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)

CDC25A phosphatase promotes cell cycle progression by activating G(1) cyclin-dependent kinases and has been postulated to be an oncogene because of its ability to cooperate with RAS to transform rodent fibroblasts. In this study, we have identified apoptosis signal-regulating kinase 1 (ASK1) as a CDC25A-interacting protein by yeast two-hybrid screening. ASK1 activates the p38 mitogen-activated protein kinase (MAPK) and c-Jun NH(2)-terminal protein kinase-stress-activated protein kinase (JNK/SAPK) pathways upon various cellular stresses. Coimmunoprecipitation studies demonstrated that CDC25A physically associates with ASK1 in mammalian cells, and immunocytochemistry with confocal laser-scanning microscopy showed that these two proteins colocalize in the cytoplasm. The carboxyl terminus of CDC25A binds to a domain of ASK1 adjacent to its kinase domain and inhibits the kinase activity of ASK1, independent of and without effect on the phosphatase activity of CDC25A. This inhibitory action of CDC25A on ASK1 activity involves diminished homo-oligomerization of ASK1. Increased cellular expression of wild-type or phosphatase-inactive CDC25A from inducible transgenes suppresses oxidant-dependent activation of ASK1, p38, and JNK1 and reduces specific sensitivity to cell death triggered by oxidative stress, but not other apoptotic stimuli. Thus, increased expression of CDC25A, frequently observed in human cancers, could contribute to reduced cellular responsiveness to oxidative stress under mitogenic or oncogenic conditions, while it promotes cell cycle progression. These observations propose a mechanism of oncogenic transformation by the dual function of CDC25A on cell cycle progression and stress responses.
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PMID:The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1. 1141 55

Increasing evidence suggests that apoptosis may be the underlying cell death mechanism in the selective loss of dopaminergic neurons in Parkinson's disease. Because the inhibition of caspases provides only partial protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP(+)) model of Parkinson's disease, we investigated the role of the proapoptotic c-Jun N-terminal kinase (JNK) signaling cascade in SH-SY5Y human neuroblastoma cells in vitro and in mice in vivo. MPTP/MPP(+) led to the sequential phosphorylation and activation of JNK kinase (MKK4), JNK, and c-Jun, the activation of caspases, and apoptosis. In mice, adenoviral gene transfer of the JNK binding domain of JNK-interacting protein-1 (a scaffold protein and inhibitor of JNK) inhibited this cascade downstream of MKK4 phosphorylation, blocked JNK, c-Jun, and caspase activation, the death of dopaminergic neurons, and the loss of catecholamines in the striatum. Furthermore, the gene transfer resulted in behavioral benefit. Therefore, inhibition of the JNK pathway offers a new treatment strategy for Parkinson's disease that blocks the death signaling pathway upstream of the execution of apoptosis in dopaminergic neurons, providing a therapeutic advantage over the direct inhibition of caspases.
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PMID:Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease. 1150 16

Using a yeast two-hybrid method, we searched for amyloid precursor protein (APP)-interacting molecules by screening mouse and human brain libraries. In addition to known interacting proteins containing a phosphotyrosine-interaction-domain (PID)-Fe65, Fe65L, Fe65L2, X11, and mDab1, we identified, as a novel APP-interacting molecule, a PID-containing isoform of mouse JNK-interacting protein-1 (JIP-1b) and its human homolog IB1, the established scaffold proteins for JNK. The APP amino acids Tyr(682), Asn(684), and Tyr(687) in the G(681)YENPTY(687) region were all essential for APP/JIP-1b interaction, but neither Tyr(653) nor Thr(668) was necessary. APP-interacting ability was specific for this additional isoform containing PID and was shared by both human and mouse homologs. JIP-1b expressed by mammalian cells was efficiently precipitated by the cytoplasmic domain of APP in the extreme Gly(681)-Asn(695) domain-dependent manner. Reciprocally, both full-length wild-type and familial Alzheimer's disease mutant APPs were precipitated by PID-containing JIP constructs. Antibodies raised against the N and C termini of JIP-1b coprecipitated JIP-1b and wild-type or mutant APP in non-neuronal and neuronal cells. Moreover, human JNK1beta1 formed a complex with APP in a JIP-1b-dependent manner. Confocal microscopic examination demonstrated that APP and JIP-1b share similar subcellular localization in transfected cells. These data indicate that JIP-1b/IB1 scaffolds APP with JNK, providing a novel insight into the role of the JNK scaffold protein as an interface of APP with intracellular functional molecules.
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PMID:c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK. 1151 49

