Diacylglycerol kinase alpha, from negative modulation of T cell activation to control of cancer progression Isabel Me ´ rida * , Antonia Avila-Flores, Job Garcı ´a, Ernesto Merino, Marı ´a Almena, Pedro Torres-Ayuso Department of Immunology and Oncology, Centro Nacional de Biotecnologı ´a/CSIC, Darwin, 3, Campus de Cantoblanco, E-28049 Madrid, Spain Introduction The diacylglycerol kinases (DGK) are a family of signaling proteins that modulate diacylglycerol (DAG) levels by catalyzing its conversion to phosphatidic acid (PA) (Merida et al., 2008). DGK belong to a superfamily that also includes the recently identified bacterial DgkB as well as the sphingosine kinase (SPK) and ceramide kinase (CEK) families. Proteins in this superfamily share a common catalytic domain (DAGKc: Pfam00781) (Marchler-Bauer et al., 2007), that encompasses a number of highly conserved motifs. The recent resolution of the bacterial DgkB structure has provided important insights into the catalytic mechanism, showing that the essential elements that define the structure and catalytic properties of the bacterial DGKB are conserved in the mammalian enzymes (Miller et al., 2008). The most striking homology occurs in the ATP-binding loop, which represents the signature motif of this superfamily. Mammalian DGKs also contain the Asp residues that bridge an Mg 2þ molecule, that in DgkB is necessary for optimal catalysis (Miller et al., 2008). 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 (Shindo et al., 2003), lack the key residues that define a canonical phorbol ester/DAG-binding C1 domain (Hurley and Misra, 2000). Mammalian cells express ten DGK isoforms grouped into five subtypes; each DGK subtype has distinct regulatory motifs that Abbreviations: Diacylglycerol kinase, DGK; Sphingosine kinase, SPK; Ceramide kinase, CERK; Vascular endo- thelial growth factor, VEGF; Hepatocyte growth factor, HGF; Epidermal growth factor, EGF; Protein kinase C, PKC; Protein kinase D, PKD; Peroxisome proliferator-activated receptor-g, PPARg; Nitric oxide, NO; Ras guanyl nucleotide-releasing protein, RasGRP1; T cell receptor, TCR; Mammalian target of rapamycin, mTOR; Phospha- tidylinositol 3 kinase, PI3K; Hypoxia-inducible factor type 1a, HIF-1a; Anaplastic large cell lymphoma, ALCL; Nucleophosmin–anaplastic lymphoma kinase, NPM–ALK. * Corresponding author. Tel.: þ34 91 5854702; fax: þ34 91 3720493. E-mail address: imerida@cnb.csic.es (I. Me ´ rida). Contents lists available at ScienceDirect Advances in Enzyme Regulation journal homepage: www.elsevier.com/locate/ advenzreg 0065-2571/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.advenzreg.2009.01.003 Advances in Enzyme Regulation 49 (2009) 174–188