DGKA gene is highly expressed in thymus, spleen, testis and lung (Sanjuan et al., 2001). DGKA displays alternative splicing; numerous splice variants are predicted, including truncated forms of the protein as well as RNAs with introns retained (Martínez-Moreno et al., 2012). The expression of some of these transcripts might be related to certain pathologies (Batista et al., 2013).

The DGKA gene encodes a protein of 80 KDa. Presence of regulatory regions in the gene was early suggested to restrain the expression of DGKA to certain tissues (Fujikawa et al., 1993). DGKA gene displays alternative use of promoter regions, in homology with the mouse gene at least two alternative promoters likely exist. The regulatory gene region contain several binding motifs for transcription factors including FoxO, p53, Egr, Smad, etc, which allow the coupling of DGKA expression with several signaling pathways. Identification of DGKA as a gene regulated by FoxO has contributed to explain its transcriptional downregulation in response to antigen stimulation and interleukin 2 (IL2) (Martinez-Moreno et al., 2012).

The protein encoded by the DGKA gene (2.7.1.107) belongs to the eukaryotic diacylglycerol kinase family. It attenuates the second messenger diacylglycerol, that activates C1-containing proteins like members of the classical and novel PKCs, PKD, RasGRP and chimaerin families. It also produces phosphatidic acid, another lipid mediator that participates in the resynthesis of phosphatidylinositols and activates different proteins like mTOR or atypical PKCs.

-The diacylglycerol kinases (DGK) are a family of signaling proteins that modulate diacylglycerol levels by catalyzing its conversion to phosphatidic acid (Merida et al., 2008). DGK belongs to a superfamily that also includes the recently identified bacterial DgkB as well as the sphingosine kinase (SPK) and ceramide kinase (CERK) families. Proteins in this superfamily share a common catalytic domain (DAGKc: Pfam00781).
-In addition to the catalytic region, all DGK family members have at least two protein kinase C-like type 1 (C1) domains that, except for the first C1 domain in DGKB and DGKG, lack the key residues that define a canonical phorbol ester/DAG-binding C1 domain (Shindo et al., 2003).
- Mammals express ten DGK isoforms grouped into five subtypes; each DGK subtype has distinct regulatory motifs that suggest the existence of diverse regulatory mechanisms and/or participation in different signaling complexes.
- Diacylglycerol Kinase alpha (DGKA) together with the beta (DGKB) and gamma (DGKG) isoforms represent the type I DGK, whose signature is the presence at the N-terminal region of a recoverin-like domain (RVH) and a tandem of EF hand motifs, characteristic of Ca²⁺-binding proteins.

- DGKA is the only DGK isoform particularly enriched in the thymus and peripheral T lymphocytes. DGKA levels are tightly coupled to the differentiation and proliferation state of T lymphocytes. Quiescent, naïve T lymphocytes express high levels of DGKA that decrease rapidly in response to antigenic and IL2-derived signals (Martinez-Moreno et al., 2012). DGKA was identified as an anergy-induced gene (Macian et al., 2002). Anergy represents an unresponsive state in T cells that is vital in immune system homeostasis and constitutes a means for avoiding response to self and thus, for preventing autoimmunity. Tumors also induce anergic-non responsive states in T cells. In agreement with this finding, DGKA-overexpressing lymphocytes are "anergic" and no longer respond to antigenic stimuli (Zha et al., 2006). On the contrary, T cells from DGKA deficient mice are resistant to anergy induction (Olenchock et al., 2006).
- Recent studies have characterized miR-297 as a highly cytotoxic microRNA expressed in glioblastoma, with minimal cytotoxicity to normal astrocytes. DGKA is shown to be a miR-297 target with a critical role in miR-297 toxicity. These studies identify miR-297 as a novel and physiologic regulator of cancer cell survival, largely through targeting of DGKA (Kefas et al., 2013).

- DGKA is a cytosolic enzyme that translocates to the membrane to phosphorylate diacylglycerol. The N-terminal region of DGKA, encompassing the Ca²⁺ regulatory elements has a negative regulatory role in enzyme activation and receptor-induced membrane localization, as shown by enhanced activity and constitutive plasma membrane localization of a mutant lacking this region (Sanjuan et al., 2001). In addition to Ca²⁺ generation, activation of Tyr kinases is required for membrane stabilization of DGKA (Sanjuan et al., 2001). Tyr335 in the human sequence, located at the hinge between the C1 and the catalytic domains, was recently identified as an Lck-dependent DGKA phosphorylation site in T lymphocytes (Merino et al., 2008).
- Membrane localization of DGKA in non-T cells requires Src-family tyrosine kinase activity and involves the association of DGKA with Src via a proline-rich sequence (Baldanzi et al., 2008). DGKA membrane localization and activation is required for cell motility, proliferation and angiogenesis, acting as a rheostat that sets the thresholds required for growth factor-induced migratory signals.
- Recent reports have suggested nuclear localization for DGKA following serum starvation and demonstrated that DGKA relocates back to the cytosol in response to serum re-addition. Serum-induced export requires c-Abl mediated Tyr-218 phosphorylation (Matsubara et al., 2012).

- The best characterized function for DGKA as a negative modulator of diacylglycerol-based signaling has been demonstrated in T lymphocytes. DGKA acts as a "switch-off" signal for Ras activation, mediated by localization to the membrane of Ras-GRP1 a GDP-exchanger for Ras with a DAG-binding domain (Sanjuan et al., 2001; Sanjuan et al., 2003).
- Contrary to its negative contribution to T cell responses, high DGKA expression in tumors appears to have a positive role in neoplastic transformation. DGKA-dependent PA generation contributes to melanoma survival through activation of the NFKB pathway (Yanagisawa et al., 2007).
- DGKA mediated PA generation has been reported to participate in tumor migration and invasion. Generation of PA downstream of DGKA is essential to facilitate the Rab coupling protein (RCP)- mediated integrin recycling that is required for tumor cell invasion (Rainiero et al., 2012).

V379I mutation in DGKA identified as a putative driver mutation for pancreatic cancer.