Diacylglycerol Kinases as Emerging Potential Drug Targets for a Variety of Diseases

Fumio      Sakane; Shin-ichi      Imai; Masahiro      Kai; Satoshi      Yasuda; Hideo      Kanoh

Abstract

Diacylglycerol (DAG) kinase (DGK) modulates the balance between the two signaling lipids, DAG and phosphatidic acid (PA), by phosphorylating (consuming) DAG to yield PA. Ten mammalian DGK isozymes have been identified to date. In addition to two or three cysteine-rich C1 domains (protein kinase C-like zinc finger structures) commonly conserved in all DGKs, these isoforms possess a variety of regulatory domains of known and/or predicted functions, such as a pair of EF-hand motifs, a pleckstrin homology domain, a sterile α motif domain, a MARCKS (myristoylated alaninerich C kinase substrate) phosphorylation site domain and ankyrin repeats. Recent studies have revealed that DGK isozymes play pivotal roles in a wide variety of mammalian signal transduction pathways conducting growth factor/ cytokine-dependent cell proliferation and motility, seizure activity, immune responses, cardiovascular responses and insulin receptor-mediated glucose metabolism. It is suggested that several DGK isozymes can serve as potential drug targets for cancer, epilepsy, autoimmunity, cardiac hypertrophy, hypertension and type II diabetes. Unfortunately, there are no DGK isozyme-specific inhibitors/activators at present. Development of these compounds is eagerly awaited for the development of novel drugs targeting DGKs.

Keywords: Protein kinase C, guanyl nucleotide-releasing protein, GTPase-activating protein, target of rapamycin, phosphatidylinositol- 4-phosphate 5-kinase, R59949, sphingosine, calcium