Aberrant regulation of growth and apoptosis, important factors in development of cancer, have recently been linked to the sphingolipid metabolites, ceramide and sphingosinel-phosphate (SPP). Whereas ceramide has been associated with cell growth arrest and apoptosis, SPP, a further metabolite of ceramide, is a growth promoter and survival factor. Ample evidence indicates that SPP, formed by activation of sphingosine kinase (SPHK), can serve as an intracellular second messenger which modulates pathways important for cell growth, motility, and survival. Moreover, because SPP antagonizes apoptosis mediated by ceramide, a stress-induced sphingolipid metabolite, we have suggested that the intracellular ratio of these two sphingolipids metabolites and consequent regulation of opposing signaling pathways, is an important factor that determines whether a cell survives or dies. It is our hypothesis that the novel lipid kinase, SPHK, which produces SPP, acting in an analogous manner to the well known actions of P13-kinase, also plays a pivotal role in regulation of proliferation, survival, and motility. In this proposal, we will examine the role of SPHK in resistance of cancer cells to apoptosis and determine potential interactions of SPHK, and its product SPP, with signaling pathways known to be involved in initiation and/or execution phases of apoptosis. Expression of SPHK not only enhances cell proliferation, but surprisingly, it inhibits motility, suggesting that SPHK may play a critical role in several biological processes affecting cancer. Our understanding of how SPHK kinase achieves its spectrum of cellular effects is rudimentary and the challenge ahead is to elucidate the hierarchical relationships between SPHK and downstream signaling and establish whether overlapping or unique signaling pathways are involved in processes regulating growth and motility of cancer cells. Remarkably, SPHK, whose activity we have shown is regulated by various stimuli, is devoid of recognizable regulatory motifs suggesting that additional components remain to be discovered. We will attempt to identify potential SPHK interacting proteins which might be important for signaling, regulation, subcellular localization, or assembly of intracellular signaling complexes Although a number of potential indirect targets of SPP have been described, to date, the bona fide direct intracellular targets for SPP are still unknown and this will be another focus of this proposal. Our studies promise great rewards in deciphering its mechanisms of action and should help to fill in the gaps linking SPP to known intracellular signaling pathways and will enhance our understanding of how these regulated pathways of sphingolipid metabolism fit into the important areas of growth regulation, survival, and cancer biology.
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