Skip to main content
SpringerLink
Log in

Diacylglycerol Kinase Malfunction in Human Disease and the Search for Specific Inhibitors

  • Chapter
  • First Online:
Lipid Signaling in Human Diseases

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 259))

Abstract

The diacylglycerol kinases (DGKs) are master regulator kinases that control the switch from diacylglycerol (DAG) to phosphatidic acid (PA), two lipids with important structural and signaling properties. Mammalian DGKs distribute into five subfamilies that regulate local availability of DAG and PA pools in a tissue- and subcellular-restricted manner. Pharmacological manipulation of DGK activity holds great promise, given the critical contribution of specific DGK subtypes to the control of membrane structure, signaling complexes, and cell-cell communication. The latest advances in the DGK field have unveiled the differential contribution of selected isoforms to human disease. Defects in the expression/activity of individual DGK isoforms contribute substantially to cognitive impairment, mental disorders, insulin resistance, and vascular pathologies. Abnormal DGK overexpression, on the other hand, confers the acquisition of malignant traits including invasion, chemotherapy resistance, and inhibition of immune attack on tumors. Translation of these findings into therapeutic approaches will require development of methods to pharmacologically modulate DGK functions. In particular, inhibitors that target the DGKα isoform hold particular promise in the fight against cancer, on their own or in combination with immune-targeting therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abdul Razak AR, Mau-Soerensen M, Gabrail NY, Gerecitano JF, Shields AF, Unger TJ, Saint-Martin JR, Carlson R, Landesman Y, McCauley D et al (2016) First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors. J Clin Oncol 34:4142–4150

    CAS  PubMed  PubMed Central  Google Scholar 

  • Almena M, Merida I (2011) Shaping up the membrane: diacylglycerol coordinates spatial orientation of signaling. Trends Biochem Sci 36:593–603

    CAS  PubMed  Google Scholar 

  • Alonso R, Mazzeo C, Rodriguez MC, Marsh M, Fraile-Ramos A, Calvo V, Avila-Flores A, Merida I, Izquierdo M (2011) Diacylglycerol kinase alpha regulates the formation and polarisation of mature multivesicular bodies involved in the secretion of Fas ligand-containing exosomes in T lymphocytes. Cell Death Differ 18:1161–1173

    CAS  PubMed  PubMed Central  Google Scholar 

  • Andrada E, Liebana R, Merida I (2017) Diacylglycerol kinase zeta limits cytokine-dependent expansion of CD8(+) T cells with broad antitumor capacity. EBioMedicine 19:39–48

    PubMed  PubMed Central  Google Scholar 

  • Antal CE, Hudson AM, Kang E, Zanca C, Wirth C, Stephenson NL, Trotter EW, Gallegos LL, Miller CJ, Furnari FB et al (2015) Cancer-associated protein kinase C mutations reveal kinase’s role as tumor suppressor. Cell 160:489–502

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arias-Romero LE, Saha S, Villamar-Cruz O, Yip SC, Ethier SP, Zhang ZY, Chernoff J (2009) Activation of Src by protein tyrosine phosphatase 1B is required for ErbB2 transformation of human breast epithelial cells. Cancer Res 69:4582–4588

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arranz-Nicolás J, Ogando J, Soutar D, Arcos-Pérez R, Meraviglia-Crivelli D, Mañes S, Mérida I, Ávila-Flores A (2018) Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals. Cancer Immunol Immunother 67:965–980

    PubMed  Google Scholar 

  • Azukaitis K, Simkova E, Majid MA, Galiano M, Benz K, Amann K, Bockmeyer C, Gajjar R, Meyers KE, Cheong HI et al (2017) The phenotypic spectrum of nephropathies associated with mutations in diacylglycerol kinase epsilon. J Am Soc Nephrol 28:3066–3075

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bacchiocchi R, Baldanzi G, Carbonari D, Capomagi C, Colombo E, van Blitterswijk WJ, Graziani A, Fazioli F (2005) Activation of alpha-diacylglycerol kinase is critical for the mitogenic properties of anaplastic lymphoma kinase. Blood 106:2175–2182

    CAS  PubMed  Google Scholar 

  • Baldanzi G (2014) Inhibition of diacylglycerol kinases as a physiological way to promote diacylglycerol signaling. Adv Biol Regul 55:39–49

    CAS  PubMed  Google Scholar 

  • Baldanzi G, Mitola S, Cutrupi S, Filigheddu N, van Blitterswijk WJ, Sinigaglia F, Bussolino F, Graziani A (2004) Activation of diacylglycerol kinase alpha is required for VEGF-induced angiogenic signaling in vitro. Oncogene 23:4828–4838

    CAS  PubMed  Google Scholar 

  • Baldanzi G, Cutrupi S, Chianale F, Gnocchi V, Rainero E, Porporato P, Filigheddu N, van Blitterswijk WJ, Parolini O, Bussolino F et al (2008) Diacylglycerol kinase-alpha phosphorylation by Src on Y335 is required for activation, membrane recruitment and Hgf-induced cell motility. Oncogene 27:942–956

