither the viability of mesangial cells for 42 h nor LDH release into the medium. Agmatine reduced TGF-beta1 and ERK levels but not PKC at concentrations of 0.1-1 mM. However, levels of fibronectin, TGF-beta1, ERK, and PKC were unaffected by either putrescine or spermidine. A decrease in fibronectin secretion was accompanied by decreases in TGF-beta1 and ERK. Such cumulative results lead us to hypothesize that agmatine reduces high glucose-induced fibronectin secretion via several pathways including ERK-TGF-beta1-fibronectin and spermine, via a decrease in TGF-beta1. Possible roles of enzymes involved in agmatine and polyamine biosynthesis are discussed in relation to secretion of ECM proteins.
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PMID:Regulation of fibronectin levels by agmatine and spermine in mesangial cells under high-glucose conditions. 1553 78

The small GTPases of the Rho family are key intermediates in cellular signalling triggered by activated cell-adhesion receptors. In this study, we took advantage of RNA interference (RNAi) using small interfering RNAs (siRNAs) to define the roles of the best-characterized members of the RhoGTPase family, RhoA, Rac1 and Cdc42, in the control of MMP-1, MMP-2 and type-I-collagen expression in normal human skin fibroblasts (HSFs). A specific and long-lasting repression, up to 7 days after transfection, of the three GTPases was achieved by transient transfection of specific siRNA. The silencing of Cdc42, but not that of RhoA or Rac1, induced a 15-fold increase in MMP-1 secretion. This upregulation was confirmed at the mRNA level and observed with two different siRNAs targeting Cdc42. Such a regulation was also observed in various human cell lines and was rescued by re-expressing wild-type Cdc42 encoded by a construct bearing silent mutations impeding its recognition by the siRNA. By contrast, MMP-2 and type-I-collagen expression was not affected by the individual silencing of each Rho GTPase. Cytokine protein array, enzyme-linked immunosorbent assays and reverse-transcription PCR measurements revealed that ablation of Cdc42 induced an overexpression of interleukin 8 and MCP-1. Although these cytokines are known to induce the expression of MMP-1, we showed that they were not involved in the Cdc42-mediated upregulation of MMP-1. Silencing of Cdc42 also induced an increased phosphorylation of ERK1/2 and p38 MAP kinase. The use of chemical inhibitors on Cdc42-ablated cells revealed that the upregulation of MMP-1 is dependent on the ERK1/2 pathways, whereas the p38 MAP kinase pathway displayed an inhibitory role. Simultaneous knock-down of two or three Rho GTPases allowed us to demonstrate that the RhoA-ROCK pathway was not involved in this regulation but that the silencing of Rac1 reduced the effect of Cdc42 suppression. These data suggest that, in vivo, when cell/extracellular-matrix interactions via integrins induce cytoskeleton organization, MMP-1 expression is maintained at a low level by Cdc42 via a repression of the Rac1 and ERK1/2 pathways. Therefore, Cdc42 contributes to ECM homeostasis and connective tissue integrity.
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PMID:Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway. 1572 53

The invasive differentiation pathway of trophoblasts is an indispensable physiological process of early human placental development. Formation of anchoring villi, proliferation of cell columns and invasion of extravillous cytotrophoblasts into maternal decidual stroma and vessels induce vascular changes ensuring an adequate blood supply to the growing fetus. Extravillous trophoblast differentiation is regulated by numerous growth factors as well as by extracellular matrix proteins and adhesion molecules expressed at the fetal-maternal interface. These regulatory molecules control cell invasion by modulating activities of matrix-degrading protease systems and ECM adhesion. The differentiation process involves numerous signalling cascades/proteins such as the GTPases RhoA, the protein kinases ROCK, ERK1, ERK2, FAK, PI3K, Akt/protein kinase B and mTOR as well as TGF-beta-dependent SMAD factors. While an increasing number of signalling pathways regulating trophoblast differentiation are being unravelled, downstream effectors such as executing transcription factors remain largely elusive. Here, we summarise our current knowledge on signal transduction cascades regulating invasive trophoblast differentiation. We will focus on cell model systems which are used to study the particular differentiation process and discuss signalling pathways which regulate trophoblast proliferation and motility.
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PMID:Signalling pathways regulating the invasive differentiation of human trophoblasts: a review. 1583 62


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