Download PDF
Thromb Haemost 2002; 88(06): 912-918
DOI: 10.1055/s-0037-1613333
Review Article
Schattauer GmbH

Diacylglycerol Kinases: Regulation and Signaling Roles

Matthew K. Topham
1   The Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
,
Stephen M. Prescott
1   The Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
› Author Affiliations
Further Information

Publication History

Received 31 May 2002

Accepted after revision 23 July 2002

Publication Date:
09 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Diacylglycerol kinases (DGKs) are thought to attenuate diacylglycerol signals by converting diacylglycerol to phosphatidic acid. The nine mammalian diacylglycerol kinases that have been identified are widely expressed, but each isoform has a unique tissue and subcellular distribution. The activity of DGKs is regulated by mechanisms that can modify their access to diacylglycerol, affect their activity, or alter their ability to bind to other proteins. Although little is known of the specific function of DGKs in platelets, they likely influence actin reorganization and other signaling events requiring diacylglycerol.

Keywords

Diacylglycerol kinases - diacylglycerol - phosphatidic acid
 

  • References

  • 1 Rhee SG, Bae YS. Regulation of phosphoinositide-specific phospholipase C isozymes. J Biol Chem 1997; 272: 15045-8.
    CrossrefPubMedGoogle Scholar
  • 2 Clapham DE. Calcium Signaling. Cell 1995; 80: 259-68.
    CrossrefPubMedGoogle Scholar
  • 3 Newton AC. Regulation of protein kinase C. Cell Biol 1997; 09: 161-7.
    PubMedGoogle Scholar
  • 4 Toker A. Signaling through protein kinase C. Front Biosci 1998; 03: d1134-47.
    CrossrefPubMedGoogle Scholar
  • 5 Parekh DB, Ziegler W, Parker PJ. Multiple pathways control protein kinase C phosphorylation. EMBO J 2000; 19: 496-503.
    CrossrefPubMedGoogle Scholar
  • 6 Ebinu JO, Bottorff DA, Chan EYW, Stang SL, Dunn RJ, Stone JC. RasGRP, a ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Science 1998; 280: 1082-6.
    CrossrefPubMedGoogle Scholar
  • 7 Kawasaki H, Springett GM, Shinichiro T. et al. A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. Proc Natl Acad Sci USA 1998; 95: 13278-83.
    CrossrefPubMedGoogle Scholar
  • 8 Tognon CE, Kirk HE, Passmore LA, Whitehead IP, Der CJ, Kay RJ. Regulation of RasGRP via a phorbol ester-responsive C1 domain. Mol Cell Biol 1998; 18: 6995-7008.
    CrossrefPubMedGoogle Scholar
  • 9 Ahmed S, Lee J, Kozma R, Best A, Monfries C, Lim L. A novel functional target for tumor-promoting phorbol esters and lysophosphatidic acid. J Biol Chem 1993; 268: 10709-12.
    PubMedGoogle Scholar
  • 10 van Blitterswijk WJ, Houssa B. Properties and functions of diacylglycerol kinases. Cell Signal 2000; 12: 595-605.
    CrossrefPubMedGoogle Scholar
  • 11 Topham MK, Prescott SM. Mammalian diacylglycerol kinases, a family of lipid kinases with signaling functions. J Biol Chem 1999; 274: 11447-50.
    CrossrefPubMedGoogle Scholar
  • 12 Hurley JH, Newton AC, Parker PJ, Blumberg PM, Nishizuka Y. Taxonomy and function of C1 protein kinase C homology domains. Protein Sci 1997; 06: 477-80.
    PubMedGoogle Scholar
  • 13 Shindo M, Irie K, Ohigashi H, Kuriyama M, Saito N. Diacylglycerol kinase gamma is one of the specific receptors of tumor-promoting phorbol esters. Biochem Biophys Res Commun 2001; 289: 451-6.
    CrossrefPubMedGoogle Scholar
  • 14 Sakane F, Kai M, Wada I, Imai S-i, Kanoh H. The C-terminal part of diacylglycerol kinase α lacking zinc fingers serves as a catalytic domain. Biochem J 1996; 318: 583-90.
    CrossrefPubMedGoogle Scholar
  • 15 Houssa B, van Blitterswijk WJ. Specificity of cysteine-rich domains in diacylglycerol kinases and protein kinases C. Biochem J 1998; 331: 677-80.
    PubMedGoogle Scholar
  • 16 Yamada K, Sakane F, Matsushima N, Kanoh H. EF-hand motifs of α, β and γ isoforms of diacylglycerol kinase bind calcium with different affinities and conformational changes. Biochem J 1997; 321: 59-64.
