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)

PC hydrolysis by PLA2, PLC or PLD is a widespread response elicited by most growth factors, cytokines, neurotransmitters, hormones and other extracellular signals. The mechanisms can involve G-proteins, PKC, Ca2+ and tyrosine kinase activities. Although an agonist-responsive cytosolic PLA2 has been purified, cloned and sequenced, the agonist-responsive form(s) of PC-PLC has not been identified and no form of PC-PLD has been purified or cloned. Regulation of PLA2 by Ca2+ and MAPK is well established and involves membrane translocation and phosphorylation, respectively. PKC regulation of the enzyme in intact cells is probably mediated by MAPK. The question of G-protein control of PLA2 remains controversial since the nature of the G-protein is unknown and it is not established that its interaction with the enzyme is direct or not. Growth factor regulation of PLA2 involves tyrosine kinase activity, but not necessarily PKC. It may be mediated by MAPK. The physiological significance of PLA2 activation is undoubtedly related to the release of AA for eicosanoid production, but the LPC formed may have actions also. There is much evidence that PKC regulates PC-PLC and PC-PLD and this is probably a major mechanism by which agonists that promote PI hydrolysis secondarily activate PC hydrolysis. Since no agonist-responsive forms of either phospholipase have been isolated, it is not clear that PKC exerts its effects directly on the enzymes. Although it is assumed that a phosphorylation mechanism is involved, this may not be the case, and regulation may be by protein-protein interactions. G-protein control of PC-PLD is well-established, although, again, it has not been demonstrated that this is direct, and the nature of the G-protein(s) involved is unknown. In some cell types, there is evidence of the participation of a soluble protein, which may be a low Mr GTP-binding protein. What role this plays in the activation of PC-PLD is obscure. Agonist activation of PC hydrolysis in cells is usually Ca(2+)-dependent, but the step at which Ca2+ is involved is unclear, since PC-PLD and PC-PLC per se are not influenced by physiological concentrations of the ion. Most growth factors promote PC hydrolysis and this is mainly due to activation of PKC as a result of PI breakdown. However, in some cases, PC breakdown occurs in the absence of PI hydrolysis, implying another mechanism that does not involve PI-derived DAG.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phosphatidylcholine breakdown and signal transduction. 815 24

Dystrophin is the 427-kDa protein product of the Duchenne muscular dystrophy gene (DMD). The function of this protein remains to be elucidated. We have recently reported that dystrophin is phosphorylated, in vivo, in rat skeletal muscle primary cell culture (RE Milner, JL Busaan, CFB Holmes, JH Wang, M Michalak (1993) J Biol Chem 268:21901-21905). This observation suggests that protein phosphorylation may have some role in modulating the function of dystrophin or its interaction with membrane associate dystroglycan. We report here that the carboxyl-terminal of dystrophin is phosphorylated by the MAP kinase p44mpk (mitogen-activated protein kinase), from the sea star oocytes and by soluble extracts of rabbit skeletal muscle. Importantly we showed that native dystrophin in isolated sarcolemmal vesicles is phosphorylated by sea star p44mpk Partial purification and immunological analysis show that a mammalian kinase related to p44mpk is present in the skeletal muscle extracts and that it contributes to phosphorylation of the carboxyl-terminal of dystrophin. This kinase phosphorylates dystrophin on a threonine residue(s). We conclude that phosphorylation of dystrophin may play an important role in the function of this cytoskeletal protein.
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PMID:Phosphorylation of the carboxyl terminal region of dystrophin by mitogen-activated protein (MAP) kinase. 860 12

Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection.
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PMID:Lymphocyte activation in health and disease. 909 51

The mechanism of arginine vasopressin (AVP)-induced arachidonic acid (AA) release was examined in the cardiac myoblast cell line, H9c2. Stimulation of cells with AVP induced dose-dependent AA release, and this effect was completely inhibited by the V1 receptor antagonist, d(CH)5[Tyr(Me)2]AVP. AVP also produced dose-dependent stimulation of inositol phosphate formation; this was not affected by pertussis toxin, indicating the presence of the V1 receptor/Gq protein/PLCbeta pathway in H9c2 cells. The concentration-response curves for these two effects of AVP overlapped. AVP induced a rapid increase in [Ca2+]i, followed by a sustained increase. The Ca2+ ionophore, A23187 or ionomycin, mimicked the effect of AVP, whereas the protein kinase C (PKC) activator, TPA, only induced a slight increase in AA release. Both the AVP- or A23187-stimulated AA release and the AVP-induced sustained [Ca2+]i increase were completely blocked in the absence of external Ca2+. The receptor-operated Ca2+ channel blocker, SKF 96365, and the inorganic Ca2+ channel blockers, Ca2+ and Ni2+, also inhibited the AVP-induced AA release. Western blots demonstrated expression of PKCalpha, betaI, epsilon, delta, and zeta in H9c2 cells; PKC inhibitors (staurosporine or Ro 31-8220) or down-regulation of PKCalpha, betaI, epsilon, and delta by long-term (24 h) TPA treatment caused a partial blockade of the AVP-induced response, whereas the A23187-induced AA release was unaffected by down-regulation of these isoforms. AVP-induced, but not A23187-induced, AA release was partially blocked by the p42 MAPK cascade inhibitor, PD 98059. AVP and TPA, but not A23187, induced an increase in activity and tyrosine phosphorylation of p42 MAPK, together with a molecular weight shift, consistent with phosphorylation, of cytosolic PLA2. AVP- or TPA-induced activation and tyrosine phosphorylation of p42 MAPK were completely blocked by down-regulation of PKCalpha, betaI, epsilon, and delta, but still occurred, together with the cytosolic PLA2 mobility shift, in the absence of external Ca2+. These results show that AVP-induced AA release in H9c2 cells is secondary to activation of the V1 receptor/Gq protein/PLCP pathway, leading to an influx of extracellular Ca2+ and activation of PKCalpha, betaI, epsilon, and delta. The influx of extracellular Ca2- and DAG act, respectively, through PKC-/MAPK-independent or PKC-dependent MAPK pathways to mediate AA release.
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PMID:Signal transduction of arginine vasopressin-induced arachidonic acid release in H9c2 cardiac myoblasts: role of Ca2+ and the protein kinase C-dependent activation of p42 mitogen-activated protein kinase. 1009 98

