The long-range goal of the proposed research is to identify molecular targets in sphingolipid signaling pathways for the development of therapeutics to treat cancer. The focus of the present proposal is the signaling enzyme sphingosine kinase-1, which produces the potent second messenger, sphingosine-1-phosphate. Sphingosine kinase represents a candidate target for cancer therapy. This concept is based on the observations that sphingosine kinase is overexpressed in many tumors and that experimental overproduction of sphingosine kinase transforms cells from a growth-controlled state to a tumorigenic state. The localization of sphingosine kinase to distinct intracellular sites is key to its ability to transform cells. The proposed experimental plan will determine why localization is important for transformation. This will form the basis for a discovery of novel molecular targets involved in the transforming ability of sphingosine kinase. To accomplish this goal, three specific aims are proposed.
Specific Aim 1. Determine the activation-dependent subcellular localization of sphingosine kinase and sphingolipid metabolites affected by SK activity.
Specific Aim 2. Determine the role of SK localization in cellular transformation and protumorigenic pathways.
Specific Aim 3. The plasma membrane sphingosine-1-phosphate transport mechanism. Determine the mechanism and functional effects of enhanced sphingosine-1-phosphate secretion by activation of hSK-1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Yassin, Rihab R,
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University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
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Siow, Deanna; Wattenberg, Binks (2011) The compartmentalization and translocation of the sphingosine kinases: mechanisms and functions in cell signaling and sphingolipid metabolism. Crit Rev Biochem Mol Biol 46:365-75
Siow, Deanna L; Anderson, Charles D; Berdyshev, Evgeny V et al. (2011) Sphingosine kinase localization in the control of sphingolipid metabolism. Adv Enzyme Regul 51:229-44
Siow, Deanna L; Anderson, Charles D; Berdyshev, Evgeny V et al. (2010) Intracellular localization of sphingosine kinase 1 alters access to substrate pools but does not affect the degradative fate of sphingosine-1-phosphate. J Lipid Res 51:2546-59
Brock, Stephanie E; Li, Chi; Wattenberg, Binks W (2010) The Bax carboxy-terminal hydrophobic helix does not determine organelle-specific targeting but is essential for maintaining Bax in an inactive state and for stable mitochondrial membrane insertion. Apoptosis 15:14-27
Lee, Jen-Fu; Gordon, Sharon; Estrada, Rosendo et al. (2009) Balance of S1P1 and S1P2 signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature. Am J Physiol Heart Circ Physiol 296:H33-42
Raben, Daniel M; Wattenberg, Binks W (2009) Signaling at the membrane interface by the DGK/SK enzyme family. J Lipid Res 50 Suppl:S35-9
Siow, Deanna L; Wattenberg, Binks W (2007) An assay system for measuring the acute production of sphingosine 1-phosphate in intact monolayers. Anal Biochem 371:184-93
Kalbfleisch, Ted; Cambon, Alex; Wattenberg, Binks W (2007) A bioinformatics approach to identifying tail-anchored proteins in the human genome. Traffic 8:1687-94
Wattenberg, Binks W; Pitson, Stuart M; Raben, Daniel M (2006) The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function. J Lipid Res 47:1128-39