    CrossrefPubMedGoogle Scholar
  • 17 Takeuchi H, Kanematsu T, Misumi Y. et al. Distinct specificity in the binding of inositol phosphates by pleckstrin homology domains of pleckstrin, RAC-protein kinase, diacylglycerol kinase and a new 130 kDa protein. Biochimica et Biophysica Acta 1997; 1359: 275-85.
    CrossrefPubMedGoogle Scholar
  • 18 Nagaya H, Wada I, Jia Y-J, Kanoh H. Diacylglycerol Kinase d Suppresses ER-to-Golgi Traffic via Its SAM and PH Domains. Mol Biol Cell 2002; 13: 302-16.
    CrossrefPubMedGoogle Scholar
  • 19 Tang W, Bunting M, Zimmerman GA, McIntyre TM, Prescott SM. Molecular cloning of a novel human diacylglycerol kinase highly selective for arachidonate-containing substrates. J Biol Chem 1996; 271: 10237-41.
    CrossrefPubMedGoogle Scholar
  • 20 Knauss TC, Jaffer FE, Abboud HE. Phosphatidic acid modulates DNA synthesis, phospholipase C, and platelet-derived growth factor mRNAs in cultured mesangial cells. Role of protein kinase C. J Biol Chem 1990; 265: 14457-63.
    PubMedGoogle Scholar
  • 21 van Corven EJ, Van Rijswijk A, Jalink K, van der Bend RL, van Blitterswijk WJ, Moolenaar WH. Mitogenic action of lysophosphatidic acid and phosphatidic acid on fibroblasts. Biochem J 1992; 281: 163-9.
    CrossrefPubMedGoogle Scholar
  • 22 Siddhanta A, Shields D. Secretory vesicle budding from the trans-golgi network is mediated by phosphatidic acid levels. J Biol Chem 1998; 273: 17995-8.
    CrossrefPubMedGoogle Scholar
  • 23 Ishihara H, Shibasaki Y, Kizuki N. et al. Type I phosphatidylinositol-4-phosphate 5-kinases. Cloning of the third isoform and deletion/substitution analysis of members of his novel lipid kinase family. J Biol Chem 1998; 273: 8741-8.
    CrossrefPubMedGoogle Scholar
  • 24 Bokoch GM, Reilly AM, Daniels RH. et al. A GTPase-independent mechanism of p21-activated kinase activation. J Biol Chem 1998; 273: 8137-44.
    CrossrefPubMedGoogle Scholar
  • 25 Tsai MH, Yu CL, Stacey DW. A cytoplasmic protein inhibits the GTPase activity of H-Ras in a phospholipid-dependent manner. Science 1990; 250: 982-5.
    CrossrefPubMedGoogle Scholar
  • 26 Limatola C, Schaap D, Moolenaar D, van Blitterswijk WJ. Phosphatidic acid activation of protein kinase C zeta overexpressed in COS cells: comparison with other protein kinase C isotypes and other acidic phospholipids. Biochem J 1994; 304: 1001-8.
    CrossrefPubMedGoogle Scholar
  • 27 Rizzo MA, Shome K, Watkins SC, Romero G. The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras. J Biol Chem 2000; 275: 23911-8.
    CrossrefPubMedGoogle Scholar
  • 28 Pettitt TR, Martin A, Horton T, Liossis C, Lord JM, Wakelam MJO. Diacylglycerol and Phosphatidate Generated by Phospholipases C and D, Respectively, Have Distince Fatty Acid Compositions and Functions. J Bio. Chem 1997; 272: 17354-9.
    CrossrefPubMedGoogle Scholar
  • 29 Hodgkin MN, Pettitt TR, Martin A, Michell RH, Pemberton AJ, Wakelam MJO. Diacylglycerols and phosphatidates: which molecular species are intracellular messenger?. Trends Biochem Sci 1998; 23: 200-4.
    CrossrefPubMedGoogle Scholar
  • 30 Flores I, Casaseca T, Martinez-A C, Kanoh H, Merida I. Phosphatidic acid generation through interleukin 2 (IL-2)-induced α-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation. J Biol Chem 1996; 271: 10334-40.
    CrossrefPubMedGoogle Scholar
  • 31 Caricasole A, Bettini E, Sala C. et al. Molecular cloning and characterization of the human diacylglycerol kinase beta (DGKbeta) gene: Alternative splicing generates DGKbeta isotypes with different properties. J Biol Chem 2001; 277: 4790-6.
    PubMedGoogle Scholar
  • 32 Ding L, Bunting M, Topham MK, McIntyre TM, Zimmerman GA, Prescott SM. Alternative splicing of the human diacylglycerol kinase ξ gene in muscle. Proc Natl Acad Sci USA 1997; 94: 5519-24.
