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)

Recently, adipose triglyceride lipase (ATGL, also called desnutrin and calcium-independent phospholipase A2 [iPLA(2)] zeta) was isolated as a novel adipose-expressed triglyceride lipase which is downregulated in obesity and may contribute to obesity-associated metabolic disorders such as hyperlipidemia and insulin resistance. To clarify expression and regulation of this fat-derived lipase, ATGL mRNA was measured in 3T3-L1 adipocytes by quantitative real-time reverse transcription-polymerase chain reaction after treatment with isoproterenol, tumor necrosis factor (TNF) alpha, insulin, and growth hormone (GH) which have been shown to influence lipolysis and insulin sensitivity profoundly. Interestingly, treatment of adipocytes with 100 nM isoproterenol, 30 ng/ml TNF alpha, and 100 nM insulin for 16 h significantly decreased ATGL mRNA to 74%, 17%, and 49% of control levels, respectively. GH did not influence ATGL synthesis. The effect of isoproterenol, TNFalpha, and insulin on ATGL expression was time- and dose-dependent. Similarly, HSL mRNA was downregulated by the three hormones. Furthermore, signaling studies suggested that activation of Gs-protein-coupled pathways by forskolin and cholera toxin is sufficient to significantly downregulate ATGL mRNA. Moreover, p44/42 mitogen-activated protein kinase appears to partly mediate the negative effect of insulin but not TNFalpha on ATGL. Taken together, downregulation of ATGL by isoproterenol, TNFalpha, and insulin might contribute to dysregulated expression and function of this lipase in obesity, hyperlipidemia, and insulin resistance.
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PMID:Isoproterenol, TNFalpha, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. 1600 85

Our laboratory has recently reported that the enzyme phospholipase D2 (PLD2) exists as a ternary complex with PTP1b and the growth factor receptor bound protein 2 (Grb2). Here, we establish the mechanistic underpinnings of the PLD2/Grb2 association. We have identified residues Y(169) and Y(179) in the PLD2 protein as being essential for the Grb2 interaction. We present evidence indicating that Y(169) and Y(179) are located within two consensus sites in PLD2 that mediate an SH2 interaction with Grb2. This was demonstrated with an SH2-deficient GSTGrb2 R86K mutant that failed to pull-down PLD2 in vitro. In order to elucidate the functions of the two neighboring tyrosines, we created a new class of deletion and point mutants in PLD2. Phenylalanine replacement of Y(169) (PLD2 Y169F) or Y(179) (PLD2 Y179F) reduced Grb2 binding while simultaneous mutation completely abolished it. The role of the two binding sites on PLD2 was found to be functionally nonequivalent: Y(169) serves to modulate the activity of the enzyme, whereas Y(179) regulates total tyrosine phosphorylation of the protein. Interestingly, binding of Grb2 to PLD2 occurs irrespectively of lipase activity, since Grb2 binds to catalytically inactive PLD2 mutants. Finally, PLD2 residues Y(169) and Y(179) are necessary for the recruitment of Sos, but only overexpression of the PLD2 Y179F mutant resulted in increased Ras activity, p44/42(Erk) phosphorylation and enhanced DNA synthesis. Since Y(169) remains able to modulate enzyme activity and is capable of binding to Grb2 in the PLD2 Y179F mutant, we propose that Y(169) is kept under negative regulation by Y(179). When this is released, Y(169) mediates cellular proliferation through the Ras/MAPK pathway.
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PMID:The elucidation of novel SH2 binding sites on PLD2. 1640 27

