Sphingosine-1-phosphate (S1P) is a bioactive lipid produced from the metabolism of sphingolipids that regulates vital biological processes, among which cell growth, survival, and motility are prominent. In the previous grant, we developed the concept that S1P has novel dual actions. It is now well established that S1P is the ligand for a family of specific GPCRs, the S1PRs. Its intracellular actions are far less understood, but it antagonizes apoptosis mediated by ceramide, a stress-induced sphingolipid metabolite. Due to the pivotal roles of S1P, its levels are low and tightly regulated in a spatial-temporal manner by the balance between sphingosine kinase-dependent synthesis and degradation by an endoplasmic reticulum S1P lyase and still not well-characterized phosphohydrolase activities. Cloning of S 1P phosphatases, prototypes of a new but highly conserved class of lipid phosphate phosphohydrolases, will now enable us to use novel molecular approaches to examine their importance in the regulation of sphingolipid metabolites and should help to unravel their physiological functions. It is our hypothesis that S 1P phosphatases are not only important in S 1P metabolism but also have previously unrecognized roles in regulating ceramide biosynthesis and are gateways that determine the dynamic balance of these two sphingolipids and consequent regulation of opposing signaling pathways that impact cell fate decisions. We will thus determine the role S 1P phosphatases in mitochondrialdependent events which are known to be involved in apoptosis and regulated by these sphingolipids. We will also evaluate the possibility that S1P phosphatases play a role in termination of S 1P signaling at the cell surface. If so, this could be an important physiological and pharmacological target for controlling the bioavailability of SIP at the S1PRs. As SIP can act in an autocrine manner, we will examine the notion that S IP phosphatases regulate """"""""inside-out"""""""" signaling by reducing intracellular levels of SIP and attenuating signals through its receptors important for cell locomotion and re-organization of the actin cytoskeleton. Emphasis will be on regulation by S 1P phosphatases of key elements of directed cell movement downstream of S1PRs. Knowledge of how the S1P phosphatases regulate the bioactive lipid mediator S1P and its functions both outside and inside cells has many biomedical implications, especially for cancer, angiogenesis, wound healing, cardiovascular disorders, inflammation and asthma.
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