    CAS  PubMed  Google Scholar 

  • Batista EL Jr, Kantarci AI, Hasturk H, van Dyke TE (2014) Alternative splicing generates a diacylglycerol kinase alpha transcript that acts as a dominant-negative modulator of superoxide production in localized aggressive periodontitis. J Periodontol 85:934–943

    CAS  PubMed  Google Scholar 

  • Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, Schulze TG, Cichon S, Rietschel M, Nothen MM et al (2008) A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13:197–207

    CAS  PubMed  Google Scholar 

  • Benziane B, Borg ML, Tom RZ, Riedl I, Massart J, Bjornholm M, Gilbert M, Chibalin AV, Zierath JR (2017) DGKzeta deficiency protects against peripheral insulin resistance and improves energy metabolism. J Lipid Res 58:2324–2333

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berrar D, Sturgeon B, Bradbury I, Downes CS, Dubitzky W (2005) Survival trees for analyzing clinical outcome in lung adenocarcinomas based on gene expression profiles: identification of neogenin and diacylglycerol kinase alpha expression as critical factors. J Comput Biol 12:534–544

    CAS  PubMed  Google Scholar 

  • Bishop WR, Ganong BR, Bell RM (1986) Attenuation of sn-1,2-diacylglycerol second messengers by diacylglycerol kinase. Inhibition by diacylglycerol analogs in vitro and in human platelets. J Biol Chem 261:6993–7000

    CAS  PubMed  Google Scholar 

  • Boroda S, Niccum M, Raje V, Purow BW, Harris TE (2017) Dual activities of ritanserin and R59022 as DGKalpha inhibitors and serotonin receptor antagonists. Biochem Pharmacol 123:29–39

    CAS  PubMed  Google Scholar 

  • Butwicka A, Lichtenstein P, Landen M, Nordenvall AS, Nordenstrom A, Nordenskjold A, Frisen L (2015) Hypospadias and increased risk for neurodevelopmental disorders. J Child Psychol Psychiatry 56:155–161

    PubMed  Google Scholar 

  • Cai K, Mulatz K, Ard R, Nguyen T, Gee SH (2014) Increased diacylglycerol kinase zeta expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion. BMC Cancer 14:208

    PubMed  PubMed Central  Google Scholar 

  • Caricasole A, Bettini E, Sala C, Roncarati R, Kobayashi N, Caldara F, Goto K, Terstappen GC (2002) Molecular cloning and characterization of the human diacylglycerol kinase beta (DGKbeta) gene: alternative splicing generates DGKbeta isotypes with different properties. J Biol Chem 277:4790–4796

    CAS  PubMed  Google Scholar 

  • Carrasco S, Merida I (2007) Diacylglycerol, when simplicity becomes complex. Trends Biochem Sci 32:27–36

    CAS  PubMed  Google Scholar 

  • de Chaffoy de Courcelles DC, Roevens P, Van Belle H (1985) R 59 022, a diacylglycerol kinase inhibitor. Its effect on diacylglycerol and thrombin-induced C kinase activation in the intact platelet. J Biol Chem 260:15762–15770

    PubMed  Google Scholar 

  • de Chaffoy de Courcelles D, Roevens P, Van Belle H, Kennis L, Somers Y, de Clerck F (1989) The role of endogenously formed diacylglycerol in the propagation and termination of platelet activation. A biochemical and functional analysis using the novel diacylglycerol kinase inhibitor, R 59 949. J Biol Chem 264:3274–3285

    PubMed  Google Scholar 

  • Chauveau A, Le Floc’h A, Bantilan NS, Koretzky GA, Huse M (2014) Diacylglycerol kinase alpha establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse. Sci Signal 7:ra82

    PubMed  PubMed Central  Google Scholar 

  • Chen SS, Hu Z, Zhong XP (2016) Diacylglycerol kinases in T cell tolerance and effector function. Front Cell Dev Biol 4:130

    PubMed  PubMed Central  Google Scholar 

  • Chibalin AV, Leng Y, Vieira E, Krook A, Bjornholm M, Long YC, Kotova O, Zhong Z, Sakane F, Steiler T et al (2008) Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance. Cell 132:375–386

    CAS  PubMed  Google Scholar 

  • Cipres A, Carrasco S, Merida I (2001) Deletion of the acidic-rich domain of the IL-2Rbeta chain increases receptor-associated PI3K activity. FEBS Lett 500:99–104

    CAS  PubMed  Google Scholar 

  • Consonni SV, Gloerich M, Spanjaard E, Bos JL (2012) cAMP regulates DEP domain-mediated binding of the guanine nucleotide exchange factor Epac1 to phosphatidic acid at the plasma membrane. Proc Natl Acad Sci U S A 109:3814–3819

