Diacylglycerol kinase ɛ regulates seizure susceptibility and long-term potentiation through arachidonoyl– inositol lipid signaling

Turco, Elena; Tang, Wen; Topham, Matthew K.; Sakane, Fumio; Marcheselli, Victor L.; Chen, Chu; Taketomi, Akinobu; Prescott, Stephen M.; Bazán, Nicolás G.

doi:10.1073/pnas.081536298

Cited by 152 publications

(168 citation statements)

References 40 publications

(55 reference statements)

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“…Rac GTPase-activating proteins) (15) and Ras guanyl nucleotide-releasing proteins (Ras-GRPs) (16 -18). Genetic evidence in Caenorhabditis elegans (19,20), Drosophila (21), and mice (22) support the hypothesis that DGK can act as a negative regulator of the PLC/PKC pathway. Alternatively or additionally, DGK may also initiate signal transduction pathways through the generation of PA, a potential second messenger that can activate phosphatidylinositol-4-phosphate kinase (23,24), Raf-1 kinase (25), atypical PKC (26), and mTOR (27), although it is not always clear whether the PA in these pathways is generated by DGK or phospholipase D.…”

mentioning

confidence: 63%

Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

Baal

Widt

Divecha

et al. 2005

Journal of Biological Chemistry

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Diacylglycerol kinase (DGK) phosphorylates the second messenger diacylglycerol (DAG) to phosphatidic acid. We previously identified DGK as one of nine mammalian DGK isoforms and reported on its regulation by interaction with RhoA and by translocation to the plasma membrane in response to noradrenaline. Here, we have investigated how the localization of DGK, fused to green fluorescent protein, is controlled upon activation of G protein-coupled receptors in A431 cells. Extracellular ATP, bradykinin, or thrombin induced DGK translocation from the cytoplasm to the plasma membrane within 2-6 min. This translocation, independent of DGK activity, was preceded by protein kinase C (PKC) translocation and was blocked by PKC inhibitors. Conversely, activation of PKC by 12-O-tetradecanoylphorbol-13-acetate induced DGK translocation. Membrane-permeable DAG (dioctanoylglycerol) also induced DGK translocation but in a PKC (staurosporin)-independent fashion. Mutations in the cysteinerich domains of DGK abrogated its hormone-and DAGinduced translocation, suggesting that these domains are essential for DAG binding and DGK recruitment to the membrane. We show that DGK interacts selectively with and is phosphorylated by PKC⑀ and -and that peptide agonist-induced selective activation of PKC⑀ directly leads to DGK translocation. Our data are consistent with the concept that hormone-induced PKC activation regulates the intracellular localization of DGK, which may be important in the negative regulation of PKC⑀ and/or PKC activity.

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confidence: 63%

Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

Baal

Widt

Divecha

et al. 2005

Journal of Biological Chemistry

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“…2c, inset), which is also regulated by physiological stimuli, generates the second messengers inositol polyphosphate 3 (which releases Ca 2+ from the endoplasmic reticulum), and 1,2-DAG, (which activates protein kinase C, protein kinase D and other effector proteins) 27,28 . In addition to acting as a second messenger molecule, 1,2-DAG is also the starting point for two important biochemical transformations: DAG-kinases catalyse the phosphorylation of 1,2-DAG to phosphatidic acid (an intracellular messenger and phospholipid precursor) 29 , whereas DAG-lipases cleave 1,2-DAG to yield monoacylglycerol 30,31 , which is further hydrolysed by 2-acyl-sn-glycerol lipases to produce fatty acid and glycerol 32 (fIG. 4).…”

Section: Liposomementioning

confidence: 99%

A neuroscientist's guide to lipidomics

2007

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| Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses.

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“…A DGK gene ( Fig. 1) in the phage-targeting vector MDASHII-2TK (Kirk Thomas, University of Utah) was electroporated into R1 ES cells, which were then isolated by positive-negative selection (24). To screen ES cell lines for homologous recombination, DNA was digested with EcoRI and probed by using a DGK -specific probe external to the targeting vector sequence.…”

Section: Methodsmentioning

confidence: 99%

Diacylglycerol kinase ι regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling

Regier

Higbee

Lund

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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To study the physiological function of diacylglycerol (DAG) kinase (DGK ), which converts DAG to phosphatidic acid, we deleted this gene in mice. In contrast to previous studies showing that DGK isoforms decrease Ras activity, signaling downstream of Ras in embryonic fibroblasts was significantly reduced in cells lacking DGK . DGKs regulate Ras signaling by attenuating the function of the DAG-dependent Ras guanyl nucleotide-releasing proteins (RasGRPs). We tested whether DGK inhibited the four known RasGRPs and found that it inhibited only RasGRP3. In addition to activating Ras, RasGRP3 also activates Rap1, which in some cases can antagonize the function of Ras. We demonstrate that DGK bound to RasGRP3 and inhibited its activation of Rap1 by metabolizing DAG. This inhibition consequently affected Ras signaling. We tested the physiological consequence of deleting DGK by crossing wild-type or DGK -deficient mice with mice carrying a v-Ha-Ras transgene, and then we assessed tumor formation. We observed significantly fewer tumors in DGK -deficient mice. Because Rap1 can antagonize the function of Ras, our data are consistent with a model in which DGK regulates RasGRP3 with a predominant effect on Rap1 activity. Additionally, we found that DGK , which is structurally similar to DGK , inhibited RasGRPs 1, 3, and 4 and predominantly affected Ras signaling. Thus, type IV DGKs regulate RasGRPs, but the downstream effects differ depending on the DGK. D iacylglycerol (DAG) is a potent activator of several signaling proteins, many of which, when abnormally active, can contribute to the initiation or promotion of cancer (1, 2). Several enzymes can metabolize signaling DAG, but the major route is thought to be by its phosphorylation, a reaction that produces phosphatidic acid and is catalyzed by the DAG kinases (DGKs) (reviewed in ref. 2). DAG exerts its effects by activating classical and novel protein kinase C isoforms, as well as other proteins including the Ras guanyl nucleotide-releasing proteins (RasGRPs) (reviewed in refs. 3-5). Although the transforming effects of DAG have been attributed to activation of PKCs, identification of the RasGRP family suggested that DAG could also transform cells by directly activating RasGRPs, which in turn could lead to excess Ras signaling. The four known RasGRP proteins are RasGRP1 [calcium DAG guanine exchange factor II (CalDAG-GEFII)], RasGRP2 (CalDAG-GEFI), RasGRP3 (CalDAG-GEFIII), and RasGRP4 (reviewed in ref. 5). Each RasGRP activates either Ras or Rap1, except RasGRP3, which is unique because it facilitates exchange for both .Activating mutations in Ras are found in a number of tumors (reviewed in ref. 11). Using a mouse model, Chin et al. (12) showed that Ras expression was an absolute requirement for melanoma tumor maintenance, and other studies have demonstrated a role for Ras in metastasis (reviewed in ref. 13). Together, these data clearly show that abnormally active Ras contributes to the maintenance and progression of many types of cancer.Rap1-dependent signaling is not a...

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Diacylglycerol kinase ɛ regulates seizure susceptibility and long-term potentiation through arachidonoyl– inositol lipid signaling

Cited by 152 publications

References 40 publications

Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

A neuroscientist's guide to lipidomics

Diacylglycerol kinase ι regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling

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