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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. Inhibitors of protein kinase C, phosphatidyl inositol 3-OH kinase, and calmodulin-dependent protein kinase do not attenuate MMP1 promoter activation. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by > 85% the phosphorylation of ERK1/ERK2) has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit.
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PMID:Fibroblast growth factor receptor signaling activates the human interstitial collagenase promoter via the bipartite Ets-AP1 element. 921 60

Cytokines, growth factors, and alterations in the extracellular matrix composition may play a role in maintaining hepatic stellate cells (HSC) in the activated state that is responsible for hepatic fibrogenesis. However, the signal transduction pathways that are stimulated by these factors in HSC remain to be fully elucidated. Recent evidence indicates that the mitogen-activated protein kinase (MAPK) family, including c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), plays an important role in the cellular response to stress. The aims of this study were to investigate whether fibronectin (FN) or the inflammatory cytokines interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) activate JNK, ERK, and AP-1 activity in HSC and induce the gene expression of the matrix metalloproteinase transin. Treatment of HSC with FN resulted in an up to 4.5-fold increase in ERK activity and a 2.1-fold increase in JNK activity. IL-1alpha and TNF-alpha produced up to a fourfold increase in JNK activity and a twofold increase in ERK activity. We then compared the effects of FN, IL-1alpha, and TNF-alpha on AP-1 activity and metalloproteinase mRNA induction. All three compounds increased AP-1 binding and promoter activity, and transin mRNA levels were increased 1.8-fold by FN, 2.2-fold by IL-1alpha, and 2.8-fold by TNF-alpha. Therefore, FN and inflammatory cytokines increase MAPK activity, stimulate AP-1 activity, and increase transin gene expression in HSC. Signal transduction pathways involving the MAPK family may play an important role in the regulation of matrix metalloproteinase expression by cytokines and FN in HSC.
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PMID:Fibronectin and cytokines increase JNK, ERK, AP-1 activity, and transin gene expression in rat hepatic stellate cells. 935 21

Interleukin-1 (IL-1) is an important inflammatory mediator and plays a central role in the destruction of connective tissue matrices in diseases such as arthritis and periodontitis. It is well established that IL-1 activation of the mitogen-activated protein (MAP) kinase pathway and induction of c-fos expression is a required step in the induction of matrix metalloproteinase expression involved in tissue degradation. Previous studies in our laboratory showed that IL-1-induced calcium flux is dependent on focal adhesion formation, suggesting a matrix-dependent restriction system for IL-1 signaling. Therefore, in the present study, we examined the consequences of this restriction on IL-1-mediated activation of the MAP kinase family and on c-fos expression. Treatment of human gingival fibroblasts with IL-1 activated extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase activity and induced c-fos expression in a dose- and time-dependent fashion. Plating cells on poly-L-lysine prevented focal adhesion formation, eliminated IL-1-induced calcium influx, abolished ERK stimulation, and blocked c-fos expression. Cells in suspension and hence with no suitable substratum for focal adhesion formation also showed no ERK activation or enhanced c-fos expression in response to IL-1. In contrast, eliminating focal adhesion formation or calcium depletion in cells plated on fibronectin had no effect on IL-1 stimulation of JNK and p38 kinases, demonstrating that their activation was mediated through pathways independent of focal adhesions and calcium. Calcium depletion abolished IL-1-induced calcium uptake, ERK activation, and c-fos expression. The focal adhesion dependence of IL-1-induced ERK activation and c-fos expression could be circumvented in cells plated on poly-L-lysine by simultaneous incubation with IL-1 and the calcium ionophore ionomycin. In transfection studies, IL-1 stimulation of serum responsive element (SRE) transcriptional activity was dependent on the presence of extracellular calcium. This is consistent with a requirement for calcium in the activation of ERKs and their involvement in the induction of c-fos expression through the SRE site on the 5' promoter of the c-fos gene. Our results demonstrate that in cells attached to substrates by focal adhesions, IL-1-mediated calcium flux is required for ERK activation and c-fos expression but not for JNK or p38 activation. We conclude that cellular interactions with the extracellular matrix play an important role in restricting ERK and c-fos-dependent processes.
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PMID:Requirements of focal adhesions and calcium fluxes for interleukin-1-induced ERK kinase activation and c-fos expression in fibroblasts. 950 15