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Keizer PL (2017) The fountain of youth by targeting senescent cells? Trends Mol Med 23:6–17

    PubMed  Google Scholar 

  • Diao J, Wu C, Zhang J, Liu J, Zhang X, Hao P, Zhao S, Zhang Z (2016) Loss of diacylglycerol kinase-zeta inhibits cell proliferation and survival in human gliomas. Mol Neurobiol 53:5425–5435

    CAS  PubMed  Google Scholar 

  • Dominguez CL, Floyd DH, Xiao A, Mullins GR, Kefas BA, Xin W, Yacur MN, Abounader R, Lee JK, Wilson GM et al (2013) Diacylglycerol kinase alpha is a critical signaling node and novel therapeutic target in glioblastoma and other cancers. Cancer Discov 3:782–797

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dotti CG, Esteban JA, Ledesma MD (2014) Lipid dynamics at dendritic spines. Front Neuroanat 8:76

    PubMed  PubMed Central  Google Scholar 

  • Dustin ML, Choudhuri K (2016) Signaling and polarized communication across the T cell immunological synapse. Annu Rev Cell Dev Biol 32:303–325

    CAS  PubMed  Google Scholar 

  • Epand RM, So V, Jennings W, Khadka B, Gupta RS, Lemaire M (2016) Diacylglycerol kinase-epsilon: properties and biological roles. Front Cell Dev Biol 4:112

    PubMed  PubMed Central  Google Scholar 

  • Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294:1942–1945

    CAS  PubMed  Google Scholar 

  • Farren MR, Hennessey RC, Shakya R, Elnaggar O, Young G, Kendra K, Landesman Y, Elloul S, Crochiere M, Klebanov B et al (2017) The Exportin-1 inhibitor selinexor exerts superior antitumor activity when combined with T-cell checkpoint inhibitors. Mol Cancer Ther 16:417–427

    CAS  PubMed  PubMed Central  Google Scholar 

  • Filigheddu N, Cutrupi S, Porporato PE, Riboni F, Baldanzi G, Chianale F, Fortina E, Piantanida P, De Bortoli M, Vacca G et al (2007) Diacylglycerol kinase is required for HGF-induced invasiveness and anchorage-independent growth of MDA-MB-231 breast cancer cells. Anticancer Res 27:1489–1492

    CAS  PubMed  Google Scholar 

  • Forbes JM, Cooper ME (2013) Mechanisms of diabetic complications. Physiol Rev 93:137–188

    CAS  PubMed  Google Scholar 

  • Franks CE, Campbell ST, Purow BW, Harris TE, Hsu KL (2017) The ligand binding landscape of diacylglycerol kinases. Cell Chem Biol 24:870–880 e875

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fukunaga-Takenaka R, Shirai Y, Yagi K, Adachi N, Sakai N, Merino E, Merida I, Saito N (2005) Importance of chroman ring and tyrosine phosphorylation in the subtype-specific translocation and activation of diacylglycerol kinase alpha by D-alpha-tocopherol. Genes Cells 10:311–319

    CAS  PubMed  Google Scholar 

  • Garcon F, Patton DT, Emery JL, Hirsch E, Rottapel R, Sasaki T, Okkenhaug K (2008) CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 111:1464–1471

    CAS  PubMed  Google Scholar 

  • Griner EM, Kazanietz MG (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7:281–294

    CAS  PubMed  Google Scholar 

  • Guarino M (2010) Src signaling in cancer invasion. J Cell Physiol 223:14–26

    CAS  PubMed  Google Scholar 

  • Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ (2017) Fragile X syndrome. Nat Rev Dis Primers 3:17065

    PubMed  Google Scholar 

  • Hansell NK, Halford GS, Andrews G, Shum DH, Harris SE, Davies G, Franic S, Christoforou A, Zietsch B, Painter J et al (2015) Genetic basis of a cognitive complexity metric. PLoS One 10:e0123886

    PubMed  PubMed Central  Google Scholar 

  • Hao X, Sun B, Hu L, Lahdesmaki H, Dunmire V, Feng Y, Zhang SW, Wang H, Wu C, Wang H et al (2004) Differential gene and protein expression in primary breast malignancies and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. Cancer 100:1110–1122

    CAS  PubMed  Google Scholar 

  • Harrison SC (2003) Variation on an Src-like theme. Cell 112:737–740

    CAS  PubMed  Google Scholar 

  • Hayashi D, Yagi K, Song C, Ueda S, Yamanoue M, Topham M, Suzaki T, Saito N, Emoto N, Shirai Y (2017) Diacylglycerol kinase alpha is involved in the vitamin E-induced amelioration of diabetic nephropathy in mice. Sci Rep 7:2597

    PubMed  PubMed Central  Google Scholar 

  • Hochgrafe F, Zhang L, O’Toole SA, Browne BC, Pinese M, Porta Cubas A, Lehrbach GM, Croucher DR, Rickwood D, Boulghourjian A et al (2010) Tyrosine phosphorylation profiling reveals the signaling network characteristics of basal breast cancer cells. Cancer Res 70:9391–9401

