Lipid second messengers have emerged as major components in a number of signaling cascades. The importance of these pathways is underscored by the observations demonstrating that defects in these pathways often contribute to pathological conditions such as diabetes, cardiovascular diseases, neurological disorders, dysfunctions of the immune system, and cancer among others. Understanding the regulation of the enzymes involved in controlling these lipid-involved pathways, therefore, will provide key insights into novel therapeutic targets

A major effort in our laboratory is focused on understanding the biochemistry and chemistry underlying the molecular aspects involved in regulating lipid metabolizing signaling enzymes and the physiological roles of this regulation. Control of lipid metabolizing enzymes involves the modulation of two key parameters; their sub-cellular distribution and their intrinsic enzymatic activity. Our studies have concentrated on three families of lipid-metabolizing signaling enzymes, diacylglycerol kinases, phospholipases C, and phospholipases D. In addition to these enzymes, we are also interested in enzymes involved in sphingolipid metabolism as these lipids also play important roles in signaling cascades. Specific areas of interest are listed below.

Enzymology of Lipid Metabolizing Signaling Enzymes: A major effort in our laboratory is centered on investigating the effects of agonist stimulation on the intrinsic activities of these enzymes. We are particularly interested in identifying the critical modulating proteins, lipids, and post-translational modifications. In these studies we consider the fact that these enzymes, like most lipid metabolizing enzymes, are interfacial enzymes and their regulation potentially includes a number of interfacial-dependent parameters. Interestingly, our recent studies show that some of the interfacial parameters are indeed altered upon agonist stimulation.

Enzyme Structure/Function Studies: We are also interested in the structural components of these enzymes that are critical for their distribution/re-distribution to specific sub-cellular compartments. Additionally, and to compliment the enzymology studies, we are interested in elucidating the catalytic mechanism(s) of these enzymes. These studies will be conducted partly in collaboration with Dr. Albert Mildvan. Our long-term goal is to understand the biochemistry and chemistry of these enzymes and determine how changes in their sub-cellular localization and/or enzymatic activity affect their signaling functions.

Nuclear Signaling Cascades: In the course of our studies we have shown that some of the lipid-metabolizing signaling enzymes redistribute to unique sub-cellular compartments including the nucleus in response to particular agonists in various cell types. In that, one of our major goals is to understand the biochemistry and physiological roles of novel agonist-induced signaling cascades that involve lipid metabolism at the nucleus. Evidence is increasing that implicates these pathways in a number of important signaling systems including, but not limited to, those that regulate growth, differentiation, mRNA export, and chromatin remodeling.

Publications:

Cheng,J., Baldassare, J.J., and Raben, D.M. (1999) Dual coupling of the α-thrombin receptor to signal-transduction pathways involving phosphatidylinositol and phosphatidylcholine metabolism. Biochem. J. 337: 97-104.
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Phillips-Mason, P.J., Raben D.M., Baldassare, J.J. (2000) Phosphatidylinositol 3-kinase activity regulates α-thrombin-stimulated G1 progression by its effect on Cyclin D1 expression and CDK4 activity. J. Biol. Chem. 275:18046-18053.
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Raben, D.M. and Baldassare, J.J. (2000) Phospholipid metabolism and nuclear envelope signaling. Advances in Enzyme Regulation 40:97-123.
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Raben, D.M. (2000) Signal Transduction. McGraw-Hill Encyclopedia of Science and Technology 9th Edition.

Raben, D.M., and Baldassare, J.J. (2000) Nuclear Envelope Signaling-Role of Phospholipid Metabolism. European Journal of Histochemistry 44: 67-80.
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Baldassare, J.J., Klaus, J., Phillips, P.J., and Raben, D.M. (2001) HamPLD1b in IIC9 Fibroblasts is Selectively Activated in the Nucleus But Not in the Golgi Apparatus. Cell Biol. Int. 25: 1207-1212.
PubMed Reference

Bregoli, L., Baldassare, J.J., Raben, D.M. (2001), Nuclear diacylglycerol kinase-θ is Activated in Response to α-Thrombin. J. Biol. Chem. 276: 23288-23295.
PubMed Reference

Gardner, A, Phillips-Mason, P.J., Raben, D.M., and Baldassare, J.J. (2002) A Novel Role for Gq alpha in α-thrombin-mediated Mitogenic Signaling Pathways. Cellular Signaling 14:499-507.
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Bregoli, L, Tu-Sekine, B., and Raben, D.M. (2002) DGK and nuclear signaling nuclear diacylglycerol kinases in IIC9 cells. Advances in Enzyme Regulation 42, 213-26.
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Goel R, Phillips-Mason PJ, Raben DM, Baldassare JJ. (2002) Alpha-Thrombin induces rapid and sustained Akt phosphorylation by beta-arrestin1-dependent and -independent mechanisms, and only the sustained Akt phosphorylation is essential for G1 phase progression.. J. Biol. Chem.J Biol Chem. 2002 May 24;277(21):18640-8. Epub 2002 Mar 18.
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Tu-Sekine B, Raben DM. (2004) Nuclear production and metabolism of diacylglycerol. Eur J Histochem.;48(1):77-82.
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Goel R, Phillips-Mason PJ, Gardner A, Raben DM, Baldassare JJ.(2004) Alpha-thrombin-mediated phosphatidylinositol 3-kinase activation through release of Gbetagamma dimers from Galphaq and Galphai2. J Biol Chem. Feb 20;279(8):6701-10. Epub 2003 Dec 9.
PubMed Reference

Raben DM, Baldassare JJ. (2005) A new lipase in regulating lipid mobilization: hormone-sensitive lipase is not alone. Trends Endocrinol Metab. Mar;16(2):35-6.
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Ostroski M, Tu-Sekine B, Raben DM. (2005) Analysis of a novel diacylglycerol kinase from Dictyostelium discoideum: DGKA. Biochemistry. Aug 2;44(30):10199-207.
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Tu-Sekine, B., Ostroski, M. and Raben, D.M. (2006) Analysis of Two Diacylglycerol Kinase Activities in Mixed Micelles. Advances in Enzyme Regulation. In press
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Wattenberg, BW, Piston, SM, and Raben, D.M. (2006) The Sphingosine- and Diacylglycerol-Kinase Superfamily of Signaling Kinases. Localization as a key to signaling function. J Lipid Res. 47(6):1128-1139.
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Raben, DM. (2006) Lipid Signaling in the Nucleus. Biochem Biophys Acta 1761(5-6):503-4.
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Tu-Sekine, B., Ostroski, M, and Raben, D.M. (2007) Modulation of DGKq Activity by a-Thrombin and Phospholipids. Biochemistry, 46(3): 924 -932.
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Wattenberg, B.W. and Raben, D.M. (2007) Diacylglycerol Kinases Put the Brakes on Immune Function. Science STKE (398) pe43
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Raben, D.M. and Tu-Sekine (2007) Nuclear Localization Of Diacylglycerol Kinases: Regulation And Roles. Frontiers in Bioscience 13:590-597.
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