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)

By using the MIN6 cell line and pancreatic islets, we show that in the presence of a low glucose concentration, corresponding to physiological glucagon release from alpha cells, glucagon treatment of the beta cell caused a rapid, time-dependent phosphorylation and activation of p44/p42 mitogen-activated protein kinase (ERK1/2) independently from extracellular calcium influx. Inhibition of either cAMP-dependent protein kinase (PKA) or MEK completely blocked ERK1/2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Shc-p21(Ras) and phosphatidylinositol 3-kinase, was observed in response to glucagon treatment. Chelation of intracellular calcium (intracellular [Ca(2+)]) reduced glucagon-mediated ERK1/2 activation. In addition, internalization of glucagon receptors through clathrin-coated pits formation is required for ERK1/2 activation. Remarkably, glucagon promotes the nuclear translocation of ERK1/2 and induces the phosphorylation of cAMP-response element-binding protein (CREB). Miniglucagon, produced from glucagon and released together with the mother hormone from the alpha cells in low glucose situations, blocks the insulinotropic effect of glucagon, whereas it does not inhibit the glucagon-induced PKA/ERK1/2/CREB pathway. We conclude that glucagon-induced ERK1/2 activation is mediated by PKA and that an increase in [Ca(2+)](i) is required for maximal ERK activation. Our results uncover a novel mechanism by which the PKA/ERK1/2 signaling network engaged by glucagon, in situation of low glucose concentration, regulates phosphorylation of CREB, a transcription factor crucial for normal beta cell function and survival.
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PMID:Glucagon promotes cAMP-response element-binding protein phosphorylation via activation of ERK1/2 in MIN6 cell line and isolated islets of Langerhans. 1498 13

In culture, cerebellar granule neurons die of apoptosis in serum-free media containing a physiologic level of K(+) but survive in a depolarizing concentration of K(+) or when insulin-like growth factor 1 (IGF-1) is added. Both Akt/PKB activation and caspase-3 inhibition were implicated as the underlying neuroprotective mechanisms. The duration of high K(+), however, induced survival effects that outlasted its transient activation of Akt, and granule neurons derived from caspase-3 knockout mice died to the same extent as did those from wild-type mice, suggesting that additional mechanisms are involved. To delineate these survival mechanisms, we compared the activities of two major survival pathways after high K(+)-induced depolarization or IGF-1 stimulation. Although IGF-1 promoted neuronal survival by activating its tyrosine kinase receptor, high K(+) depolarization provided the same effect by increasing the Ca(2+) influx through the L Ca(2+) channel. Moreover, high K(+)-induced depolarization resulted in sustained activation of MAP kinase, whereas IGF-1 activated Akt in 4 hr. Inhibition of MEK (MAP kinase kinase) by either PD98059 or UO126 abolished the protective effect of high K(+)-induced depolarization, but not that of IGF-1, suggesting that activation of the MAP kinase pathway is necessary for high K(+) neuroprotective effects. We demonstrated also that high K(+)-induced depolarization, but not IGF-1, increased phosphorylation of cAMP-response element-binding protein (CREB) and protein synthesis, both of which can be blocked by UO126. Overall, our findings suggested that high K(+)-induced depolarization, unlike IGF-1, promoted neuronal survival via activating MAP kinase, possibly by increasing CREB-dependent transcriptional activation of specific proteins that promote neuronal survival.
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PMID:High K+ and IGF-1 protect cerebellar granule neurons via distinct signaling pathways. 1499 40

Repeated exposure to cocaine can induce neuroadaptations in the brain. One mechanism by which persistent changes occur involves alterations in gene expression mediated by the dopamine receptors. Both the dopamine D1 and D3 receptors have been shown to mediate gene expression changes. Moreover, the D1 and D3 receptors are also coexpressed in the same neurons, particularly in the nucleus accumbens and also caudoputamen (CPu). Little is known however, whether these two receptors coordinately regulate gene expression after cocaine administration and the underlying mechanisms. We have used various gene mutant mice to address this issue. We show that extracellular signal-regulated kinase (ERK) activation and c-fos induction in the CPu in response to acute cocaine administration is mediated by the D1 receptor and inhibited by the D3 receptor. Moreover, ERK activation mediates acute cocaine-induced expression of Fos family genes, including c-fos, fosB and fra2. Interestingly, dynorphin, neogenin, and synaptotagmin VII, genes that possess cAMP-response element binding protein and AP-1 transcription complex-binding consensus sequences in their promoters, are also oppositely regulated by the D1 and D3 receptors after repeated exposure to cocaine. Furthermore, such regulation depends on proper ERK activation and c-fos function. These results suggest that the D1 and D3 receptors elicit opposite regulation of target gene expression by regulating ERK activation and c-fos induction after acute and chronic cocaine treatment.
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PMID:Cocaine-induced intracellular signaling and gene expression are oppositely regulated by the dopamine D1 and D3 receptors. 1505 14