    PubMed  Google Scholar 

  • Hokin LE, Hokin MR (1959) Diglyceride phosphokinase: an enzyme which catalyzes the synthesis of phosphatidic acid. Biochim Biophys Acta 31:285–287

    CAS  PubMed  Google Scholar 

  • Hornsveld M, Dansen TB, Derksen PW, Burgering BMT (2017) Re-evaluating the role of FOXOs in cancer. Semin Cancer Biol 50:90–100

    PubMed  Google Scholar 

  • Hurley JH, Newton AC, Parker PJ, Blumberg PM, Nishizuka Y (1997) Taxonomy and function of C1 protein kinase C homology domains. Protein Sci 6:477–480

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ishisaka M, Hara H (2014) The roles of diacylglycerol kinases in the central nervous system: review of genetic studies in mice. J Pharmacol Sci 124:336–343

    CAS  PubMed  Google Scholar 

  • Iwazaki K, Tanaka T, Hozumi Y, Okada M, Tsuchiya R, Iseki K, Topham MK, Kawamae K, Takagi M, Goto K (2017) DGKzeta downregulation enhances osteoclast differentiation and bone resorption activity under inflammatory conditions. J Cell Physiol 232:617–624

    CAS  PubMed  Google Scholar 

  • Jiang Y, Sakane F, Kanoh H, Walsh JP (2000) Selectivity of the diacylglycerol kinase inhibitor 3-[2-(4-[bis-(4-fluorophenyl)methylene]-1-piperidinyl)ethyl]-2, 3-dihydro-2-thioxo-4(1H)quinazolinone (R59949) among diacylglycerol kinase subtypes. Biochem Pharmacol 59:763–772

    CAS  PubMed  Google Scholar 

  • Jiang LQ, de Castro Barbosa T, Massart J, Deshmukh AS, Lofgren L, Duque-Guimaraes DE, Ozilgen A, Osler ME, Chibalin AV, Zierath JR (2016) Diacylglycerol kinase-delta regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics. Am J Physiol Endocrinol Metab 310:E51–E60

    PubMed  Google Scholar 

  • Jing W, Gershan JA, Holzhauer S, Weber J, Palen K, McOlash L, Pulakanti K, Wesley E, Rao S, Johnson BD, Riese MJ (2017) T cells deficient in diacylglycerol kinase zeta are resistant to PD-1 inhibition and help create persistent host immunity to leukemia. Cancer Res 77:5676–5686

    CAS  PubMed  Google Scholar 

  • Kai M, Yamamoto E, Sato A, Yamano HO, Niinuma T, Kitajima H, Harada T, Aoki H, Maruyama R, Toyota M et al (2017) Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer. Mol Carcinog 56:1743–1752

    CAS  PubMed  Google Scholar 

  • Kakefuda K, Oyagi A, Ishisaka M, Tsuruma K, Shimazawa M, Yokota K, Shirai Y, Horie K, Saito N, Takeda J, Hara H (2010) Diacylglycerol kinase beta knockout mice exhibit lithium-sensitive behavioral abnormalities. PLoS One 5:e13447

    PubMed  PubMed Central  Google Scholar 

  • Kantarci A, Oyaizu K, van Dyke TE (2003) Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings from localized aggressive periodontitis. J Periodontol 74:66–75

    CAS  PubMed  Google Scholar 

  • Kazanietz MG (2002) Novel “nonkinase” phorbol ester receptors: the C1 domain connection. Mol Pharmacol 61:759–767

    CAS  PubMed  Google Scholar 

  • Kim K, Yang J, Zhong XP, Kim MH, Kim YS, Lee HW, Han S, Choi J, Han K, Seo J et al (2009) Synaptic removal of diacylglycerol by DGKzeta and PSD-95 regulates dendritic spine maintenance. EMBO J 28:1170–1179

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kong Y, Zheng Y, Jia Y, Li P, Wang Y (2016) Decreased LIPF expression is correlated with DGKA and predicts poor outcome of gastric cancer. Oncol Rep 36:1852–1860

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kooijman EE, Tieleman DP, Testerink C, Munnik T, Rijkers DT, Burger KN, de Kruijff B (2007) An electrostatic/hydrogen bond switch as the basis for the specific interaction of phosphatidic acid with proteins. J Biol Chem 282:11356–11364

    CAS  PubMed  Google Scholar 

  • Labesse G, Douguet D, Assairi L, Gilles AM (2002) Diacylglyceride kinases, sphingosine kinases and NAD kinases: distant relatives of 6-phosphofructokinases. Trends Biochem Sci 27:273–275

    CAS  PubMed  Google Scholar 

  • Lee D, Kim E, Tanaka-Yamamoto K (2016) Diacylglycerol kinases in the coordination of synaptic plasticity. Front Cell Dev Biol 4:92

