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)

The signal transduction initiated by the human cytokine interleukin-8 (IL-8), the main chemotactic cytokine for neutrophils, was investigated and found to encompass the stimulation of protein kinases. More specifically, IL-8 caused a transient, dose and time dependent activation of a Ser/Thr kinase activity towards myelin basic protein (MBP) and the MBP-derived peptide APRTPGGRR patterned after the specific concensus sequence in MBP for ERK enzymes. The activated MBP kinase was furthermore identified as an extracellular signal regulated kinase (ERK1) based on several criteria such as substrate specificity, molecular weight, activation-dependent mobility shift, and recognition by anti-ERK antibodies. For comparison, the chemotactic response of neutrophils to a stimulus of bacterial origin (fMet-Leu-Phe or fMLP) was also examined and found to involve the activation of a similar ERK enzyme. The present data clearly indicate that in terminally differentiated, non-proliferating human cells, the MBP kinase/ERK activity can serve other purposes than mitogenic signaling, and that processes such as chemotaxis, induced by bacterial peptides as well as by human cytokines like IL-8, involve the regulation of ERK enzymes.
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PMID:Interleukin-8 activates microtubule-associated protein 2 kinase (ERK1) in human neutrophils. 752 47

A variant cell line, designated E2, characterized by more rapid responses to nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) and markedly more robust responses to interleukin-6 and 8-Br-cAMP, has been subcloned from the rat PC12 cell line. The enhanced responsiveness to NGF in E2 cells is not due to receptor overexpression as judged by TrkA protein levels and tyrosine kinase activity, but may be associated with the increased and prolonged tyrosine phosphorylation of ERK1 (extracellular signal regulated kinase 1) and ERK2. The rapid morphological differentiation induced by different growth factors in E2 cells is mediated in a transcription-independent manner suggesting that E2 cells may constitutively express some differentiation-associated molecules that allow direct entry into the neuronal program.
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PMID:PC12-E2 cells: a stable variant with altered responses to growth factor stimulation. 754 55

The molecular mechanism underlying the cAMP inhibition of nuclear activation events in T lymphocytes is unknown. Recently, the activation of fibroblasts and muscle cells are shown to be antagonized by cAMP through the inhibition of mitogen-activated protein (MAP) kinases signaling pathway. Whether a similar antagonism may account for the late inhibitory effect of cAMP in T cell was examined. Surprisingly, extracellular signal regulated kinase 2 (ERK1, ERK2, and ERK3) of MAP kinase were poorly inhibited by cAMP. High concentration of cAMP also only weakly antagonized Raf-1 in T cells. The resistance of ERK and Raf-1 to cAMP clearly distinguishes T cells from fibroblasts. In contrast, another MAP kinase homologue c-Jun N-terminal kinase (JNK) was inhibited by cAMP in good correlation with that of IL-2 suppression. Moreover, JNK was antagonized by a delayed kinetics which is characteristic of cAMP inhibition. Despite that both ERK and JNK are essential for T cell activation, selective inhibition by cAMP further supports the specific role of JNK in T cell activation.
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PMID:c-Jun N-terminal kinase but not mitogen-activated protein kinase is sensitive to cAMP inhibition in T lymphocytes. 762 20

In order to evaluate the intracellular signaling pathway of endothelin 1 (ET-1), we examined mitogen-activated protein kinase (MAPK) cascade in cultured rat glomerular mesangial cells. Treatment of quiescent mesangial cells with ET-1 increased kinase activities toward bovine myelin basic protein (MBP). Maximal activation was at 10 min and ED50 was about 5 nM. The 44- and 42-kDa kinases were activated in MBP containing gel kinase assay. These kinases were identified as extracellular signal regulated kinase (ERK) 1 and ERK2 with immunoblotting, respectively. MAPK or ERK kinase (MEK), one of the MAPK kinases, was present in rat mesangial cells and ET-1 also activated this MAPK kinase. These results indicate that MAPK kinase and MAP kinase are rapidly activated by ET-1 and may modulate cellular functions in rat mesangial cells.
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PMID:[MAP kinase cascade in cultured rat mesangial cells]. 773 Nov 2

