Disease relevance of DGKE

• A search for disease gene linkage revealed that a locus for autosomal dominant retinitis pigmentosa (adRP) known as RP17 resided in that region, and Northern blot analysis showed that hDGK epsilon was expressed in human retina [1].
• Here we show that exposure of various cell types to hypoxia raises the intracellular level of phosphatidic acid primarily through the action of diacylglycerol kinase (DGK) [2].
• DGK activity was increased in lysates of insect cells infected with recombinant baculovirus containing this cDNA [3].
• In order to clone novel diacylglycerol kinase (DGK) isozymes, we first obtained a DGK-related cDNA fragment by polymerase chain reaction using the human hepatoma cell line HepG2 mRNA and degenerated primers [4].
• A previously cloned full-length human 86 kDa DG kinase cDNA was expressed as fusion protein in Escherichia coli, to aid in the generation of DG-kinase-specific monoclonal antibodies suitable for immunoprecipitation experiments [5].

High impact information on DGKE

• Diacylglycerol kinase (DGK) plays a central role in the metabolism of diacylglycerol released as a second messenger in agonist-stimulated cells [6].
• Production of a novel calmodulin-binding DGK by alternative splicing [7].
• The nuclear transportation of DGKgamma didn't necessarily need DGK activity, but its C1 domain was indispensable, suggesting that the C1 domain of DGKgamma acts as a nuclear transport signal [8].
• Diacylglycerol kinase (DGK) plays an important role in signal transduction through modulating the balance between two signaling lipids, diacylglycerol and phosphatidic acid [9].
• Here we explored the contribution to this pathway of the enzyme diacylglycerol kinase (DGK), which produces PA through phosphorylation of diacylglycerol [10].

Chemical compound and disease context of DGKE

• D609 inhibits PA accumulation triggered by hypoxia, suggesting that DAG could act as substrate for its conversion into PA by DGK upon these conditions [11].
• We report that upon muscarinic stimulation of SK-N-BE(2) human neuroblastoma cells, the extent of phosphoinositide-derived diacylglycerol (DG) conversion to phosphatidic acid (PA), operated by a DG kinase, is dependent on the potency of receptor stimulation and correlates with the reduction of phosphatidylinositol 4,5-bisphosphate mass [12].

Biological context of DGKE

• Cytogenetic assignment and physical mapping of the human DGKE gene to chromosome 17q22 [13].
• The catalytic domain of DGK epsilon, which is related to other DGKs, contains two ATP-binding motifs [14].
• Direct sequencing following PCR amplification of two affected DNA samples from that type of adRP patients, however, did not reveal any mutation in hDGK epsilon exons [1].
• Gene expression for DGK isozymes was detected with variable regional distributions and intensities in the spinal cord [15].
• Thus, precise control of DGK activity is essential for proper signal transduction [16].

Anatomical context of DGKE

• Northern blotting demonstrated that DGK epsilon is expressed predominantly in testis [14].
• DGK kappa, when expressed in HEK293 cells, was persistently localized at the plasma membrane even in the absence of cell stimuli [9].
• These observations indicate that human platelet cytosol contains DGK isozymes with different enzymological properties [17].
• 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 [18].
• In contrast the truncated cDNA failed to give DGK activity in spite of the expression of its mRNA and enzyme protein in COS cells, thus demonstrating that the truncated DGK gamma is catalytically inactive [4].

Associations of DGKE with chemical compounds

• Human diacylglycerol kinase epsilon (hDGK epsilon) displays high selectivity for arachidonate-containing substrates and may be essential in the termination of signals transmitted through arachidonoyl-diacylglycerol and/or the synthesis of phospholipids with defined fatty acid composition [1].
• Diacylglycerol kinase (DGK) is suggested to attenuate diacylglycerol-induced cell responses through the phosphorylation of this second messenger to phosphatidic acid [19].
• These findings provide evidence that ceramide may serve as a competitive inhibitor of DG kinase [20].
• The DGK inhibitor, R59022, inhibited DGK-II and to a lesser extent DGK-III, but little affected DGK-I activity [17].
• Here, we investigated pRB binding to another lipid kinase in the phosphoinositide cycle, diacylglycerol kinase (DGK) that phosphorylates the second messenger diacylglycerol to yield phosphatidic acid [21].

Other interactions of DGKE

• Characterization of the human diacylglycerol kinase epsilon gene and its assessment as a candidate for inherited retinitis pigmentosa [1].
• The hDGK epsilon gene was then localized to one of the YAC clones containing a STS marker for the RP17 locus by YAC contig mapping [1].

Analytical, diagnostic and therapeutic context of DGKE

• We herein report the genomic structure, chromosomal mapping, and mutation screening of hDGK epsilon gene. hDGK epsilon gene contains at least 12 exons spanning approximately 30 kb of genomic sequence and was mapped to chromosome 17q22 by fluorescence in situ hybridization [1].
• In an effort to identify new intracellular transducers operative in ALK-positive malignancies, we have investigated the potential involvement of diacylglycerol kinase (DGK) [22].
• DG kinase was purified to homogeneity from human white blood cells, showing an Mr of 86 kDa as determined by SDS-PAGE and gel filtration [23].
• Incubation of DG-kinase with the catalytic subunit of PKA led to the phosphorylation of DG-kinase as revealed by autoradiography [24].
• After cell fractionation, ceramide levels judged not only by diacylglycerol kinase (DGK) assay but also by NHCER-2 were shown to increase in the microsomal and the nuclear fraction in apoptosis-sensitive cells, but not in apoptosis-resistant cells [25].

References