    PubMed  PubMed Central  Google Scholar 

  • Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F et al (2013) Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45:531–536

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leon-Ponte M, Ahern GP, O’Connell PJ (2007) Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood 109:3139–3146

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu CH, Machado FS, Guo R, Nichols KE, Burks AW, Aliberti JC, Zhong XP (2007) Diacylglycerol kinase zeta regulates microbial recognition and host resistance to toxoplasma gondii. J Exp Med 204:781–792

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu K, Kunii N, Sakuma M, Yamaki A, Mizuno S, Sato M, Sakai H, Kado S, Kumagai K, Kojima H et al (2016) A novel diacylglycerol kinase alpha-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response. J Lipid Res 57:368–379

    CAS  PubMed  PubMed Central  Google Scholar 

  • Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A (2002) Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109:719–731

    CAS  PubMed  Google Scholar 

  • Malek RL, Irby RB, Guo QM, Lee K, Wong S, He M, Tsai J, Frank B, Liu ET, Quackenbush J et al (2002) Identification of Src transformation fingerprint in human colon cancer. Oncogene 21:7256–7265

    CAS  PubMed  Google Scholar 

  • Manneras-Holm L, Kirchner H, Bjornholm M, Chibalin AV, Zierath JR (2015) mRNA expression of diacylglycerol kinase isoforms in insulin-sensitive tissues: effects of obesity and insulin resistance. Physiol Rep 3:e12372

    PubMed  PubMed Central  Google Scholar 

  • Manneras-Holm L, Schonke M, Brozinick JT, Vetterli L, Bui HH, Sanders P, Nascimento EBM, Bjornholm M, Chibalin AV, Zierath JR (2017) Diacylglycerol kinase epsilon deficiency preserves glucose tolerance and modulates lipid metabolism in obese mice. J Lipid Res 58:907–915

    PubMed  PubMed Central  Google Scholar 

  • Marchet A, Mocellin S, Belluco C, Ambrosi A, DeMarchi F, Mammano E, Digito M, Leon A, D’Arrigo A, Lise M, Nitti D (2007) Gene expression profile of primary gastric cancer: towards the prediction of lymph node status. Ann Surg Oncol 14:1058–1064

    PubMed  Google Scholar 

  • Martinez-Moreno M, Garcia-Lievana J, Soutar D, Torres-Ayuso P, Andrada E, Zhong XP, Koretzky GA, Merida I, Avila-Flores A (2012) FoxO-dependent regulation of diacylglycerol kinase alpha gene expression. Mol Cell Biol 32:4168–4180

    CAS  PubMed  PubMed Central  Google Scholar 

  • McMurray HR, Sampson ER, Compitello G, Kinsey C, Newman L, Smith B, Chen SR, Klebanov L, Salzman P, Yakovlev A, Land H (2008) Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype. Nature 453:1112–1116

    CAS  PubMed  PubMed Central  Google Scholar 

  • Merida I, Avila-Flores A, Merino E (2008) Diacylglycerol kinases: at the hub of cell signalling. Biochem J 409:1–18

    CAS  PubMed  Google Scholar 

  • Merida I, Andrada E, Gharbi SI, Avila-Flores A (2015) Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions. Sci Signal 8:re6

    PubMed  Google Scholar 

  • Merida I, Torres-Ayuso P, Avila-Flores A, Arranz-Nicolas J, Andrada E, Tello-Lafoz M, Liebana R, Arcos R (2017) Diacylglycerol kinases in cancer. Adv Biol Regul 63:22–31

    CAS  PubMed  Google Scholar 

  • Merino E, Avila-Flores A, Shirai Y, Moraga I, Saito N, Merida I (2008) Lck-dependent tyrosine phosphorylation of diacylglycerol kinase alpha regulates its membrane association in T cells. J Immunol 180:5805–5815

    CAS  PubMed  Google Scholar 

  • Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S et al (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527:95–99

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miller DJ, Jerga A, Rock CO, White SW (2008) Analysis of the Staphylococcus aureus DgkB structure reveals a common catalytic mechanism for the soluble diacylglycerol kinases. Structure 16:1036–1046

    CAS  PubMed  PubMed Central  Google Scholar 

  • Monsalve M, Olmos Y (2011) The complex biology of FOXO. Curr Drug Targets 12:1322–1350

    CAS  PubMed  Google Scholar 

  • Moya PR, Murphy DL, McMahon FJ, Wendland JR (2010) Increased gene expression of diacylglycerol kinase eta in bipolar disorder. Int J Neuropsychopharmacol 13:1127–1128

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nascimento EBM, Manneras Holm L, Chibalin AV, Bjornholm M, Zierath JR (2017) Diacylglycerol kinase alpha deficiency alters inflammation markers in adipose tissue in response to high fat diet. J Lipid Res 59:273–282

    PubMed  PubMed Central  Google Scholar 

  • Nelson CD, Perry SJ, Regier DS, Prescott SM, Topham MK, Lefkowitz RJ (2007) Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins. Science 315:663–666