MAP kinases (MAPK) are a family of serine/threonine (Ser/Thr) kinases that link cell surface signals to changes in enzyme activity and gene expression. They are the products of the newly described gene family referred to as extracellular signal regulated kinases (ERKs). Moreover, MAPKs phosphorylate tau in vitro at Ser/Thr Proline sites, generating a multiply phosphorylated tau protein that is similar to the hyperphosphorylated tau found in Alzheimer neurofibrillary tangles (NFTs). We studied MAPK immunoreactivity and in situ hybridization patterns of the two major genes that comprise MAPK activity, ERK1 and ERK2, in the human hippocampal formation. Our goal was to determine whether the pattern of ERK expression is consistent with the hypothesis that MAPKs contribute to NFT formation. ERK1 mRNA is present in small amounts and confined primarily to dentate gyrus granule cells. ERK2 mRNA, by contrast, gives a much stronger hybridization signal and is present in dentate gyrus granule cells and pyramidal cells throughout all hippocampal subfields and adjacent temporal neocortex. Quantitative measures of ERK2 mRNA reveal that NFT-bearing neurons contain approximately 15% less ERK2 mRNA than nearest neighbors that do not contain NFT. NFT-bearing neurons contain approximately 25% less polyA mRNA, suggesting a relative preservation of ERK2 mRNA even in metabolically compromised cells. MAPK immunoreactivity (which represents both ERK1 and ERK2) is seen in neuronal soma, dendrites, axons, and in reactive astrocytes. In Alzheimer's disease, neurons that contain NFTs are also MAPK immunoreactive, but neurons that contain the highest amounts of MAPK immunoreactivity are not necessarily vulnerable for NFT. MAPK immunoreactivity is present in the same neurons as NFT and in the same subcellular compartments as tau, supporting a role for MAPKs in tau phosphorylation in Alzheimer's disease. However, the presence of ERK immunoreactivity is not sufficient to predispose neurons to NFT formation.
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PMID:Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease. 812 42

p74raf-1, a serine/threonine kinase, is structurally related to the protein kinase C (PKC) family and contains a cysteine motif in its N-terminal domain, which is essential for its regulation. It has been shown that p74raf-1 functions upstream of mitogen-activated protein (MAP) kinase kinase. We have constructed a p74raf-1 mutant (N delta raf) that only contains the N-terminal regulatory domain. When transiently expressed in COS-M6 cells, N delta raf efficiently blocked the activation of the MAP extracellular signal regulated kinase (ERK2), induced by either epidermal growth factor, phorbol ester, serum, or oncogenic p21ras. Similar constructs with the cysteine motifs from either PKC-alpha or diacylglycerol kinase did not inhibit activation of ERK2. Overexpression of full-length p74raf-1 rescued the inhibition of ERK2 by N delta raf in a stimulus dependent manner, indicating that N delta raf acts as a competitive inhibitor of wild-type p74raf-1. In contrast, overexpression of either PKC-alpha, -epsilon, or -zeta in N delta raf-containing cells could not rescue the inhibition of ERK2. We conclude that p74raf-1 is an essential mediator of epidermal growth factor- and phorbol ester-induced ERK2 activation and that the MAP kinase kinase activity of p74raf-1 cannot be substituted with either PKC-alpha, -epsilon or -zeta.
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PMID:A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. 839 1

Local infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) can prevent and reverse the ability of chronic morphine or cocaine exposure to induce tyrosine hydroxylase (TH) in this brain region. The present study examined a possible role for extracellular signal regulated kinases (ERKs), the major effector for BDNF and related neurotrophins, in morphine and cocaine action in the VTA. Chronic, but not acute, administration of morphine or cocaine increased ERK catalytic activity specifically in the VTA. This increase in ERK activity reflected an increase in the state of phosphorylation of ERK, with no change in levels of total ERK immunoreactivity. Chronic infusions of BDNF into the VTA reduced total ERK immunoreactivity with no change in ERK activity, and also blocked the morphine-induced increase in ERK activity. These results suggest that chronic BDNF elicits a compensatory increase in the phosphorylation of the remaining ERK molecules and thereby prevents any additional increase in response to drug exposure. Such a role for ERK in morphine action was demnostrated directly by chronically infusing antisense oligonucleotides to ERK1 into the VTA. This treatment selectively reduced levels of ERK1 immunoreactivity in a sequence-specific manner without detectable toxicity. Intra-VTA infusion of ERK1 antisense oligonucleotides mimicked the effects of chronic BDNF infusions on ERK immunoreactivity, ERK activity, and TH immunoreactivity in the VTA under both control and morphine-treated conditions. The chronic morphine-induced increases in ERK activity and TH expression in the VTA also were blocked by local infusion of NMDA glutamate receptor antagonists, suggesting a role for glutamate in mediating these drug effects. Together, these findings support a scheme whereby chronic, systemic administration of morphine or cocaine leads to a sustained increase in ERK phosphorylation state and activity in the VTA, which, in turn, contributes to drug-induced increases in TH, and perhaps other drug-induced adaptations, elicited selectively in this brain region.
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PMID:Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. 876 58

