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)

Incubation of murine C2C12 myotubes with tumour necrosis factor-alpha (TNF-alpha) leads to significant changes in protein content and turnover, suggesting that the cytokine exerts direct effects in skeletal muscle. The effects of the cytokine on protein content show a clear bimodal behaviour. At low concentrations (1 U/ml or less), TNF-alpha decreases both total and myofibrillar protein content, while at relatively high concentrations (100 U/ml or more), the effects are opposite and TNF-alpha increases the total and myofibrillar protein content in C2C12 myotubes. The mechanisms responsible for this latter, unexpected anabolic effect of the cytokine on muscle cells are related to a 40% increase in the rate of protein synthesis and to a significant decrease (14%) in the rate of protein degradation. At high concentrations, TNF-alpha decreased the expression of the mRNA of components of both the ATP- (ubiquitin, E2, C8) and Ca2+-dependent (m-calpain) proteolytic systems. The effects of TNF-alpha (10 U/ml or higher) on protein content of cultured murine myotubes (differentiated myogenic cells) were similar to those induced by insulin (1 or 5 microg/ml), but the effects of TNF-alpha and those of insulin were not additive. Experiments using inhibitors of the signalling pathways mediated by PI3K and MAP kinases (MAPKs) ERK1/2 and p38 suggest that insulin and TNF-alpha may share some intracellular signalling pathways involving MAPKs in the enhanced protein accretion observed in the muscle cell cultures.
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PMID:Direct effects of tumor necrosis factor alpha (TNF-alpha) on murine skeletal muscle cell lines. Bimodal effects on protein metabolism. 1156 20

How m-calpain is activated in cells has challenged investigators because in vitro activation requires near-millimolar calcium. Previously, we demonstrated that m-calpain activation by growth factors requires extracellular signal-regulated kinase (ERK); this enables tail deadhesion and allows productive motility. We now show that ERK directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (EGF)-induced calpain activation in vitro and in vivo. Replacing the serine with alanine limits activation by EGF and subsequent cell deadhesion and motility. A construct with the serine converted to glutamic acid displays constitutive activity in vivo; expression of an estrogen receptor fusion construct produces a tamoxifen-sensitive enzyme. Interestingly, EGF-induced m-calpain activation occurs in the absence of increased intracellular calcium levels; EGF triggers calpain even in the presence of intracellular calcium chelators and in calcium-free media. These data provide evidence that m-calpain can be activated through the ERK cascade via direct phosphorylation and that this activation may occur in the absence of cytosolic calcium fluxes.
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PMID:Epidermal growth factor activates m-calpain (calpain II), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation. 1499 87

Mounting evidence indicates that cigarette smoking not only promotes tumorigenesis but also may increase the spread of cancer cells in the body. However, the intracellular mechanism(s) by which cigarette smoking promotes metastasis of human lung cancer remains enigmatic. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an important component in cigarette smoke and is formed by nitrosation of nicotine. mu- and m-calpain (calpain I and calpain II) are major members of the calpain family, which are ubiquitously expressed in both small cell lung cancer and non-small cell lung cancer cells. Our findings indicated that NNK potently induces phosphorylation of both mu- and m-calpain in association with their activation and increased migration as well as invasion of lung cancer cells. Treatment of cells with PD98059 blocked phosphorylation of m- and mu-calpain and resulted in suppression of NNK-induced cell migration and invasion. p44 MAPK/extracellular signal-regulated kinase 1 (ERK1) and p42 MAPK/ERK2 were activated by NNK, co-localized with mu- and m-calpain in cytoplasm, and directly phosphorylated mu- and m-calpain in vitro. These findings suggest a role for the ERK1/2 kinases as NNK-activated physiological calpain kinases. Specific knock-down of mu- and/or m-calpain expression by RNA interference blocked NNK-stimulated migration and invasion, suggesting that mu- and m-calpain may act as required targets in a NNK-induced metastatic signaling pathway. Furthermore, NNK promotes secretion of active mu- and m-calpain from lung cancer cells through vesicles, which may have the potential to cleave substrates in the extracellular matrix. Thus, NNK-induced cell migration and invasion may occur, at least in part, through a novel mechanism involving phosphorylation of calpains that leads to their activation and secretion, which may contribute to metastasis and/or progression of lung cancer.
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PMID:Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces phosphorylation of mu- and m-calpain in association with increased secretion, cell migration, and invasion. 1547 77