    CrossrefPubMedGoogle Scholar
  • 33 Sanjuan MA, Jones DA, Izquierdo M, Merida I. Role of diacylglycerol kinase α in the attenuation of receptor signaling. J. Cell Biol 2001; 153: 207-19.
    CrossrefPubMedGoogle Scholar
  • 34 Sakane F, Yamada K, Kanoh H. Different effects of sphingosine, R59022 and anionic amphiphiles on two diacylglycerol kinase isozymes purified from porcine thymus cytosol. FEBS Lett 1989; 255: 409-13.
    CrossrefPubMedGoogle Scholar
  • 35 Yamada K, Sakane F. The different effects of sphingosine on diacylglycerol kinase isozymes in Jurkat cells, a human T-cell line. Biochimica et Biophysica Acta 1993; 1169: 211-6.
    CrossrefPubMedGoogle Scholar
  • 36 Schaap D, van der Wal J, van Blitterswijk WJ, van der Bend RL, Ploegh HL. Diacylglycerol kinase is phosphorylated in vivo upon stimulation of the epidermal growth factor receptor and serine/threonine kinases, including protein kinase C-ε. Biochem J 1993; 289: 875-81.
    CrossrefPubMedGoogle Scholar
  • 37 Kanoh H, Ono T. Phosphorylation of pig brain diacylglycerol kinase by endogenous protein kinase. FEBS Lett 1986; 201: 97-100.
    CrossrefPubMedGoogle Scholar
  • 38 Cutrupi S, Baldanzi G, Gramaglia D. et al. Src-mediated activation of α-diacylglycerol kinase is required for hepatocyte growth factor-induced cell motility. EMBO J 2000; 19: 4614-22.
    CrossrefPubMedGoogle Scholar
  • 39 Sakane F, Imai SI, Kai M, Wada I, Kanoh H. Molecular cloning of a novel diacylglycerol kinase isozyme with a pleckstrin homology domain and a C-terminal tail similar to those of the EPH family of protein tyrosine kinases. J Biol Chem 1996; 271: 8394-401.
    CrossrefPubMedGoogle Scholar
  • 40 Thirugnannam S, Topham MK, Epand RM. Physiological Implications of the Contrasting Modulation of the Activities of the ε and ξ-Isoforms of Diacylglycerol Kinases. Biochemistry 2001; 40: 10607-13.
    CrossrefPubMedGoogle Scholar
  • 41 Topham MK, Bunting M, Zimmerman GA, McIntyre TM, Blackshear PJ, Prescott SM. Protein kinase C regulates the nuclear localization of diacylglycerol kinase-zeta [see comments]. Nature 1998; 394: 697-700.
    CrossrefPubMedGoogle Scholar
  • 42 Ding L, Traer E, McIntyre TM, Zimmerman GA, Prescott SM. The cloning and characterization of a novel human diacylglycerol kinase, DGKi. J Biol Chem 1998; 273: 32746-52.
    CrossrefPubMedGoogle Scholar
  • 43 Hogan A, Shepherd L, Chabot J. et al. Interaction of γ1-syntrophin with Diacylglycerol Kinase-ξ. J Biol Chem 2001; 276: 26526-33.
    CrossrefPubMedGoogle Scholar
  • 44 Houssa B, de Widt J, Kranenburg O, Moolenaar WH, van Blitterswijk WJ. Diacylglycerol Kinase θ binds to and is negatively regulated by active RhoA. J Biol Chem 1999; 274: 6820-2.
    CrossrefPubMedGoogle Scholar
  • 45 van der Bend RL, de Widt J, Hilkmann H, van Blitterswijk WJ. Diacylglycerol kinase in receptor-stimulated cells converts its substrate in a topologically restricted manner. J Biol Chem 1994; 269: 4098-102.
    PubMedGoogle Scholar
  • 46 Hartwig JH, Barkalow K, Azim A, Italiano J. The Elegant Platelet: Signals Controlling Actin Assembly. Thromb Haemost 1999; 82: 392-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Shibasaki Y, Ishihara H, Kizuki N, Asano T, Oka Y, Yazaki Y. Massive Actin Polymerization Induced by Phosphatidylinositol-4-phosphate 5-Kinase in Vivo. J Biol Chem 1997; 272: 7578-81.
    CrossrefPubMedGoogle Scholar
  • 48 Jenkins GH, Fisette PL, Anderson RA. Type I Phosphatidylinositol 4-Phosphate 5-Kinases are Specifically Stimulated by Phosphatidic Acid. J Biol Chem 1994; 269: 11547-54.
    PubMedGoogle Scholar
  • 49 Divecha N, Roefs M, Halstead JR. et al. Interaction of the Type Ia PIPkinase with Phospholipase D: a role for the local generation of phosphatidylinositol 4,5-bisphosphate in the regulation of PLD2 activity. EMBO Journal 2000; 19: 5440-9.
    CrossrefPubMedGoogle Scholar