Exposure of cells to either proliferative or stressful stimuli elicits a complex response involving one or more distinct phosphorylation cascades culminating in the activation of multiple members of the mitogen-activated protein kinase (MAPK) family, including extracellular signal regulated kinase (ERK), stress-activated c-Jun N-terminal kinase (JNK/SAPK), and p38/RK/CSBP protein kinase. While the pathways transducing mitogenic stimuli to these kinases are relatively well established, the early signalling events leading to their activation in response to stress are poorly understood. In the present study, we examined ERK, JNK/SAPK, and p38 activation in cells treated with the sulfhydryl-reactive agent sodium arsenite. Arsenite treatment potently activated both JNK/SAPK and p38, but only moderately activated ERK. Activation of all three kinases was prevented by the free radical scavenger N-Acetyl-L-cysteine, suggesting that an oxidative signal initiates the responses. Suramin, a growth factor receptor poison, significantly inhibited ERK activation by arsenite, but had little effect on either JNK/SAPK or p38 activity. In contrast, suramin inhibited the activation of all three kinases by short wavelength ultraviolet light (UVC) irradiation. In addition, comparative studies with wild-type PC12 cells and PC12 cells expressing a dominant negative Ras mutant allele indicated that arsenite activates ERK primarily through a Ras-dependent pathway(s), while activation of both JNK/SAPK and p38 occurs through a mechanism relatively independent of Ras. These results suggest that JNK/SAPK and p38 may share common upstream regulators distinct from those involved in ERK activation.
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PMID:Differential activation of ERK, JNK/SAPK and P38/CSBP/RK map kinase family members during the cellular response to arsenite. 890 23

Stress-activated protein kinases are MAP kinase homologues that are activated by cellular stresses, bacterial endotoxin and inflammatory cytokines. They are activated by a dual threonine/tyrosine phosphorylation within a TPY sequence in the case of stress-activated protein kinase-1 and its isoforms (also called JNKs) or a TGY sequence in the case of stress-activated protein kinase-2 and its isoforms (also called p38, p40, RK, CSBPs, XMpk2 and Mxi2). Here we report the cloning and sequencing of a new protein kinase from rat with a TGY sequence in the activation domain. This stress-activated protein kinase-3 is 60% identical to mouse stress-activated protein kinase-2 and 45% identical to HOG1 from Saccharomyces cerevisiae. Transcripts encoding stress-activated protein kinase-3 are widely expressed, with high levels in skeletal muscle.
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PMID:SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. 892 12

The sphingomyelin pathway is a ubiquitous, evolutionarily conserved signaling system initiated by hydrolysis of the plasma membrane phospholipid sphingomyelin to generate the second messenger ceramide. Sphingomyelin degradation is catalyzed by acid and neutral sphingomyelinase (SMase) isoforms. Most, if not all mammalian cells, appear capable of signaling though the sphingomyelin pathway. Diverse receptor types and environmental stresses utilize the sphingomyelin pathway as a downstream effector system. In some cellular systems, ceramide initiates differentiation or cell proliferation, while in other systems, ceramide signals apoptosis. Recent investigations link the activation of neutral SMase to the extracellular signal regulated kinase (ERK) cascade and pro-inflammatory responses, and acid SMase to the stress-activated protein kinase/c-jun kinase (SAPK/JNK) cascade and apoptotic responses. Environmental stresses act directly on membrane to activate acid pH-dependent sphingomyelinase (ASMase), whereas cytokine receptors signal ASMase activation through motifs termed death domains. The present review focuses on mechanisms of activation of ASMase and on ceramide signaling of the apoptotic response.
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PMID:Stress-induced apoptosis and the sphingomyelin pathway. 911 79


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