Tumor cell invasion and metastasis requires precise coordination of adherence to the extracellular matrix (ECM) and controlled degradation of its components. lnvasive cells secrete proteolytic enzymes known as matrix metalloproteinases which degrade specific basement membrane molecules. Expression of these enzymes is regulated by multiple signaling mechanisms, including attachment to the extracellular matrix via integrins. All-trans retinoic acid can inhibit tumor cell invasion of ECM by regulating matrix metalloproteinase expression. Using a series of squamous cell carcinoma lines, we investigated the interactions between integrin and retinoic acid signaling in these cells. In a cell line sensitive to RA-mediated inhibition of invasion, this ligand downregulated MMP-9 activity in cells grown on specific ECM molecules but not on plastic. Inhibition of integrin signaling with anti-alpha1 antibodies or MAPK pathway inhibitors abrogated RA mediated down-regulation of MMP-9 activity and invasion. The effects of RA and MAPK signaling on MMP-9 activity was mediated at the transcriptional level. These data indicate that crosstalk between RA- and integrin dependent signaling pathways regulate MMP activity and invasion in squamous cell carcinoma lines.
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PMID:alpha2beta1 integrin signaling via the mitogen activated protein kinase pathway modulates retinoic acid-dependent tumor cell invasion and transcriptional downregulation of matrix metalloproteinase 9 activity. 982 20

Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimensional collagen. Collagen-related induction of MMP-13 expression was dependent on tyrosine kinase activity, as it was abolished by treatment of fibroblasts with tyrosine kinase inhibitors genistein and herbimycin A. Contact of fibroblasts to three-dimensional collagen resulted in simultaneous activation of mitogen-activated protein kinases (MAPKs) in three distinct subgroups: extracellular signal-regulated kinase (ERK)1 and ERK2, Jun N-terminal kinase/stress-activated protein kinase, and p38. Induction of MMP-13 expression was inhibited by treatment of fibroblasts with a specific p38 inhibitor, SB 203580, whereas blocking the ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by PD 98059, a selective inhibitor of MEK1,2 activation potently augmented MMP-13 expression. Furthermore, specific activation of ERK1,2 pathway by 12-O-tetradecanoylphorbol-13-acetate markedly suppressed MMP-13 expression in dermal fibroblasts in collagen gel. These results show that collagen-dependent induction of MMP-13 in dermal fibroblasts requires p38 activity, and is inhibited by activation of ERK1,2. Therefore, the balance between the activity of ERK1,2 and p38 MAPK pathways appears to be crucial in regulation of MMP-13 expression in dermal fibroblasts, suggesting that p38 MAPK may serve as a target for selective inhibition of collagen degradation, e.g. in chronic dermal ulcers.
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PMID:Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. 989 Oct 15

Activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway is required for ligand-dependent regulation of numerous cellular functions by receptor tyrosine kinases. We have shown previously that although many receptor tyrosine kinase ligands are mitogens for keratinocytes, cell migration and induction of the 92-kilodalton gelatinase/matrix metalloproteinase (MMP)-9 are selectively regulated by the epidermal growth factor and scatter factor/hepatocyte growth factor receptors. In this report we present evidence of an underlying mechanism to account for these observed differences in receptor tyrosine kinase-mediated response. Ligands that are mitogenic, but do not induce MMP-9 or colony dispersion, transiently activate the p42/p44 ERK/MAP kinases. In contrast, ligands that stimulate MMP-9 induction and colony dispersion induced sustained activation of these kinases. The functional significance of sustained MAPK activation was demonstrated by inhibition of the MAP kinase kinase MEK1. Disruption of the prolonged signal by addition of the MEK1 inhibitor PD 98059 up to 4 h after growth factor stimulation substantially impaired ligand-dependent colony dispersion and MMP-9 induction. These findings support the conclusion that duration of MAPK activation is an important determinant for certain growth factor-mediated functions in keratinocytes.
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PMID:Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. 993 37

