Sphingolipids metabolites are emerging as a new class of intracellular second messengers involved in the regulation of cell growth and transformation. Recently we discovered that a metabolite of sphingosine, sphingosine-1-phosphate, could mediate cellular processes previously attributed to sphingosine and may be a novel intracellular second messenger involved in the regulation of cell growth and calcium homeostasis. Sphingosine-1-phosphate triggers dual signal transduction pathways, releasing calcium from internal sources by a previously undescribed mechanism and also activating phospholipase D, leading to an increase in phosphatidic acid which in turn may regulate ras, a key component of growth factor induced signaling cascades. Ras could represent a convergence point where signals carried by sphingolipid-derived messengers are integrated. Elucidation of the involvement of sphingolipid metabolites in the regulation of ras activity and their mechanism of action might reveal additional regulatory molecules and, provide insight into the control of normal and abnormal cell growth. The focus of this research proposal is the elucidation of the molecular mechanisms of sphingolipid metabolites in transmembrane signaling pathways and cell growth regulation. Cross-talk between signaling pathways and the involvement of heterotrimeric GTP-binding regulatory proteins will also be examined. Unearthing the molecular mechanisms by which sphingosine-1-phosphate mobilizes calcium from internal pools and the regulation of this process may aid in understanding the complex events regulating intracellular calcium levels and provides a potential missing link to other cellular processes that involve calcium release independently of inositol 1,4,5- trisphosphate. The rapid calcium release in response to sphingosine-1- phosphate has many of the hallmarks of a receptor-mediated event. Thus, an important goal is the identification and characterization of a putative intracellular sphingosine-1-phosphate binding protein(s) which may act as a calcium channel. Our recent results suggest that activation of sphingosine kinase, the enzyme that catalyzes the phosphorylation of sphingosine, and consequent formation of sphingosine-1-phosphate may have important biological roles in signal transduction pathways activated by platelet-derived growth factor and serum. Little is yet known of the properties, structure, or mechanism of regulation of this ubiquitous kinase. Elucidation of the molecular mechanisms of the intracellular pathways which regulate sphingosine kinase and also its purification and characterization are crucial for understanding its role in signal transduction pathways. Increased knowledge of the spectrum of bioactive products of sphingolipid turnover and their mechanisms of action could add new perspectives to the understanding of cell growth regulation and perhaps other fundamental cellular processes.
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