    CAS  PubMed  Google Scholar 

  • Newton AC, Brognard J (2017) Reversing the paradigm: protein kinase C as a tumor suppressor. Trends Pharmacol Sci 38:438–447

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD et al (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297:1031–1034

    CAS  PubMed  Google Scholar 

  • Olenchock BA, Guo R, Carpenter JH, Jordan M, Topham MK, Koretzky GA, Zhong XP (2006a) Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol 7:1174–1181

    CAS  PubMed  Google Scholar 

  • Olenchock BA, Guo R, Silverman MA, Wu JN, Carpenter JH, Koretzky GA, Zhong XP (2006b) Impaired degranulation but enhanced cytokine production after Fc epsilonRI stimulation of diacylglycerol kinase zeta-deficient mast cells. J Exp Med 203:1471–1480

    CAS  PubMed  PubMed Central  Google Scholar 

  • Olmez I, Love S, Xiao A, Manigat L, Randolph P, McKenna BD, Neal BP, Boroda S, Li M, Brenneman B et al (2018) Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha. Neuro-Oncology 20:192–202

    CAS  PubMed  Google Scholar 

  • Perez Y, Maffei M, Igea A, Amata I, Gairi M, Nebreda AR, Bernado P, Pons M (2013) Lipid binding by the unique and SH3 domains of c-Src suggests a new regulatory mechanism. Sci Rep 3:1295

    PubMed  PubMed Central  Google Scholar 

  • Prinz PU, Mendler AN, Masouris I, Durner L, Oberneder R, Noessner E (2012) High DGK-alpha and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention. J Immunol 188:5990–6000

    CAS  PubMed  Google Scholar 

  • Prinz PU, Mendler AN, Brech D, Masouris I, Oberneder R, Noessner E (2014) NK-cell dysfunction in human renal carcinoma reveals diacylglycerol kinase as key regulator and target for therapeutic intervention. Int J Cancer 135:1832–1841

    CAS  PubMed  Google Scholar 

  • Purow B (2015) Molecular pathways: targeting diacylglycerol kinase alpha in cancer. Clin Cancer Res 21:5008–5012

    CAS  PubMed  PubMed Central  Google Scholar 

  • Quann EJ, Merino E, Furuta T, Huse M (2009) Localized diacylglycerol drives the polarization of the microtubule-organizing center in T cells. Nat Immunol 10:627–635

    CAS  PubMed  Google Scholar 

  • Rainero E, Caswell PT, Muller PA, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJ, Vousden KH, Graziani A, Norman JC (2012) Diacylglycerol kinase alpha controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol 196:277–295

    CAS  PubMed  PubMed Central  Google Scholar 

  • Riese MJ, Wang LC, Moon EK, Joshi RP, Ranganathan A, June CH, Koretzky GA, Albelda SM (2013) Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res 73:3566–3577

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez-Linares B, Walker T, Watson S (1991) The diacylglycerol kinase inhibitor, R59949, potentiates secretion but not increased phosphorylation of a 47 kDalton protein in human platelets. Biochem Pharmacol 41:835–838

    CAS  PubMed  Google Scholar 

  • Ruffo E, Malacarne V, Larsen SE, Das R, Patrussi L, Wulfing C, Biskup C, Kapnick SM, Verbist K, Tedrick P et al (2016) Inhibition of diacylglycerol kinase alpha restores restimulation-induced cell death and reduces immunopathology in XLP-1. Sci Transl Med 8:321ra327

    Google Scholar 

  • Sakane F, Yamada K, Kanoh H, Yokoyama C, Tanabe T (1990) Porcine diacylglycerol kinase sequence has zinc finger and E-F hand motifs. Nature 344:345–348

    CAS  PubMed  Google Scholar 

  • Sanchez Chinchilla D, Pinto S, Hoppe B, Adragna M, Lopez L, Justa Roldan ML, Pena A, Lopez Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2014) Complement mutations in diacylglycerol kinase-epsilon-associated atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 9:1611–1619

    PubMed  PubMed Central  Google Scholar 

  • Sanjuan MA, Jones DR, Izquierdo M, Merida I (2001) Role of diacylglycerol kinase alpha in the attenuation of receptor signaling. J Cell Biol 153:207–220

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanjuan MA, Pradet-Balade B, Jones DR, Martinez AC, Stone JC, Garcia-Sanz JA, Merida I (2003) T cell activation in vivo targets diacylglycerol kinase alpha to the membrane: a novel mechanism for Ras attenuation. J Immunol 170:2877–2883

    CAS  PubMed  Google Scholar 

  • Shin JJ, Loewen CJ (2011) Putting the pH into phosphatidic acid signaling. BMC Biol 9:85

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shirai Y, Saito N (2014) Diacylglycerol kinase as a possible therapeutic target for neuronal diseases. J Biomed Sci 21:28