During certain developmental processes, as well as during tumor progression, polarized epithelial cells integrated within multicellular structures convert into scattered, freely migrating fibroblast-like cells. Despite the biological and clinical importance of this phenomenon, the intracellular biochemical cascades that control the switch between the epithelial and mesenchymal phenotypes have not been elucidated. Using Madin-Darby canine kidney (MDCK) cells (clone C7) as a model system, we have assessed the potential role of the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) cascade in the modulation of epithelial plasticity. When grown in three-dimensional collagen gels, MDCK-C7 cells form spherical cysts composed of polarized epithelial cells circumscribing a central lumen. This morphogenetic behavior is profoundly subverted in MDCK-C7 cells expressing a constitutively active MAPK/ERK kinase 1 (caMEK1) mutant (C7-caMEK1 cells). When suspended in collagen gels, C7-caMEK1 cells assume an elongated fibroblastoid shape and are unable to generate multicellular cysts. In addition, when seeded onto the surface of a collagen gel, C7-caMEK1 cells penetrate extensively into the underlying matrix, unlike wild-type and mock-transfected MDCK-C7 cells, which remain confined to the surface of the gel. Similar changes in morphogenetic and invasive properties are observed in MDCK-C7F cells, a nontransfected, stably dedifferentiated derivative of MDCK-C7 cells that expresses substantially increased ERK2 activity. Both C7-caMEK1 and MDCK-C7F cells but not wild-type or mock-transfected MDCK-C7 cells express activated M(r) 72,000 gelatinase A [matrix metalloproteinase (MMP)-2] as well as elevated levels of membrane type-1 MMP. Synthetic MMP inhibitors as well as recombinant tissue inhibitor of metalloproteinases 2 and 3 suppress the invasion of collagen gels and restore the capacity of C7-caMEK1 cells to form cysts, thereby implicating the membrane type-1 MMP/MMP-2 proteolytic system in epithelial cell invasiveness and loss of multicellular organization. Taken together, our data demonstrate that increased activity of the MEK1-ERK2 signaling module in MDCK-C7 cells is associated with failure of morphogenesis and expression of a highly invasive phenotype. Sustained activation of the MAPK cascade therefore results in the destabilization of the three-dimensional architecture and the conversion of polarized epithelial cells into migrating mesenchymal-like cells.
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PMID:Constitutively active mitogen-activated protein kinase kinase MEK1 disrupts morphogenesis and induces an invasive phenotype in Madin-Darby canine kidney epithelial cells. 1035 13

Synovial fluid basic calcium phosphate (BCP) crystals are markers of severe joint degeneration in osteoarthritis. These crystals are mitogenic and induce protooncogene expression and matrix metalloproteinase (MMP) synthesis and secretion in human fibroblasts, effects that are specifically blocked by phosphocitrate (PC). We have recently determined that crystals transduce signals to the nucleus via the activation of the p42 and p44 mitogen-activated protein (MAP) kinases (Nair et al., 1997, J Biol Chem 272:18920-18925). Treatment of human fibroblasts (HF) with BCP induces phosphorylation of p42/44 MAPK, which is inhibited by PC in a dose-dependent manner. Blocking of p42/44 MAPK signal transduction with an inhibitor (PD98059) of MEK1, an upstream activator of MAPKs, reduces crystal-induced p42/44 MAPK activation and significantly inhibits crystal-induced cell proliferation. Based on these findings, we sought to determine the role of the p42/44 MAPK signal transduction pathway in crystal-induced expression of matrix MMPs. We demonstrate suppression of crystal-induced MMPs via the utilization of two different MEK inhibitors: PD98059 and the recently described U0126, a novel inhibitor of MEK1 and MEK2. Treatment of HF with PD98059 blocks the induction of crystal-stimulated collagenase 1 (MMP-1) and stromelysin (MMP-3) expression. PD98059 and PC reduced the level of crystal-induced MMP-1 and MMP-3 mRNA expression to that observed in nonstimulated cells. Likewise, PD98059 treatment of HF blocked the epidermal growth factor (EGF)- and crystal-induced increases in MMP-1 and MMP-3 protein expression and secretion as demonstrated by Western blotting and zymography. Treatment of HF with U0126 inhibits EGF-induced phosphorylation of p42/44 MAPK as well as crystal- and EGF-induced upregulation of MMP-1 mRNA. Additionally, we demonstrate that treatment of HF with BCP, EGF, or PD98059 does not significantly alter levels of gelatinase A (MMP-2) mRNA and protein expression.
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PMID:Basic calcium phosphate crystal induction of collagenase 1 and stromelysin expression is dependent on a p42/44 mitogen-activated protein kinase signal transduction pathway. 1039 91

Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically expressed by transformed squamous epithelial cells, i.e. squamous cell carcinoma (SCC) cells in culture and in vivo. Here, we have elucidated the signaling pathways regulating MMP-13 expression in transformed human epidermal keratinocytes, i.e. ras-transformed HaCaT cell line A-5 and cutaneous SCC cell line (UT-SCC-7). Treatment with tumor necrosis factor-(alpha) (TNF-(alpha) resulted in activation of extracellular signal-regulated kinase (ERK)1,2, Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) in both cell lines. In addition, transforming growth factor-(beta) (TGF-(beta) activated p38 MAPK in both cell lines, and ERK2 in A-5 cells. Selective inhibition of p38 activity with SB 203580 abolished the enhancement of MMP-13, as well as collagenase-1 (MMP-1) and 92-kDa gelatinase (MMP-9) expression by TNF-(alpha) and TGF-(beta). Blocking the ERK1, 2 pathway by PD 98059 had no effect on the induction of MMP-13 expression by TNF-(alpha) or TGF-(beta), but potently suppressed MMP-1 and MMP-9 production. Inhibition of p38 activity by SB 203580 also suppressed collagenolytic activity produced by both cell lines and inhibited invasion of TNF-(alpha) or TGF-(beta) stimulated A-5 cells through type I collagen and reconstituted basement membrane (Matrigel). These results show that activation of p38 MAPK pathway plays a crucial role in the invasive phenotype of transformed squamous epithelial cells, suggesting p38 MAPK as a target to specifically inhibit their invasion.
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PMID:Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. 1063 74

Insulin-like growth factor II (IGF-II), highly expressed in a number of human tumours, has been recently known to promote neovascularization in vivo. Yet, the detailed mechanism by which IGF-II induces angiogenesis has not been well defined. In the present study, we explored an angiogenic activity of IGF-II in in vitro angiogenesis model. Human umbilical vein endothelial cells (HUVECs) treated with IGF-II rapidly aligned and formed a capillary-like network on Matrigel. In chemotaxis assay, IGF-II remarkably increased migration of HUVECs. A rapid and transient activation of p38 mitogen-activated protein kinase (p38 MAPK) and p125 focal adhesion kinase (p125FAK) phosphorylation was detected in HUVECs exposed to IGF-II. IGF-II also stimulated invasion of HUVECs through a polycarbonate filter coated with Matrigel. Quantitative gelatin-based zymography identified that matrix metalloproteinase-2 (MMP-2) activity generated from HUVECs was increased by IGF-II. This induction of MMP-2 activity was correlated with Northern blot analysis, showing in HUVECs that IGF-II increased the expression of MMP-2 mRNA, while it did not affect that of TIMP-2, a tissue inhibitor of MMP-2. These results provide the evidence that IGF-II directly induces angiogenesis by stimulating migration and morphological differentiation of endothelial cells, and suggest that IGF-II may play a crucial role in the progression of tumorigenesis by promoting the deleterious neovascularization.
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PMID:Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models. 1064 93


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