To investigate the molecular mechanism(s) of insulin action on the expression of the angiotensinogen (ANG) gene in kidney proximal tubular cells, we constructed a fusion gene, pOGH (hANG N-1064/+27), containing the 5'-flanking regulatory sequence of the human ANG gene fused with the human growth hormone (hGH) gene as a reporter and stably integrated the fusion gene into the opossum kidney (OK) cell genomes. The level of expression of pOGH (hANG N-1064/+27) was quantified by the amount of immunoreactive hGH secreted into the medium. The addition of a high level of D(+)-glucose (25 mM) or phorbol 12-myristate 13-acetate (PMA, 10(-7) M) stimulated the expression of the fusion gene in OK cells. The stimulatory effect of glucose (25 mM) was blocked by insulin and tolrestat (an inhibitor of aldose reductase). Tolrestat also inhibited the increase of cellular DAG and PKC activity stimulated by 25 mM glucose. While insulin did not affect the cellular DAG and PKC activity, it did block the stimulatory effect of high glucose (25 mM) and PMA on the expression of the fusion gene. Finally, PD98059 (an inhibitor of mitogen-activated protein kinase kinase (MEK)) enhanced the stimulatory effect of high levels of glucose and blocked the inhibitory effect of insulin on the expression of the fusion gene as well as on the phosphorylation of MEK and mitogen-activated protein kinase (MAPK). In contrast, Wortmannin (an inhibitor of phosphatidylinositol-3-kinase) did not block the inhibitory effect of insulin on the ANG gene expression. These studies demonstrate that the action of insulin, blocking the stimulatory effect of a high level of D(+)-glucose (25 mM) on the ANG gene expression is mediated, at least in part, via the 5'-flanking region of the ANG gene and MAPK signal transduction pathway.
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PMID:Molecular mechanism(s) of insulin action on the expression of the angiotensinogen gene in kidney proximal tubular cells. 1196 9

Laminin-integrin interactions can in some settings activate the extracellular signal-regulated kinases (ERKs) but the control mechanisms are poorly understood. Herein, we studied ERK activation in response to two laminins isoforms (-1 and -10/11) in two epithelial cell lines. Both cell lines expressed beta1-containing integrins and dystroglycan but lacked integrin alpha6beta4. Antibody perturbation assays showed that both cell lines bound to laminin-10/11 via the alpha3beta1and alpha6beta1 integrins. Although laminin-10/11 was a stronger adhesion complex than laminin-1 for both cell lines, both laminins activated ERK in only one of the two cell lines. The ERK activation was mediated by integrin alpha6beta1 and not by alpha3beta1 or dystroglycan. Instead, we found that dystroglycan-binding domains of both laminin-1 and -10/11 suppressed integrin alpha6beta1-mediated ERK activation. Moreover, the responding cell line expressed the two integrin alpha6 splice variants, alpha6A and alpha6B, whereas the nonresponding cell line expressed only alpha6B. Furthermore, ERK activation was seen in cells transfected with the integrin alpha6A subunit, but not in alpha6B-transfected cells. We conclude that laminin-1 and -10/11 share the ability to induce ERK activation, that this is regulated by integrin alpha6Abeta1, and suggest a novel role for dystroglycan-binding laminin domains as suppressors of this activation.
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PMID:Opposing roles of integrin alpha6Abeta1 and dystroglycan in laminin-mediated extracellular signal-regulated kinase activation. 1280 77