In the human kinome, vaccinia-related kinase-1 (VRK1) is a new Ser-Thr kinase associated with proliferating tissues. VRK1 colocalizes with ATF2 in the nucleus and can form a stable complex. We have studied the phosphorylation of the transcription factor ATF2, which regulates gene expression by forming dimers with proteins with basic region-leucine zipper domains and recognizing cAMP-response element or AP1 sequences implicated in cellular responses to stress. VRK1 phosphorylates ATF2 mainly on Thr-73, stabilizing the ATF2 protein and increasing its intracellular level. Mutagenesis studies showed that Thr-73 and Ser-62 are implicated in ATF2 transcriptional activation by VRK1 detected in a functional assay based on ATF2 dimerization. VRK1 can activate the collagenase gene promoter that is regulated by ATF2 in a dose-dependent manner. Loss of kinase activity (K179E mutant) or the T73A substitution in ATF2 prevents both its accumulation and activation of transcription. VRK1 and JNK, which phosphorylates ATF2 in Thr-69 and Thr-71, have an additive effect on ATF2-dependent transcription at suboptimal doses. Therefore, two groups of amino acids in the ATF2 amino-terminal region can integrate different cellular signals mediated by at least five different kinases. VRK1 is an element of a novel signaling pathway that regulates gene transcription.
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PMID:Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK. 1510 25

Regulation of gene expression is purported as a major component in the long-term action of antidepressants. The transcription factor cAMP-response element-binding protein (CREB) is activated by chronic antidepressant treatments, although a number of studies reported different effects on CREB, depending on drug types used and brain areas investigated. Furthermore, little is known as to what signaling cascades are responsible for CREB activation, although cAMP-protein kinase A (PKA) cascade was suggested to be a central player. We investigated how different drugs (fluoxetine (FLX), desipramine (DMI), reboxetine (RBX)) affect CREB expression and phosphorylation of Ser(133) in the hippocampus and prefrontal/frontal cortex (PFCX). Acute treatments did not induce changes in these mechanisms. Chronic FLX increased nuclear phospho-CREB (pCREB) far more markedly than pronoradrenergic drugs, particularly in PFCX. We investigated the function of the main signaling cascades that were shown to phosphorylate and regulate CREB. PKA did not seem to account for the selective increase of pCREB induced by FLX. All drug treatments markedly increased the enzymatic activity of nuclear Ca2+/calmodulin (CaM) kinase IV (CaMKIV), a major neuronal CREB kinase, in PFCX. Activation of this kinase was due to increased phosphorylation of the activatory residue Thr196, with no major changes in the expression levels of alpha- and beta-CaM kinase kinase, enzymes that phosphorylate CaMKIV. Again in PFCX, FLX selectively increased the expression level of MAP kinases Erk1/2, without affecting their phosphorylation. Our results show that FLX exerts a more marked effect on CREB phosphorylation and suggest that CaMKIV and MAP kinase cascades are involved in this effect.
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PMID:Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. 1513 45