The minimal adipose phenotype of hormone-sensitive lipase (HSL)-null mice suggested that other hormonally responsive lipase(s) were present in adipocytes. Recent studies have characterized a new adipose tissue triglyceride lipase, ATGL/PNPLA2/destnutrin/iPLA2zeta/TTS2.2 (ATGL). We had previously cloned a novel adipose-enriched transcript by differential screening and recently determined its identity with murine ATGL. We report here on the regulation of ATGL by TNF-alpha and insulin in 3T3-L1 adipocytes and identify ATGL as a target for transcriptional activation by the key adipogenic transcription factor PPARgamma. Insulin at 100 nM resulted in a marked decrease in ATGL transcript that was effectively blocked by inhibitors for PI 3-kinase and p70 ribosomal protein S6 kinase. TNF-alpha treatment decreased ATGL transcript in a time-dependent manner that paralleled TNF-alpha downregulation of PPARgamma with a maximal decrease noted by 6 h. TNF-alpha effects on ATGL were attenuated by pretreatment with PD-98059, LY-294002, or rapamycin, suggesting involvement of the p44/42 MAP kinase, PI 3-kinase, and p70 ribosomal protein S6 kinase signals. To study transcriptional regulation of ATGL, we cloned 2,979 bp of the murine ATGL 5'-flanking region. Compared with promoterless pGL2-Basic, the -2979/+21 ATGL luciferase construct demonstrated 120- and 40-fold increases in activity in white and brown adipocytes, respectively. Luciferase reporter activities for a series of eight ATGL promoter deletions revealed that the -928/+21, -1738/+21, -1979/+21, and -2979/+21 constructs were transactivated by PPARgamma. Our findings identify the novel lipase ATGL to be a target gene for TNF-alpha and insulin action in adipocytes and reveal that it is subject to transcriptional control by PPARgamma-mediated signals.
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PMID:The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma. 1670 60

Epstein-Barr virus (EBV) latent infection of B cells blocks the interrelated signaling and antigen-trafficking functions of the BCR through the activity of its latent membrane protein 2A (LMP2A). At present, the molecular mechanisms by which LMP2A exerts its control of BCR functions are only poorly understood. Earlier studies showed that in B cells expressing LMP2A containing a tyrosine mutation at position 112 in its cytoplasmic domain (Y112-LMP2A), the BCR could initiate signaling but could not properly traffic antigen for processing. Here, we show that BCR signaling in Y112-LMP2A-expressing cells is attenuated with a reduction in both the degree and duration of phosphorylation of key components of the BCR signaling cascade including Syk, BLNK, PI3K, and Btk. Notably, Y112-LMP2A expression completely blocked the BCR-induced activation of phospholipase D (PLD), a lipase implicated in the intracellular trafficking of a variety of surface receptors. We show that blocking PLD activity, by expressing Y112-LMP2A, treating cells with the PLD inhibitor 1-butanol or reducing PLD expression by siRNA, blocked BCR trafficking to class II-containing compartments. Moreover, Y112-LMP2A expression blocked the recruitment of phosphorylated forms of the downstream BCR signaling components, Erk and JNK, through both PLD-dependent and PLD-independent mechanisms. Thus, the investigation of the mechanism by which Y112-LMP2A blocks BCR function revealed an essential role for PLD in BCR trafficking for antigen processing.
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PMID:A mutation in Epstein-Barr virus LMP2A reveals a role for phospholipase D in B-Cell antigen receptor trafficking. 1688 41

Bacterial infection triggers an acute inflammatory response that might alter phospholipid metabolism. We have investigated the acute-phase response of murine lung epithelia to Pseudomonas aeruginosa infection. Ps. aeruginosa triggered secretion of the pro-inflammatory lipase, sPLA2 IB (phospholipase A2 IB), from lung epithelium. Ps. aeruginosa and sPLA2 IB each stimulated basolateral PtdCho (phosphatidylcholine) efflux in lung epithelial cells. Pre-treatment of cells with glyburide, an inhibitor of the lipid-export pump, ABCA1 (ATP-binding cassette transporter A1), attenuated Ps. aeruginosa and sPLA2 IB stimulation of PtdCho efflux. Effects of Ps. aeruginosa and sPLA2 IB were completely abolished in human Tangier disease fibroblasts, cells that harbour an ABCA1 genetic defect. Ps. aeruginosa and sPLA2 IB induced the heterodimeric receptors, PPARa (peroxisome-proliferator-activated receptor-a) and RXR (retinoid X receptor), factors known to modulate ABCA1 gene expression. Ps. aeruginosa and sPLA2 IB stimulation of PtdCho efflux was blocked with PD98059, a p44/42 kinase inhibitor. Transfection with MEK1 (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase 1), a kinase upstream of p44/42, increased PPARa and RXR expression co-ordinately with increased ABCA1 protein. These results suggest that pro-inflammatory effects of Ps. aeruginosa involve release of an sPLA2 of epithelial origin that, in part, via distinct signalling molecules, transactivates the ABCA1 gene, leading to export of phospholipid.
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PMID:Pseudomonas aeruginosa and sPLA2 IB stimulate ABCA1-mediated phospholipid efflux via ERK-activation of PPARalpha-RXR. 1722 97

