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

Abstract

The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the mammalian cells. Studies on the regulation of diacylglycerol and phosphatidic acid levels by various enzymes, the identification and characterization of various diacylglycerol and phosphatidic acid-regulated proteins, and the overlap of different diacylglycerol and phosphatidic acid metabolic and signaling processes have revealed the complex and non-redundant roles of diacylglycerol kinases in regulating multiple biochemical and biological networks. In this review article, we summarized recent progress in the complex and non-redundant roles of diacylglycerol kinases, which is expected to aid in restoring dysregulated biochemical and biological networks in various pathological conditions at the bed side.

Keywords: diacylglycerol; diacylglycerol kinase; lipid signaling; phosphatidic acid; tissue microenvironment; tumor microenvironment.

Figure 1

Structure of phosphoglycerolipid including diacylglycerol (DAG) and phosphatidic acid (PA). (A) The sites for phospholipase-mediated hydrolysis of phosphoglycerolipid are marked in letters. Structure of DAG is presented in a rounded red rectangle. (B) The head groups (Y) of selected phosphoglycerolipid classes are presented. Y is ethanolamine, choline, serine and inositol from top to bottom. O in red indicates hydroxyl group of phosphoglycerolipid where the inositol residue is bound. ATP, adenosine triphosphate; DGK, diacylglycerol kinase; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D. R₁ and R₂ are fatty acid residues.

Figure 2

The structures of DGKs. DGK isoforms are classified into five types. Gly/Pro, glycine/proline; PH, pleckstrin homology; RVH, recoverin homology domain; MARCKS, myristoylated alanine rich protein kinase C substrate phosphorylation site; SAM, sterile alpha motif.

Figure 3

Representative pathways involved in the metabolism of diacylglycerol (DAG) and phosphatidic acid (PA). The biosynthetic pathways of DAG and PA are shown in blue and orange, respectively. The key enzymes of the DAG and PA biosynthetic pathway are shown in blue and orange italics, respectively. The enzyme inhibitors are represented in green font. The pathways involved in the degradation of DAG and PA are shown in black font. AT, acyltransferase; DHAP, dihydroxyacetone-3-phosphate; G3P, glycerol-3-phosphate; LPA, lysophosphatidic acid; LPAAT, LPA acyl transferase; LPP, lipid phosphate phosphatase; NPC, non-specific phospholipase C; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PIK, phosphatidylinositol kinase; PLC, phospholipase C; PLD, phospholipase D.

Figure 4

Representative signaling pathways regulated by diacylglycerol kinases (DGKs) in the activated T cells. Our understanding about diacylglycerol (DAG)-mediated regulation of Ras-MEK-ERK and PKC-NF-κB is majorly based on T cell biology. Immunological synapse formation between T cell and cancer cell is shown as a representative model here. Signals originating from T cell receptor (TCR) engagement of peptide/MHC complex in the presence of co-stimulatory signal lead to the recruitment of adaptor molecules and degranulation, which promote the lysis of the target cells and secretion of IFNγ (T cell effector function). DGKs downregulate the levels of DAG, which activates the TCR distal signaling through Ras-ERK and NF-κB (green arrow). The biosynthesis of phosphatidic acid (PA) in the T cells is mediated by DGKs and phospholipase D (PLD) (not shown). PA is shown to activate Raf1 and mTORC1 in the immune and non-immune cells (dotted black arrow).