Diacylglycerol kinase alpha (DGKA) (DGKA)

Diacylglycerol kinase alpha (DGKα) is an intracellular enzyme that regulates the levels of the second messenger diacylglycerol (DAG) by phosphorylating it into phosphatidic acid (PA) (UniProt: P23743). In the context of immunology, DGKα is a key negative regulator of T-cell receptor (TCR) signaling; its activity leads to the depletion of DAG, which is essential for activating the RasGRP1/Ras/ERK pathway and protein kinase C (PKC) signaling (PubMed: 27103559). High expression or overactivity of DGKα is associated with T-cell anergy and exhaustion, a state often found in the tumor microenvironment that allows cancer cells to evade the immune system (PubMed: 24035149). Therapeutic strategies targeting DGKα, including small molecule inhibitors and potentially mRNA-targeting approaches, aim to restore T-cell function and enhance the body's anti-tumor response. Clinical candidates such as BMS-986408 and ASP1570 are currently being evaluated for their ability to potentiate immune responses in patients with solid tumors (ClinicalTrials.gov: NCT04136756, NCT04416087). By maintaining DAG levels, these therapies aim to reinvigorate exhausted T-cells and overcome resistance to existing immunotherapies.

Other names

DGK-alphaDAGK180 kDa diacylglycerol kinaseDiacylglycerol kinase alpha 80kDaDiglyceride kinase alpha

Inhibition of the enzymatic conversion of diacylglycerol to phosphatidic acid to sustain diacylglycerol-mediated signaling in T-cells.