In pituitary gonadotropes, gonadotropin-releasing hormone (GnRH) activates all three major mitogen-activated protein kinase (MAPK) cascades. The MAPKs play key roles in transcriptional activation of GnRH-responsive genes. MAPK phosphatases (MKPs) are dual specificity protein phosphatases involved in feedback regulation of MAPK activity. Previous studies indicate that GnRH activates MKP-2 expression in gonadotropes, dependent upon activation of multiple MAPKs and discrete Ca(2+) signals. To further understand the transcriptional mechanism(s) of MKP-2 induction by GnRH, we studied the activity of a 198-nucleotide MKP-2 proximal promoter region that supports GnRH responsiveness in reporter gene assays. Functional analysis of the MKP-2 promoter confirmed a requirement for the protein kinase C-extracellular signal-regulated kinase (ERK) pathway and VGCC-derived Ca(2+) signals in transcriptional activation of the MKP-2 gene. However, the inhibitory effect of thapsigargin on MKP-2 protein expression previously identified was not mediated at the level of promoter activation, suggesting a distinct mechanism for the action of thapsigargin-sensitive Ca(2+) signals. MGRE (MKP-2 GnRH response element) within the MKP-2 promoter mediated promoter activation through the protein kinase C-ERK pathway. The zinc finger transcription factor Egr-1 was identified in the MGRE-binding complex. Egr-1/MGRE binding was induced by GnRH in an ERK-dependent manner. Transcriptional activity of Egr-1 protein was enhanced by GnRH treatment. In addition, overexpression of the Egr-interacting protein, NAB1, resulted in increased GnRH-stimulated MKP-2 gene transcription. Consistent with the putative role of Egr-1 in MKP-2 promoter regulation, Egr-1 protein expression closely correlated with the expression of MKP-2 protein in alpha T3-1 cells. Together, these data suggest that Egr-1 may be a key factor in mediating GnRH-dependent transcriptional activation of the MKP-2 gene.
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PMID:An early growth response protein (Egr) 1 cis-element is required for gonadotropin-releasing hormone-induced mitogen-activated protein kinase phosphatase 2 gene expression. 1159 7

Cytokines have been shown to have dramatic effects on pancreatic islets and insulin-secreting beta-cell lines. It is well established that cytokines such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and gamma-interferon (IFN-gamma) inhibit beta-cell function and are cytotoxic to human and rodent pancreatic islets in vitro. Despite the pleiotropic effects of cytokines on beta-cells, the specific signal transduction pathways and molecular events involved in beta-cell dysfunction remain largely unresolved. In this report, we have examined IL-1beta stimulation of c-Jun NH(2)-terminal kinase (JNK) activity in insulin-secreting clonal cell lines. We demonstrate that IL-1beta transiently activates 46- and 54-kDa isoforms of JNK in cultured RINm5F beta-cells. Furthermore, IL-1beta stimulation of JNK activity is specific, because TNF-alpha and IFN-gamma were without effect. Stable overexpression of JNK1 in RINm5F cells increased levels of activated JNK without affecting kinase activity. JNK-interacting protein (JIP) associates with endogenous as well as overexpressed JNK, suggesting that JIP may serve to regulate JNK activity. Finally, we demonstrate that activated JNK is fully retained in cytoplasmic and membrane compartments without any nuclear translocation. Together, these data indicate that IL-1beta-stimulated JNK activity may be distinctly targeted to cytoplasmic and/or membrane compartments in clonal insulin-producing cells, and that JIP may serve to localize JNK activity to specific substrates.
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PMID:Interleukin-1beta stimulation of c-Jun NH(2)-terminal kinase activity in insulin-secreting cells: evidence for cytoplasmic restriction. 1172 54

The familial Alzheimer's disease gene product amyloid beta precursor protein (APP) is sequentially processed by beta- and gamma-secretases to generate the Abeta peptide. The biochemical pathway leading to Abeta formation has been extensively studied since extracellular aggregates of Abeta peptides are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of APP processing is unknown. Cleavage of APP by gamma-secretase releases, together with Abeta, a COOH-terminal APP intracellular domain, termed AID. This peptide has recently been identified in brain tissue of normal control and patients with sporadic Alzheimer's disease. We have previously shown that AID acts as a positive regulator of apoptosis. Nevertheless, the molecular mechanism by which AID regulates this process remains unknown. Hoping to gain clues about the function of APP, we used the yeast two-hybrid system to identify interaction between the AID region of APP and JNK-interacting protein-1 (JIP1). This molecular interaction is confirmed in vitro, in vivo by fluorescence resonance energy transfer (FRET), and in mouse brain lysates. These data provide a link between APP and its processing by gamma-secretase, and stress kinase signaling pathways. These pathways are known regulators of apoptosis and may be involved in the pathogenesis of Alzheimer's disease.
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PMID:Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein (APP). 1172 84

The expression of alpha-synuclein, a synaptic molecule implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Lewy body disease is increased upon injury to the nervous system, indicating that it might play a role in regeneration and plasticity; however, the mechanisms are unclear. Because c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, plays an important role in stress response, the main objective of the present study was to better understand the involvement of this pathway in the signaling responses associated with resistance to injury in cells expressing alpha-synuclein. For this purpose, the JNK-signaling pathway was investigated in alpha-synuclein-transfected neuronal cell line glucose transporter (GT) 1-7 under oxidative stress conditions. Although hydrogen peroxide challenge resulted in JNK activation and cell death in cells transfected with vector control or beta-synuclein, alpha-synuclein-transfected cells were resistant to hydrogen peroxide, and JNK was not activated. The inactivation of JNK in the alpha-synuclein-transfected cells was associated with increased expression and activity of JNK-interacting protein (JIP)-1b/islet-brain (IB)1, the scaffold protein for the JNK pathway. Similarly, cells transfected with JIP-1b/IB1 were resistant to hydrogen peroxide associated with inactivation of the JNK pathway. In these cells, expression of endogenous alpha-synuclein was significantly increased at the protein level. Furthermore, alpha-synuclein was co-localized with JIP-1b/IB1 in the growth cones. Taken together, these results suggest that increased alpha-synuclein expression might protect cells from oxidative stress by inactivation of JNK via increased expression of JIP-1b/IB1. Furthermore, interactions between alpha-synuclein and JIP-1b/IB1 may play a mutual role in the neuronal response to injury and neurodegeneration.
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PMID:alpha-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. 1179 Jul 92

