Diacylglycerol Kinase Malfunction in Human Disease and the Search for Specific Inhibitors

Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling

“…The analysis of epigenetic silencing revealed that the methylation of the DGKγ promoter is positively correlated with KRAS and BRAF mutations and that the methylation is frequently observed in colorectal adenomas, which suggested the significance of methylation in early colorectal tumorigenesis [181]. Consistent with this finding, the downregulated expression of DGKα synergizes with oncogenic mutations of p53 and Ras genes to promote transformation [16,[176][177][178].…”

“…DGK deficiency is directly or indirectly involved in human diseases, such as cancer, atypical hemolytic uremic syndrome, hypospadias (DGKκ) [170], diabetes, and mood and cognitive disorders, including Parkinson's disease and fragile X syndrome, a primary cause of autism and inherited cognitive disorder [168]. Currently, the closest association between the loss-of-function mutation and human disease appears to be observed from DGKε [16]. Recessive mutations of DGKε are associated with atypical hemolytic uremic syndrome, a disease characterized by renal vascular endothelial injury due to diminished poly-unsaturated fatty acids, which are required for prostanoid synthesis [171,172].…”

“…The upregulated DGKα expression is required for the growth and survival of highly metastatic cancer cells but not for those of non-transformed primary cells [75]. However, recent studies have also demonstrated the anti-tumoral effect of DGKα in different cancer types [16,[176][177][178]. Thus, DGKα appears to be both pro-and anti-tumoral depending on cancer cell-context.…”

“…Currently, 10 mammalian DGK isozymes have been identified (α [ 2 , 4 ], β [ 5 ], γ [ 6 , 7 ], δ [ 8 ], η [ 9 ], κ [ 10 ], ε [ 11 ], ζ [ 12 ], ι [ 13 ], and θ [ 14 ]). The activity of DGK is detected in various tissues and organisms (from Escherichia coli to mammals) [ 15 , 16 , 17 ]. The number of DGK isoforms varies from yeast (single enzyme) to mammals (10 isozymes, some with splicing variants) and the specialized activity of DGK increases with the complexity of organisms.…”

Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases

“…Diacylglycerol kinases (DGKs) are a family of ten PI metabolic kinases (α, β, γ, δ, ε, ζ, η, θ, ι, and κ) that participate in the PI cycle by catalyzing the phosphorylation of diacylglycerol (DAG) to generate phosphatidic acid (PA), hence, regulating these two-second messengers [9]. DAG and PA are involved in the regulation of several critical enzymes, including mammalian target of rapamycin (mTOR) [10], phosphatidylinositol-4-phosphate 5-kinase (PIP5K), the Ras GTPase-activating protein (GAP), rapidly accelerated fibrosarcoma-1 (Raf-1) kinase, protein kinases C (PKCs), mammalian uncoordinated 13 (Unc-13), Chimaerins (which activate Rac GTPase), and rat sarcoma virus guanyl nucleotide-releasing protein (RasGRP), which are involved in cell proliferation and migration [11,12].…”