Sphingolipid metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate, are emerging as novel class of lipid second messengers. Branching pathways of sphingolipid metabolism mediate either growth arrest, stress, or proliferation, depending on the cell type and the nature of the stimulus. Ceramide is an important regulatory component of stress responses, whereas, sphingosine-1- phosphate, a metabolite of ceramide, has been implicated as a second messenger in cellular proliferation and survival induced by platelet- derived growth factor, nerve growth factor, and serum. This led to the proposal that the dynamic balance between cellular levels of ceramide and sphingosine-1-phosphate, and consequent regulation of opposing signaling pathways, is an evolutionarily conserved stress regulatory mechanism influencing cell growth and survival. Progress in determining the importance of sphingolipid metabolites has been hampered because most of the relevant metabolic enzymes have not yet been purified or cloned. This renewal application is focused on characterization and cloning of the enzymes which regulate levels of sphingosine-1-phosphate in mammalian cells and in Saccharomyces cerevisiae, sphingosine kinase which regulates its formation, and sphingosine-1-phosphate phosphatase which plays an important role in its turnover. This will result in the development of new tools to aid in understanding the role of sphingosine-1-phosphate in cell growth and survival and the molecular mechanisms of its pleiotropic actions. In addition, the innovative concept of dual actions of the lipid second messenger sphingosine-1-phosphate extracellular to regulate G protein coupled orphan receptor-dependent signaling pathways leading to morphogenetic differentiation, and intracellular to regulate cell growth and survival, opens important avenues for future research on the role of bioactive lipids in normal and aberrant physiology. This proposal provides a new paradigm for dissecting the complex interplay between intra and extracellular actions of sphingosine-1-phosphate.
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