The cholecystokine (CCK) analogue cerulein causes pathophysiological, morphological, and biochemical events similar to various aspects of human pancreatitis. Doses of CCK or cerulein beyond those that cause the maximum pancreatic secretion of amylase and lipase result in pancreatitis, which is characterized by a dysregulation of the digestive enzyme production and cytoplasmic vacuolization and the death of acinar cells, edema formation, and an infiltration of inflammatory cells into the pancreas. This study aims to investigate whether cerulein induces IL-8 expression in pancreatic acinar cells, and whether cerulein-induced IL-8 expression is inhibited in the cells transfected with mutant genes for c-jun (TAM-67), or IkappaBalpha (MAD-3) or treated inhibitors of mitogen-activated protein kinases (MAPKs). As a result, cerulein induced IL-expression, which was inhibited in the cells transfected with TAM-67 or MAD-3 or treated inhibitors of MAPK. In conclusion, activation of MAPK, nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1) may be the upstream signaling for cerulein-induced IL-8 expression in pancreatic acinar cells.
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PMID:Role of mitogen-activated protein kinases, NF-kappaB, and AP-1 on cerulein-induced IL-8 expression in pancreatic acinar cells. 1738 81

Fusarium graminearum is a ubiquitous pathogen of cereal crops, including wheat, barley, and maize. Diseases caused by F. graminearum are of particular concern because harvested grains frequently are contaminated with harmful mycotoxins such as deoxynivalenol (DON). In this study, we explored the role of Ras GTPases in pathogenesis. The genome of F. graminearum contains two putative Ras GTPase-encoding genes. The two genes (RAS1 and RAS2) showed different patterns of expression under different conditions of nutrient availability and in various mutant backgrounds. RAS2 was dispensable for survival but, when disrupted, caused a variety of morphological defects, including slower growth on solid media, delayed spore germination, and significant reductions in virulence on wheat heads and maize silks. Intracellular cAMP levels were not affected by deletion of RAS2 and exogenous treatment of the ras2 mutant with cAMP did not affect phenotypic abnormalities, thus indicating that RAS2 plays a minor or no role in cAMP signaling. However, phosphorylation of the mitogen-activated protein (MAP) kinase Gpmk1 and expression of a secreted lipase (FGL1) required for infection were reduced significantly in the ras2 mutant. Based on these observations, we hypothesize that RAS2 regulates growth and virulence in F. graminearum by regulating the Gpmk1 MAP kinase pathway.
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PMID:RAS2 regulates growth and pathogenesis in Fusarium graminearum. 1755 71

Src homology (SH) domains of phospholipase C-gamma1 (PLC-gamma1) impair NGF-mediated PC12 cells differentiation. However, whether the enzymatic activity is also implicated in this process remains elusive. Here, we report that the enzymatic activity of phospholipase C-gamma1 (PLC-gamma1) is at least partially involved to the blockage of neuronal differentiation via an abrogation of MAPK activation, as well as sustained Akt activation. By contrast, Overexpression of WT-PLC-gamma1 exhibited sustained NGF-induced MAPK activation, and triggered transient Akt activation resulting in profound inhibition of neurite outgrowth. However, lipase-inactive mutant (LIM) PLC-gamma1 cells fail to suppress neurite outgrowth, although it contains intact SH domains, specifically enhancing the expression of cyclin D1 and p21 proteins, which regulate the function of retinoblastoma Rb protein. These observations show that the lipase inactive mutant of PLC-gamma1 does not alter NGF-induced neuronal differentiation via enzymatic inability and the odulation of cell cycle regulatory proteins independent on SH3 domain.
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PMID:Lipase inactive mutant of PLC-gamma1 regulates NGF-induced neurite outgrowth via enzymatic activity and regulation of cell cycle regulatory proteins. 1804 83