  • 50 Honda A, Nogami M, Yokozeki T. et al. Phosphatidylinositol 4-phosphate 5-kinase α is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell 2000; 99: 521-32.
    PubMedGoogle Scholar
  • 51 Tolias KF, Couvillon AD, Cantley LC, Carpenter CL. Characterization of a Rac1- and RhoGDI-associated lipid kinase signaling complex. Mol Cell Biol 1998; 18: 762-70.
    CrossrefPubMedGoogle Scholar
  • 52 Topham MK, Prescott SM. Diacylglycerol kinase ξ regulates Ras activation by a novel mechanism. J Cell Biol. 2001 152. in press.
    PubMedGoogle Scholar
  • 53 Divecha N, Banfic H, Irvine RF. Inositides and the nucleus and inositides in the nucleus. Cell 1993; 74: 405-7.
    CrossrefPubMedGoogle Scholar
  • 54 Divecha N, Banfic H, Irvine RF. The polyphosphoinositide cycle exists in the nuclei of Swiss 3T3 cells under the control of a receptor (for IGF-1) in the plasma membrane, and stimulation of the cycle increases nuclear diacylglycerol and apparently induces translocation of protein kinase C to the nucleus. EMBO J 1991; 10: 3207-14.
    PubMedGoogle Scholar
  • 55 Leach KL, Ruff VA, Jarpe MB, Adams LD, Fabbro D, Raben DM. α-Thrombin stimulates nuclear diglyceride levels and differential nuclear localization of protein kinase C isozymes in IIC9 cells. J Biol Chem 1992; 267: 21816-22.
    PubMedGoogle Scholar
  • 56 Cocco L, Capitani S, Maraldi NM. et al. Inositol lipid cycle and autonomous nuclear signalling. Advan Enzym. Regul 1996; 36: 101-14.
    PubMedGoogle Scholar
  • 57 Banfic H, Zizak M, Divecha N, Irvine RF. Nuclear diacylglycerol is increased during cell proliferation in vivo. Biochem J 1993; 290: 633-6.
    CrossrefPubMedGoogle Scholar
  • 58 Jackowski S. Cell cycle regulation of membrane phospholipid metabolism. J Biol Chem 1996; 271: 20219-22.
    PubMedGoogle Scholar
  • 59 Boronenkov IV, Loijens JC, Umeda M, Anderson RA. Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors. Mol Biol Cell 1998; 09: 3547-60.
    CrossrefPubMedGoogle Scholar
  • 60 Vann LR, Wooding FB, Irvine RF, Divecha N. Metabolism and possible compartmentalization of inositol lipids in isolated rat liver nuclei. Biochem J 1997; 327: 569-76.
    CrossrefPubMedGoogle Scholar
  • 61 D’Santos CS, Clarke JH, Irvine RF, Divecha N. Nuclei contain two differentially regulated pools of diacylglycerol. Curr Biol 1999; 09: 437-40.
    CrossrefPubMedGoogle Scholar
  • 62 Nurrish S, Segalat L, Kaplan JM. Serotonin inhibition of synaptic transmission: Gαo decreases the abundance of UNC-13 at release sites. Neuron 1999; 24: 231-42.
    CrossrefPubMedGoogle Scholar
  • 63 Prescott SM, Majerus PW. The fatty acid composition of phosphatidylinositol from thrombin-stimulated human platelets. J Biol Chem 1981; 256: 579-82.
    PubMedGoogle Scholar
  • 64 Rodriquez EBde Turco, Tang W, Topham MK. et al. Diacylglycerol kinase ε regulates siezure susceptibility and long-term potentiation through arachidonoyl-inositol lipid signaling. Proc Natl Acad Sci USA 2001; 98: 4740-5.
    CrossrefPubMedGoogle Scholar
  • 65 Levy-Toledano S. Platelet Signal Transduction Pathways: Could we Organize them into a Hierarchy?. Haemostasis 1999; 29: 4-15.
    PubMedGoogle Scholar
  • 66 Bishop WR, Bell RM. Attenuation of sn-1,2-diacylglycerol second messengers. J Biol Chem 1986; 261: 12513-9.
    PubMedGoogle Scholar
  • 67 Nunn DL, Watson SP. A diacylglycerol kinase inhibitor, R59022, potentiates secretion by and aggregation of thrombin-stimulated platelets. Biochem J 1987; 243: 809-13.
    CrossrefPubMedGoogle Scholar
  • 68 Yada Y, Toshihiko O, Kanoh H, Nozawa Y. Purification and Characterization of Cytosolic Diacylglycerol Kinases of Human Platelets. J Biol Chem 1990; 265: 19237-43.
    PubMedGoogle Scholar
  • 69 Jiang Y, Sakane F, Kanoh H, Walsh JP. Selectivity of the Diacylglycerol Kinase Inhibitor R59949 among Diacylglycerol Kinase Subtypes. Biochem Pharmacol 2000; 59: 763-72.
    CrossrefPubMedGoogle Scholar