The roles played by specific transcription factors during the regulation of early T cell development remain largely undefined. Several key genes induced during the primary checkpoint of T cell development, beta-selection, contain cAMP response element sites within their enhancer-promoter region that are regulated by CREB activation. In this study, we show that CREB is constitutively phosphorylated in the thymus, but not the spleen. We also show that CREB is activated downstream of the pre-TCR complex, and that the induction of CREB activity is regulated by protein kinase C alpha- and ERK-MAPK-mediated signals. We addressed the importance of this activation by expressing a naturally occurring inhibitor of CREB, inducible cAMP early repressor in wild-type fetal liver-derived lymphoid progenitor cells, and assessed their developmental potential. Fetal thymic organ cultures reconstituted with cells constitutively expressing inducible cAMP early repressor displayed a delay in generating CD4(+)CD8(+) thymocytes and a decrease in cellularity compared with control fetal thymic organ cultures. Taken together, our studies establish that CREB plays a central role in relaying proliferation and differentiation signals from the pre-TCR complex into the nucleus in developing thymocytes.
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PMID:Cyclic adenosine 5'-monophosphate response element binding protein plays a central role in mediating proliferation and differentiation downstream of the pre-TCR complex in developing thymocytes. 1526 11

Ca(2+)-regulated exocytosis is required for rapid resealing of disrupted plasma membranes. It has been previously demonstrated that repeated membrane disruptions reseal more quickly than the initial wound and that this facilitated response requires the transcription factor cAMP-response element-binding protein (CREB). This study examines the signaling pathway between membrane disruption and CREB-dependent gene expression in 3T3 fibroblasts. A reporter gene assay using pCRE-d2EGFP revealed that membrane disruption induced CRE-mediated transcription. Immunofluorescence observations suggested that membrane disruption activated CREB, p38 mitogen-activated protein kinase (p38 MAPK), and MAPK kinase3/6, the kinase responsible for activation of p38 MAPK. CREB phosphorylation upon membrane disruption was inhibited by a specific p38 MAPK inhibitor, SB203580. Both CRE-mediated transcription and long-term potentiation of membrane resealing and wound-induced exocytosis were suppressed when cells were wounded in the presence of either SB203580 or Go-6976, a specific protein kinase C (PKC) inhibitor. Furthermore, activation of MAPK kinase3/6 was impaired by PKC inhibition during membrane disruption. These results suggest that PKC mediates the stimulation of CREB-dependent gene expression through a p38 MAPK pathway upon membrane disruption.
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PMID:Long-term potentiation of wound-induced exocytosis and plasma membrane repair is dependent on cAMP-response element-mediated transcription via a protein kinase C- and p38 MAPK-dependent pathway. 1531 14

Protein kinase-mediated signaling cascades play a fundamental role in translating extracellular signals into cellular responses in CNS neurons. The mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) pathway participates in regulating diverse neuronal processes such as proliferation, differentiation, survival, synaptic efficacy, and long-term potentiation by inducing cAMP-response element (CRE)-mediated gene transcription. Central olfactory structures show plasticity throughout the lifespan, but the role of the MAPK/ERK pathway in odor-evoked activity has yet to be determined. Therefore, we examined the effect of odorant exposure and early postnatal deprivation on ERK activity. We found that odor stimulation induced ERK phosphorylation, that activation of the ERK pathway was decreased with early postnatal deprivation, and that ERK phosphorylation was subsequently increased by restoring stimulation. Further, locations of ERK activation in bulbar neurons after exposure to single odorants corresponded to odor-evoked activity patterns found with other measures of activity in the bulb. Finally, due to the cytoplasmic location of pERK, activated dendrites belonging to the primary excitatory output neurons of the bulb were observed following a single odor exposure. The results indicate that the MAPK/ERK pathway is activated by odorant stimulation and may play an important role in developmental sensory plasticity in the olfactory bulb.
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PMID:Experience-dependent activation of extracellular signal-related kinase (ERK) in the olfactory bulb. 1545 54

