[
Adv Biol Regul,
2014]
Diacylglycerol is a key regulator of cell physiology, controlling the membrane recruitment and activation of signaling molecules. Accordingly, diacylglycerol generation and metabolism are strictly controlled, allowing for localized regulation of its concentration. While the increased production of diacylglycerol upon receptor triggering is well recognized, the modulation of diacylglycerol metabolism by diacylglycerol kinases (DGKs) is less characterized. Some agonists induce DGK activation and recruitment to the plasma membrane, promoting diacylglycerol metabolism to phosphatidic acid. Conversely, several reports indicate that signaling pathways that selectively inhibits DGK isoforms can enhance cellular diacylglycerol levels and signal transduction. For example, the impairment of DGK activity by RhoA binding to the catalytic domain represents a conserved mechanism controlling diacylglycerol signaling from Caenorhabditis elegans motoneurons to mammalian hepatocytes. Similarly, DGK activity is inhibited in lymphocytes by TCR signaling, thus contributing to a rise in diacylglycerol concentration for downstream signaling. Finally, DGK activity is inhibited by ischemia-reperfusion-generated reactive oxygen species in airway endothelial cells, promoting diacylglycerol-mediated ion channel opening and edema. In those systems, DGKs provide a gatekeeper function by blunting diacylglycerol levels or possibly establishing permissive domains for diacylglycerol signaling. In this review, I discuss the possible general relevance of DGK inhibition to enhanced diacylglycerol signaling.
[
Biochem J,
2008]
DGKs (diacylglycerol kinases) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate DAG (diacylglycerol), catalysing its conversion into PA (phosphatidic acid). This reaction leads to attenuation of DAG levels in the cell membrane, regulating a host of intracellular signalling proteins that have evolved the ability to bind this lipid. The product of the DGK reaction, PA, is also linked to the regulation of diverse functions, including cell growth, membrane trafficking, differentiation and migration. In multicellular eukaryotes, DGKs provide a link between lipid metabolism and signalling. Genetic experiments in Caenorhabditis elegans, Drosophila melanogaster and mice have started to unveil the role of members of this protein family as modulators of receptor-dependent responses in processes such as synaptic transmission and photoreceptor transduction, as well as acquired and innate immune responses. Recent discoveries provide new insights into the complex mechanisms controlling DGK activation and their participation in receptor-regulated processes. After more than 50 years of intense research, the DGK pathway emerges as a key player in the regulation of cell responses, offering new possibilities of therapeutic intervention in human pathologies, including cancer, heart disease, diabetes, brain afflictions and immune dysfunctions.