    PubMed  PubMed Central  Google Scholar 

  • Shirai Y, Kouzuki T, Kakefuda K, Moriguchi S, Oyagi A, Horie K, Morita SY, Shimazawa M, Fukunaga K, Takeda J et al (2010) Essential role of neuron-enriched diacylglycerol kinase (DGK), DGKbeta in neurite spine formation, contributing to cognitive function. PLoS One 5:e11602

    PubMed  PubMed Central  Google Scholar 

  • Simons M, Gault WJ, Gotthardt D, Rohatgi R, Klein TJ, Shao Y, Lee HJ, Wu AL, Fang Y, Satlin LM et al (2009) Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization. Nat Cell Biol 11:286–294

    CAS  PubMed  PubMed Central  Google Scholar 

  • Singh BK, Kambayashi T (2016) The immunomodulatory functions of diacylglycerol kinase zeta. Front Cell Dev Biol 4:96

    PubMed  PubMed Central  Google Scholar 

  • Solimini NL, Luo J, Elledge SJ (2007) Non-oncogene addiction and the stress phenotype of cancer cells. Cell 130:986–988

    CAS  PubMed  Google Scholar 

  • Soto-Nieves N, Puga I, Abe BT, Bandyopadhyay S, Baine I, Rao A, Macian F (2009) Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance. J Exp Med 206:867–876

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stace CL, Ktistakis NT (2006) Phosphatidic acid- and phosphatidylserine-binding proteins. Biochim Biophys Acta 1761:913–926

    CAS  PubMed  Google Scholar 

  • Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D, Jelenik T, Muller J, Herder C, Nowotny P et al (2014) Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci U S A 111:9597–9602

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tabet R, Moutin E, Becker JA, Heintz D, Fouillen L, Flatter E, Krezel W, Alunni V, Koebel P, Dembele D et al (2016) Fragile X mental retardation protein (FMRP) controls diacylglycerol kinase activity in neurons. Proc Natl Acad Sci U S A 113:E3619–E3628

    CAS  PubMed  PubMed Central  Google Scholar 

  • Takeishi K, Taketomi A, Shirabe K, Toshima T, Motomura T, Ikegami T, Yoshizumi T, Sakane F, Maehara Y (2012) Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras-Raf-MEK-ERK pathway. J Hepatol 57:77–83

    CAS  PubMed  Google Scholar 

  • Tam WL, Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19:1438–1449

    CAS  PubMed  PubMed Central  Google Scholar 

  • Torres-Ayuso P, Daza-Martin M, Martin-Perez J, Avila-Flores A, Merida I (2014) Diacylglycerol kinase alpha promotes 3D cancer cell growth and limits drug sensitivity through functional interaction with Src. Oncotarget 5:9710–9726

    PubMed  PubMed Central  Google Scholar 

  • Torres-Ayuso P, Tello-Lafoz M, Merida I, Avila-Flores A (2015) Diacylglycerol kinase-zeta regulates mTORC1 and lipogenic metabolism in cancer cells through SREBP-1. Oncogene 4:e164

    CAS  Google Scholar 

  • Valdor R, Macian F (2013) Induction and stability of the anergic phenotype in T cells. Semin Immunol 25:313–320

    CAS  PubMed  PubMed Central  Google Scholar 

  • Valinciute G, Weigel C, Veldwijk MR, Oakes CC, Herskind C, Wenz F, Plass C, Schmezer P, Popanda O (2017) BET-bromodomain inhibitors modulate epigenetic patterns at the diacylglycerol kinase alpha enhancer associated with radiation-induced fibrosis. Radiother Oncol 125:168–174

    CAS  PubMed  Google Scholar 

  • van der Zanden LF, van Rooij IA, Feitz WF, Knight J, Donders AR, Renkema KY, Bongers EM, Vermeulen SH, Kiemeney LA, Veltman JA et al (2011) Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet 43:48–50

    PubMed  Google Scholar 

  • Veillette A, Perez-Quintero LA, Latour S (2013) X-linked lymphoproliferative syndromes and related autosomal recessive disorders. Curr Opin Allergy Clin Immunol 13:614–622

    CAS  PubMed  Google Scholar 

  • Verrier E, Wang L, Wadham C, Albanese N, Hahn C, Gamble JR, Chatterjee VK, Vadas MA, Xia P (2004) PPARgamma agonists ameliorate endothelial cell activation via inhibition of diacylglycerol-protein kinase C signaling pathway: role of diacylglycerol kinase. Circ Res 94:1515–1522

    CAS  PubMed  Google Scholar 

  • Weber H, Kittel-Schneider S, Gessner A, Domschke K, Neuner M, Jacob CP, Buttenschon HN, Boreatti-Hummer A, Volkert J, Herterich S et al (2011) Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD. Neuropsychopharmacology 36:2076–2085

    PubMed  PubMed Central  Google Scholar 

  • Weigel C, Veldwijk MR, Oakes CC, Seibold P, Slynko A, Liesenfeld DB, Rabionet M, Hanke SA, Wenz F, Sperk E et al (2016) Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis. Nat Commun 7:10893