The c-Jun N-terminal kinase (JNK) is critical for cell survival, differentiation, apoptosis and tumorigenesis. This signalling pathway requires the presence of the scaffold protein Islet-Brain1/c-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1). Immunolabeling and in situ hybridisation of bladder sections showed that IB1/JIP-1 is expressed in urothelial cells. The functional role of IB1/JIP-1 in the urothelium was therefore studied in vivo in a model of complete rat bladder outlet obstruction. This parietal stress, which is due to urine retention, reduced the content of IB1/JIP-1 in urothelial cells and consequently induced a drastic increase in JNK activity and AP-1 binding activity. Using a viral gene transfer approach, the stress-induced activation of JNK was prevented by overexpressing IB1/JIP-1. Conversely, the JNK activity was increased in urothelial cells where the IB1/JIP-1 content was experimentally reduced using an antisense RNA strategy. Furthermore, JNK activation was found to be increased in non-stressed urothelial cells of heterozygous mice carrying a selective disruption of the IB1/JIP-1 gene. These data established that mechanical stress in urothelial cells in vivo induces a robust JNK activation as a consequence of regulated expression of the scaffold protein IB1/JIP-1. This result highlights a critical role for that scaffold protein in the homeostasis of the urothelium and unravels a new potential target to regulate the JNK pathway in this tissue.
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PMID:The scaffold protein IB1/JIP-1 controls the activation of JNK in rat stressed urothelium. 1183 89

Members of the mitogen-activated protein kinase (MAPK) superfamily, including p38 kinase and SAPK/JNK, play a central role in mediating cellular response to environmental stress, growth factors and cytokines. Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine capable of eliciting mitogenic, motogenic and morphogenetic activities in responsive cells, and has been implicated in tumor development and metastasis. Binding of HGF/SF to its tyrosine kinase receptor c-Met stimulates multiple signal transduction pathways, leading to the activation of numerous transcription factors. We here report that HGF/SF can induce cyclin D1 expression in mouse melanoma cells, and that this up-regulation is mediated in part by the activating transcription factor-2 (ATF-2). HGF/SF-mediated phosphorylation of ATF-2 was reduced in the presence of either the p38 kinase-specific inhibitor SB203580, a dominant negative p38 mutant, the SAPK/JNK inhibitor JNK-interacting protein-1 (JIP-1), or the phosphatidylinositol 3-kinase (PI3K)-specific inhibitor LY294002. Activation of p38 kinase by HGF/SF was partially blocked by the PI3K-specific inhibitor as well. The upstream kinases for p38, MKK3/6, did not become activated following HGF/SF exposure, and ATF-2 activation was undiminished by transient transfection of a dominant negative MKK6 mutant. However, transcriptional up-regulation of cyclin D1 by HGF/SF was partially inhibited by the p38 kinase-specific inhibitor, and cyclin D1 protein induction was partially blocked by a dominant negative ATF-2 mutant. Notably, the p38 kinase-specific inhibitor was able to block melanoma cell proliferation but not motility. We conclude that the ATF-2 transcription factor becomes activated by HGF/SF through p38 MAPK and SAPK/JNK. Moreover, the p38-ATF-2 pathway can help mediate proliferation signals in tumor cells through transcriptional activation of key cell cycle regulators.
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PMID:Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. 1185 Aug 17

The proline-rich tyrosine kinase 2 (Pyk2) was first identified as a key kinase linked to the MAP kinase and JNK signaling pathways that play important roles in cell growth and adhesion. The linkage between Pyk2 and the androgen receptor (AR), an important transcription factor in prostate cancer progression, however, remains unclear. Here we report that using the full-length androgen receptor-associated protein, ARA55, coregulator as bait, we were able to isolate an ARA55-interacting protein, Pyk2, and demonstrated that Pyk2 could repress AR transactivation via inactivation of ARA55. This inactivation may result from the direct phosphorylation of ARA55 by Pyk2 at tyrosine 43, impairing the coactivator activity of ARA55 and/or sequestering ARA55 to reduce its interaction with AR. Our finding that Pyk2 can indirectly modulate AR function via interaction and/or phosphorylation of ARA55 not only expands the role of Pyk2 in AR-mediated prostate cancer growth but also strengthens the role of ARA55 as an AR coregulator.
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PMID:Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator. 1185 38


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