Nongenomic actions mediated by androgens have now been described in more than 10 cell types. Some of these cells transduce androgen signals using surface receptors that await final characterization, whereas other cells employ the classical AR. Various second messengers can be activated by androgens, including cAMP, IP3, phospholipase C, DAG, and Ca2+. Each of these second messengers is capable of activating multiple kinases. One of the most important kinase networks to be regulated by androgens is the MAP kinase cascade. This series of kinase reactions is capable of altering the activity of many transcription factors with important implications for the regulation of gene expression. Because there is evidence that androgen is capable of regulating CREB-mediated gene expression via the MAP kinase pathway, it is now somewhat misleading to characterize androgen actions in Sertoli cells as nongenomic. Instead, it may be more appropriate to label these activities as independent of AR-DNA interactions, or more simply as nonclassical. The nonclassical regulation of gene expression in Sertoli cells is particularly relevant for providing an answer to the paradox of how testosterone can support spermatogenesis yet regulate few genes via AR-promoter interactions. It is expected that with the increasing use of microarray and related technologies, additional AR-regulated genes will be identified. However, the androgen-induced increases in [Ca2+]i, the activation of Src kinase, and the MAP kinase cascade that have been characterized thus far have the potential to regulate the expression of many more genes than is possible by direct AR-promoter interactions. Thus, it is likely that nonclassical actions of testosterone in Sertoli cells will be found to be a necessary complement to the classical actions that are required to maintain spermatogenesis.
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PMID:Nongenomic actions of androgen in Sertoli cells. 1458 25

Genome-wide gene expression analysis of the hippocampal CA1 region was conducted in a rat global ischemia model for delayed neuronal death and induced ischemic tolerance using an oligonucleotide-based DNA microarray containing 8,799 probes. The results showed that expression levels of 246 transcripts were increased and 213 were decreased following ischemia, corresponding to 5.1% of the represented probe sets. These changes were divided into seven expression clusters using hierarchical cluster analysis, each with distinct conditions and time-specific patterns. Ischemic tolerance was associated with transient up-regulation of transcription factors (c-Fos, JunB Egr-1, -2, -4, NGFI-B), Hsp70 and MAP kinase cascade-related genes (MKP-1), which are implicated cell survival. Delayed neuronal death exhibited complex long-lasting changes of expression, such as up-regulation of proapoptotic genes (GADD153, Smad2, Dral, Caspase-2 and -3) and down-regulation of genes implicated in survival signaling (MKK2, and PI4 kinase, DAG/PKC signaling pathways), suggesting an imbalance between death and survival signals. Our study provides a differential gene expression profile between delayed neuronal death and induced ischemic tolerance in a genome-wide analysis, and contributes to further understanding of the complex molecular pathophysiology in cerebral ischemia.
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PMID:Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rats. 1474 48

Dystroglycan is an important cell adhesion receptor linking the actin cytoskeleton, via utrophin and dystrophin, to laminin in the extracellular matrix. To identify adhesion-related signalling molecules associated with dystroglycan, we conducted a yeast two-hybrid screen and identified mitogen-activated protein (MAP) kinase kinase 2 (MEK2) as a beta-dystroglycan interactor. Pull-down experiments and localization studies substantiated a physiological link between beta-dystroglycan and MEK and localized MEK with dystroglycan in membrane ruffles. Moreover, we also identified active extracellular signal-regulated kinase (ERK), the downstream kinase from MEK, as another interacting partner for beta-dystroglycan and localized both active ERK and dystroglycan to focal adhesions in fibroblast cells. These studies suggest a role for dystroglycan as a multifunctional adaptor or scaffold capable of interacting with components of the ERK-MAP kinase cascade including MEK and ERK. These findings have important implications for our understanding of the role of dystroglycan in normal cellular processes and in disease states such as muscular dystrophy.
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PMID:Dystroglycan, a scaffold for the ERK-MAP kinase cascade. 1507 96

The presence of many laminin receptors of the beta1 integrin family on most cells makes it difficult to define the biological functions of other major laminin receptors such as integrin alpha6beta4 and dystroglycan. We therefore tested the binding of a beta1 integrin-null cell line GD25 to four different laminin variants. The cells were shown to produce dystroglycan, which based on affinity chromatography bound to laminin-1, -2/4, and -10/11, but not to laminin-5. The cells also expressed the integrin alpha6Abeta4A variant. GD25 beta1 integrin-null cells are known to bind poorly to laminin-1, but we demonstrate here that these cells bind avidly to laminin-2/4, -5, and -10/11. The initial binding at 20 min to each of these laminins could be inhibited by an integrin alpha6 antibody, but not by a dystroglycan antibody. Hence, integrin alpha6Abeta4A of GD25 cells was identified as a major receptor for initial GD25 cell adhesion to three out of four tested laminin isoforms. Remarkably, cell adhesion to laminin-5 failed to promote cell spreading, proliferation, and extracellular signal-regulated kinase (ERK) activation, whereas all these responses occurred in response to adhesion to laminin-2/4 or -10/11. The data establish GD25 cells as useful tools to define the role integrin alpha6Abeta4A and suggest that laminin isoforms have distinctly different capacities to promote cell adhesion and signaling via integrin alpha6Abeta4A.
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PMID:Laminin isoforms differentially regulate adhesion, spreading, proliferation, and ERK activation of beta1 integrin-null cells. 1538 18


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