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wheeler ML, Dong MB, Brink R, Zhong XP, DeFranco AL (2013) Diacylglycerol kinase zeta limits B cell antigen receptor-dependent activation of ERK signaling to inhibit early antibody responses. Sci Signal 6:ra91

    PubMed  PubMed Central  Google Scholar 

  • Woodham EF, Machesky LM (2014) Polarised cell migration: intrinsic and extrinsic drivers. Curr Opin Cell Biol 30:25–32

    CAS  PubMed  Google Scholar 

  • Yanagisawa K, Yasuda S, Kai M, Imai S, Yamada K, Yamashita T, Jimbow K, Kanoh H, Sakane F (2007) Diacylglycerol kinase alpha suppresses tumor necrosis factor-alpha-induced apoptosis of human melanoma cells through NF-kappaB activation. Biochim Biophys Acta 1771:462–474

    CAS  PubMed  Google Scholar 

  • Yang J, Seo J, Nair R, Han S, Jang S, Kim K, Han K, Paik SK, Choi J, Lee S et al (2011) DGKiota regulates presynaptic release during mGluR-dependent LTD. EMBO J 30:165–180

    CAS  PubMed  Google Scholar 

  • Yang E, Singh BK, Paustian AM, Kambayashi T (2016) Diacylglycerol kinase zeta is a target to enhance NK cell function. J Immunol 197:934–941

    CAS  PubMed  PubMed Central  Google Scholar 

  • You JS, Lincoln HC, Kim CR, Frey JW, Goodman CA, Zhong XP, Hornberger TA (2014) The role of diacylglycerol kinase zeta and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy. J Biol Chem 289:1551–1563

    CAS  PubMed  Google Scholar 

  • Young BP, Shin JJ, Orij R, Chao JT, Li SC, Guan XL, Khong A, Jan E, Wenk MR, Prinz WA et al (2010) Phosphatidic acid is a pH biosensor that links membrane biogenesis to metabolism. Science 329:1085–1088

    CAS  PubMed  Google Scholar 

  • Zamani A, Decker C, Cremasco V, Hughes L, Novack DV, Faccio R (2015) Diacylglycerol kinase zeta (DGKzeta) is a critical regulator of bone homeostasis via modulation of c-Fos levels in osteoclasts. J Bone Miner Res 30:1852–1863

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng Z, Wang T, Li T, Li Y, Chen P, Zhao Q, Liu J, Li J, Feng G, He L, Shi Y (2011) Common SNPs and haplotypes in DGKH are associated with bipolar disorder and schizophrenia in the Chinese Han population. Mol Psychiatry 16:473–475

    CAS  PubMed  Google Scholar 

  • Zha Y, Marks R, Ho AW, Peterson AC, Janardhan S, Brown I, Praveen K, Stang S, Stone JC, Gajewski TF (2006) T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat Immunol 7:1166–1173

    CAS  PubMed  Google Scholar 

  • Zheng Y, Zha Y, Driessens G, Locke F, Gajewski TF (2012) Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo. J Exp Med 209:2157–2163

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng Y, Zha Y, Spaapen RM, Mathew R, Barr K, Bendelac A, Gajewski TF (2013) Egr2-dependent gene expression profiling and ChIP-Seq reveal novel biologic targets in T cell anergy. Mol Immunol 55:283–291

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

JAN holds predoctoral FPI fellowships from the Spanish Ministry of Economy and Competitiveness (MINECO). This work was supported in part by grants from the MINECO/FEDER/UE (BFU2013-47640-P) and from the Madrid regional government (IMMUNOTHERCAM Consortium B2017/BMD-3733) to IM. We thank Catherine Mark for excellent editorial assistance.

Author information

Authors and Affiliations

  1. Department of Immunology and Oncology, National Center of Biotechnology (CNB-CSIC), Madrid, Spain

    Isabel Merida, Javier Arranz-Nicolás & Antonia Ávila-Flores

  2. Laboratory of Cell and Developmental Signaling, National Cancer Institute (NCI-NIH), Frederick, MD, USA

    Pedro Torres-Ayuso

Authors
  1. Isabel Merida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javier Arranz-Nicolás
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pedro Torres-Ayuso
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonia Ávila-Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isabel Merida .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA

    Julian Gomez-Cambronero

  2. Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA

    Michael A. Frohman

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Merida, I., Arranz-Nicolás, J., Torres-Ayuso, P., Ávila-Flores, A. (2019). Diacylglycerol Kinase Malfunction in Human Disease and the Search for Specific Inhibitors. In: Gomez-Cambronero, J., Frohman, M. (eds) Lipid Signaling in Human Diseases. Handbook of Experimental Pharmacology, vol 259. Springer, Cham. https://doi.org/10.1007/164_2019_221

Download citation

Publish with us

Policies and ethics

Search

Navigation