Fibroblasts stimulated by EGF within collagen matrices generate contraction forces that are likely of importance to cell migration and matrix compaction during wound healing. We have employed an in vitro fibroblast-embedded collagen matrix compaction assay to ascertain signaling pathway components downstream of EGFR activation leading to generation and transmission of contractile force. EGF compacts this floating collagen matrix to a similar extent as PDGF. We demonstrate that compaction requires EGFR kinase activity, yet is maximal in magnitude at intermediate EGF concentrations. This suggests that transmission of EGFR-induced contractile force to the matrix can be mitigated by consequent anti-adhesive effects of EGFR signaling in a dose-dependent manner. Treatment with pharmacological inhibitors demonstrated involvement of the signaling components extracellular signal-regulated kinase (ERK), Rho kinase, and myosin light chain kinase (MLCK) in the force generation and/or transmission process. Moreover, treatment with the pan-calpain inhibitor ALLN and isoform-specific downregulation of m-calpain (CAPN2) using RNA interference determined m-calpain to be a key component of the EGF-induced force response. ALLN treatment modulated the compaction response in a biphasic manner, enhancing matrix deformation to the greatest extent at intermediate concentrations. Our findings have thus identified key signals downstream of EGFR, which integrate in a complex manner to generate and transmit contractile forces to yield matrix deformation.
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PMID:Multiple signaling pathways mediate compaction of collagen matrices by EGF-stimulated fibroblasts. 1659 33

Ubiquitously expressed mu- and m-calpain proteases are implicated in development and apoptosis. They consist of 80-kDa catalytic subunits encoded by the capn1 and capn2 genes, respectively, and a common 28-kDa regulatory subunit encoded by the capn4 gene. The regulatory subunit is required to maintain the stability and activity of mu- and m-calpains. Accordingly, genetic disruption of capn4 in the mouse eliminated both ubiquitous calpain activities. In embryonic fibroblasts derived from these mice, calpain deficiency correlated with resistance to endoplasmic reticulum (ER) stress-induced apoptosis, and this was directly related to a calpain requirement for activation of both caspase-12 and the ASK1-JNK cascade. This study provides compelling genetic evidence for calpain's role in caspase-12 activation at the ER, and reveals a novel role for the ubiquitous calpains in ER-stress induced apoptosis and JNK activation.
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PMID:Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. 1659 16

To isolate pharmacologically safe compounds that can induce apoptosis of tumor cells, leaves of an aromatic plant (Zanthoxylum schinifolium), which are widely used as a food flavor and herbal medicine in Korea and Japan, were sequentially extracted by organic solvents. An apoptogenic ingredient in the methylene chloride extract was further purified by silica gel column chromatography and identified as auraptene (AUR). The IC(50) value of AUR against Jurkat T cells was 16.5 microg/ml. After the treatment of Jurkat T cells with AUR, the endoplasmic reticulum (ER) stress-mediated activation of caspase-12 and -8 and subsequent apoptotic events including c-Jun N-terminal kinase (JNK) activation, cleavage of FLICE inhibitory protein and Bid, mitochondrial cytochrome c release, activation of caspase-9 and -3, degradation of poly (ADP-ribose) polymerase and apoptotic DNA fragmentation were induced in a dose-dependent manner. The cytotoxicity of AUR was not blocked by the anti-Fas neutralizing antibody ZB-4. The AUR-induced cytotoxicity and apoptotic events were abrogated by ectopic over-expression of Bcl-xL or addition of the pan-caspase inhibitor z-VAD-fmk. The individual or simultaneous addition of the m-calpain inhibitor (E64d), JNK inhibitor (SP600125) and mitochondrial permeability transition pore inhibitor (CsA) failed to prevent apoptotic events including caspase-8 activation and Bid cleavage, unless the caspase-8 inhibitor (z-IETD-fmk) was combined, whereas AUR-induced caspase-12 activation was sustained even in the concomitant presence of z-IETD-fmk. These results demonstrated that the apoptotic effect of AUR on Jurkat T cells was exerted by the ER stress-mediated activation of caspase-8, and the subsequent induction of mitochondria-dependent or -independent activation of caspase cascade, which could be suppressed by Bcl-xL.
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PMID:Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade. 1730 Oct 64