Cadherin-11 is a cell-cell adhesion molecule whose expression is often correlated with cellular migratory phenomena. We recently demonstrated that cadherin-11 activation by immobilized cad11-Fc (cadherin-11 ectodomain fused to Fc fragment) promotes axonal extension of spinal cord explants. Here, we show that this induced neurite outgrowth is dependent on the FGF receptor (FGFR) activity. Downstream, DAG lipase/CAM kinase and PI3 kinase pathways are required, but not the MAP kinase signalling. We also demonstrate that a tagged form of FGFR1 co-immunoprecipitates with beta-catenin containing cadherin-11 immunocomplexes. FGFR1 and beta-catenin show colocalization and enhanced association during cadherin-11 engagement, suggesting that FGFR1 interaction with cadherin-11 adhesion complexes is reinforced during cell contact formation. In vitro pull-down experiments using recombinant ectodomains suggest that cadherin-11/FGFR interact directly through their extracellular domains. Altogether, we propose that cadherin-11 recruits the FGFR upon adhesive engagement at nascent contacts, triggering the activation of downstream pathways involved in growth cone progression.
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PMID:Cadherin-11 interacts with the FGF receptor and induces neurite outgrowth through associated downstream signalling. 1830 81

This study was conducted to test the effects of 2-arachidonylglycerol (2-AG), an endocannabinoid, on aqueous humor outflow facility, to study the cellular mechanisms of 2-AG, and to investigate the possible existence and activity of monoacylgylcerol lipase (MGL), a 2-AG metabolic enzyme, in the trabecular meshwork (TM). The effects of 2-AG on aqueous humor outflow facility were measured using an anterior segment perfused organ culture model. The expression and activity of MGL in TM tissues were assessed using Western blot analysis and an enzyme activity assay respectively. 2-AG induced activation of p42/44 mitogen-activated protein (MAP) kinase was determined by Western blot analysis using an anti-phospho p42/44 MAP kinase antibody. AlexaFluor 488-labeled phalloidin staining was used to examine actin filament in cultured TM cells. Administration of 10nM of 2-AG caused a transient enhancement of aqueous humor outflow. In the presence of 100nM of LY2183240, an inhibitor of MGL, the effect of 10nM of 2-AG on outflow was prolonged by at least 4h. The 2-AG-induced enhancement of outflow was blocked by SR141716A, a CB1 antagonist, and SR144528, a CB2 antagonist. In Western blot studies, a 35kDa band representing MGL was detected on TM tissues with an anti-MGL antibody. The 2-AG enzymatic hydrolysis activity was detected in TM tissues and this activity was reduced by 70.1+/-5.3% with the addition of 100 nM of LY2183240. Treatment of trabecular meshwork cells with 10nM of 2-AG plus 100 nM LY2183240 for 5h evoked phosphorylation of p42/44 MAP kinase. The 2-AG-induced enhancement of p42/44 MAP kinase phosphorylation was blocked by pretreatment with SR141716A, SR144528, as well as PD98059, an inhibitor of the p42/44 MAP kinase pathway. In addition, the outflow-enhancing effect of 2-AG was blocked by pretreatment with PD98059. Furthermore, treatment with 2-AG plus LY2183240 caused rounding of TM cells and a reduction of actin stress fibers in TM cells. Pretreatment with SR141716A, SR144528, and PD98059 blocked these 2-AG-induced morphology and cytoskeleton changes in TM cells. In conclusion, the results from this study demonstrate that administration of 2-AG increases aqueous humor outflow facility and this effect of 2-AG is mediated through both the CB1 and CB2 cannabinoid receptors. In addition, this study reveals the existence and the activity of MGL, a 2-AG metabolizing enzyme, in the TM tissues. Furthermore, this study suggests that 2-AG-induced enhancement of outflow facility involves the p42/44 MAP kinase signaling pathway and changes in actin cytoskeletons in TM cells.
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PMID:Aqueous humor outflow effects of 2-arachidonylglycerol. 1859 52


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