A cure for prostate cancer (CaP) will be possible only after a complete understanding of the mechanisms causing this disease to progress from androgen dependence to androgen independence. To carry on a careful characterization of the phenotypes of CaP cell lines before and after acquisition of androgen independence, we used two human CaP LNCaP sublines: LNCaP(nan), which is androgen dependent (AD), and LNCaP-HP, which is androgen independent (AI). In AD LNCaP(nan) cells, dihydrotestosterone (DHT) stimulated in an androgen receptor (AR)-dependent way a phosphorylation signaling pathway involving steroid receptor coactivator (Src)-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)-1/2-ERK-1/2-cAMP-response element binding-protein (CREB). Activation of this pathway was associated with increased [(3)H]thymidine incorporation and resistance to apoptosis. Use of dominant-negative forms of MEK-1/2 and CREB demonstrated in LNCaP(nan) cells that DHT induced [(3)H]thymidiine incorporation through a thus far unidentified molecule activated downstream of MEK-1/2, and antiapoptosis through phosphorylation of the transcription factor CREB. In contrast, in AI LNCaP-HP cells, the Src-MEK-1/2-ERK-1/2-CREB pathway was constitutively active. Because it was not further stimulated by addition of DHT, no increase of [(3)H]thymidine incorporation or apoptosis resistance was demonstrated in LNCaP-HP cells. Additional experiments showed that Src and the scaffold protein MNAR coimmunoprecipitated with AR, indicating a role for Src as an apical molecule in the Src-MEK-1/2-ERK-1/2-CREB pathway. Interestingly, differences between the two cell lines were that in LNCaP-HP cells presence of an AI phenotype and lack of response to DHT were associated with constitutive activation of the protein kinase Src and interaction among Src, AR, and MNAR. In contrast, in LNCaP(nan) cells, presence of an AD phenotype and ability to respond to DHT were associated with DHT-dependent activation of Src kinase activity and interaction among Src, AR, and MNAR. Intriguingly, in LNCaP(nan) cells, we found that transcription through the prototypical CREB-responsive promoter c-fos could be induced in a DHT-dependent way, and this action was inhibited by the AR antagonist Casodex and MEK-1 inhibitor PD98059. In contrast, transcription through the PSA P/E promoter, a prototypical AR-dependent promoter directly activated by agonist, was obliterated only by Casodex. Additional experiments with genital skin fibroblasts derived from patients with a variety of AR abnormalities indicated that nongenotropic AR signaling does not depend on an intact DNA-binding domain or on the ability of AR to translocate to the nucleus. The results suggest the following: (1) Constitutive activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is associated with the AI phenotype observed in LNCaP-HP cells. (2) Activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is DHT dependent in AD LNCaP(nan) cells. (3) DHT activation of this pathway is associated with induction of [(3)H]thymidine incorporation by a molecule activated downstream of MEK-1/2 and of antiapoptosis through activation of the transcription factor CREB in AD LNCaP(nan) cells. (4) AR regulates transcription either directly upon ligand binding and nuclear translocation or indirectly through kinase pathways leading to activation of downstream transcription factors. (5) Nuclear translocation and ability of the DNA-binding domain of AR to interact with DNA are not prerequisites for nongenotropic AR activity.
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PMID:Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. 1546 14

ATP and ADP activate functionally distinct G protein-coupled purinergic (P2Y) receptors. We determined the expression and function of adenine nucleotide-specific P2Y receptors on cord blood-derived human mast cells (hMCs). Human MCs expressed mRNA encoding the ADP-specific P2Y1, P2Y12, and P2Y13 receptors; the ATP/UTP-specific P2Y2 receptor; and the ATP-selective P2Y11 receptor. ADP (0.05-50 muM) induced calcium flux that was completely blocked by a P2Y1 receptor-selective antagonist and was not cross-desensitized by ATP. Low doses of ADP induced strong phosphorylation of ERK and p38 MAPKs; higher doses stimulated eicosanoid production and exocytosis. Although MAPK phosphorylation was blocked by a combination of P2Y1- and P2Y12-selective antagonists, neither interfered with secretion responses. Unexpectedly, both ADP and ATP inhibited the generation of TNF-alpha in response to the TLR2 ligand, peptidoglycan, and blocked the production of TNF-alpha, IL-8, and MIP-1beta in response to leukotriene D(4). These effects were mimicked by two ATP analogues, adenosine 5'-O-(3-thiotriphosphate) and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate (BzATP), but not by adenosine. ADP, ATP, adenosine 5'-O-(3-thiotriphosphate), and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate each induced cAMP accumulation, stimulated the phosphorylation of CREB, and up-regulated the expression of inducible cAMP early repressor, a CREB-dependent inhibitor of cytokine transcription. Human MCs thus express several ADP-selective P2Y receptors and at least one G(s)-coupled ADP/ATP receptor. Nucleotides could therefore contribute to MC-dependent microvascular leakage in atherosclerosis, tissue injury, and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs.
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PMID:Adenine nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor. 1558 81


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