Recent research carried out in our laboratory has shown that IGF-1, TGF-beta1, and insulin were able to strongly stimulate myoblast migration by increasing milli-calpain expression and activity. However, the signalling pathways involved in these phenomena remain unknown. The aim of this study was to identify the signalling pathway(s) responsible for the effects of IGF-1, TGF-beta1, and insulin on myoblast migration and on milli-calpain expression and activity. For this purpose, wound healing assays were carried out in the presence of growth factors with or without specific inhibitors of ERK/MAP kinase and PI3K/Akt pathways. The results clearly showed that the inhibition of the ERK/MAP kinase pathway prevents the effects of growth factors on myoblast migration. Secondly, the expression and the activity of milli-calpain were studied in cells treated with growth factor, alone or with ERK/MAP kinase inhibitor. The results demonstrated that the up-regulation of milli-calpain expression and activity was mediated by the ERK/MAP kinase pathway. Finally, the possible implication of MyoD and myogenin, myogenic regulatory factors able to regulate milli-calpain expression, was studied. Taken together our results clearly showed that the ERK/MAP kinase signalling pathway is responsible for the effects of the three growth factors on myoblast migration and on milli-calpain expression and activity. On the opposite, the PI3K/Akt signalling pathway, MyoD and myogenin seem to be not implicated in these phenomena.
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PMID:Involvement of the ERK/MAP kinase signalling pathway in milli-calpain activation and myogenic cell migration. 1743 58

The 14th EGFL-repeat (Ten14) of human tenascin cytotactin activates the epidermal growth factor receptor (EGFR) with micromolar affinity; however, unlike EGF, Ten14-mediated activation of EGFR does not lead to receptor internalization. As the divergent signaling pathways downstream of EGFR have been shown to be triggered from plasma membrane and cytosolic locales, we investigated whether Ten14-mediated surface restriction of EGFR resulted in altered biochemical and cellular responses as compared to EGF. Molecules associated with migratory cascades were activated to a relatively greater extent in response to Ten14, with very weak activation of proliferation-associated cascades. Activation of phospholipase C gamma (PLCgamma) and m-calpain, associated with lamellipod protrusion and tail retraction, respectively, were noted at even at sub-saturating doses of Ten14. However, activation of ERK/MAPK, p90RSK, and Elk1, factors affecting proliferation, remained low even at high Ten14 concentrations. Similar activation profiles were observed for EGF-treated cells at 4 degrees C, a maneuver that limits receptor internalization. We demonstrate a concurrent effect of such altered signaling on biophysical responses-sustained migration was observed at levels of Ten14 that activated PLCgamma, but did not stimulate proliferation significantly. Here, we present a novel class of EGFR ligands that can potentially signal as a part of the extracellular matrix, triggering specific intracellular signaling cascades leading to a directed cellular response from an otherwise pleiotropic receptor. This work extends the signaling paradigm of EGFL repeat being presented in a restricted fashion as part of the extracellular matrix.
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PMID:Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signaling. 1770 41

Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin II motor. However, the role of myosin II in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Pharmacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of beta1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SK-CO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression.
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PMID:Non-muscle myosin IIA differentially regulates intestinal epithelial cell restitution and matrix invasion. 1914 24

TRPM7 is a Ca(2)(+)-permeant and Mg(2)(+)-permeant ion channel in possession of its own kinase domain. In a previous study, we showed that overexpression of the channel-kinase in HEK-293 cells produced cell rounding and loss of adhesion, which was dependent on the Ca(2+)-dependent protease m-calpain. The TRPM7-elicited change in cell morphology was channel-dependent and occurred without any significant increase in cytosolic Ca(2+). Here we demonstrate that overexpression of TRPM7 increased levels of cellular reactive oxygen species (ROS) and nitric oxide, causing the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Application of inhibitors of p38 MAPK and JNK blocked TRPM7-induced cell rounding and activation of m-calpain, without affecting the phosphorylation state of the protease. Overexpression of TRPM7 increased intracellular Mg(2+); however, when the concentration of either external Ca(2+) or Mg(2+) was increased to favor the permeation of one divalent cation over the other, a similar increase in cell rounding and calpain activity was detected, indicating that TRPM7-mediated activation of m-calpain is not dependent on the nature of the divalent conducted by the channel. Application of inhibitors of nitric oxide synthase and mitochondrial-derived ROS reduced TRPM7-induced increases in nitric oxide and ROS production, blocked the change in cell morphology, and reduced cellular calpain activity. Collectively, our data reveal that excessive TRPM7 channel activity causes oxidative and nitrosative stresses, producing cell rounding mediated by p38 MAPK/JNK-dependent activation of m-calpain.
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PMID:TRPM7 activates m-calpain by stress-dependent stimulation of p38 MAPK and c-Jun N-terminal kinase. 2007 Sep 45


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