Mammalian Diacylglycerol Kinases, a Family of Lipid Kinases with Signaling Functions

Topham, Matthew K.; Prescott, Stephen M.

doi:10.1074/jbc.274.17.11447

Cited by 273 publications

(308 citation statements)

References 84 publications

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“…Standard phosphorylation assays were performed (10 min; 37°C) in a final volume of 50 l. The reaction was terminated by adding 100 l of 1 M HCl, and lipids were extracted with 20 l of CHCl 3 /MeOH (1:1, v/v). Organic layers were recovered, dried, dissolved in 20 l of CHCl 3 , and applied to silica gel TLC plates with dioleoyl-PA as a standard. Plates were developed with a CHCl 3 /MeOH/4 M NH 4 OH solvent system (9:7:2, v/v/v).…”

Section: Dgk Assaymentioning

confidence: 99%

“…By catalyzing a reaction in which both substrate and product are signaling molecules, DGKs can control the intensity and duration of intracellular events. Cumulative evidence suggests a central role for this enzyme family as mediators of various cellular responses, an idea strengthened by the presence in mammals of nine DGK isozymes, which represent a highly conserved gene family (3). A conserved C-terminal region and at least two cysteine-rich motifs (CRM) are characteristic of all family members.…”

mentioning

confidence: 99%

“…T he bioactive lipids diacylglycerol (DAG) 3 and phosphatidic acid (PA), pivotal in signal transduction after receptor stimulation, are implicated in many cellular responses including cell proliferation, differentiation, and apoptosis. Receptor-mediated phospholipase C (PLC) activation catalyzes the transient generation of DAG, which binds and activates several signaling proteins (1).…”

mentioning

confidence: 99%

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T Cell Activation In Vivo Targets Diacylglycerol Kinase α to the Membrane: A Novel Mechanism for Ras Attenuation

Sanjuán

Pradet‐Balade

Jones

et al. 2003

The Journal of Immunology

110

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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol to produce phosphatidic acid, leading to decreased and increased levels, respectively, of these two lipid messengers that play a central role in T cell activation. Nine DGK isoforms, grouped into five subtypes, are found in higher organisms; all contain a conserved C-terminal domain and at least two cysteine-rich motifs of unknown function. In this study, we have researched in vivo the regulation of DGKα, using a transgenic mouse model in which injection of an antigenic peptide activates the majority of peripheral T cells. We demonstrate that DGKα, highly expressed in resting T lymphocytes, is subject to complex control at the mRNA and protein levels during in vivo T cell activation. Subcellular fractionation of T lymphocytes shortly after in vivo engagement of the TCR shows rapid translocation of cytosolic DGKα to the membrane fraction. At early time points, DGKα translocation to the membrane correlates with rapid translocation of Ras guanyl nucleotide-releasing protein (RasGRP), a nucleotide exchange activator for Ras that associates to the membrane through a diacylglycerol-binding domain. To demonstrate a causal relationship between DGKα activity and RasGRP relocation to the membrane, we determined RasGRP translocation kinetics in a T cell line transiently transfected with constitutive active and dominant-negative DGKα mutants. We show that membrane localization of DGKα is associated with a negative regulatory signal for Ras activation by reversing RasGRP translocation. This study is the first demonstration of in vivo regulation of DGKα, and provides new insight into the functional role of a member of this family of lipid kinases in the regulation of the immune response.

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Section: Dgk Assaymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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T Cell Activation In Vivo Targets Diacylglycerol Kinase α to the Membrane: A Novel Mechanism for Ras Attenuation

Sanjuán

Pradet‐Balade

Jones

et al. 2003

The Journal of Immunology

110

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“…Thus cross-talk between G q PLC-β signaling and PLD exists. Cellular compartmentalization of DGK (45) and PLD (46) suggests that agonist stimulated increases in PA levels may be localized.…”

Section: Phosphatidic Acidmentioning

confidence: 99%

“…PA is formed from DAG generated in response to activation of PIP 2 -PLC activity. The diacylglycerol kinase (DGK) family of kinases mediate phosphorylation of DAG to PA (45). PA is also synthesized by phospholipase D (PLD).…”

Section: Phosphatidic Acidmentioning

confidence: 99%