ROLES OF SPHINGOSINE-1-PHOSPHATE IN CELL-GROWTH, DIFFERENTIATION, ANDDEATH

Recent evidence suggests that branching pathways of sphingolipid metab olism may mediate either apoptotic or mitogenic responses depending on the cell type and the nature of the stimulus. While ceramide has been shown to be an important regulatory component of apoptosis induced by tumor necrosis factor a and the Fas ligand, sphingosine-l-phosphate ( SPP), a further metabolite of ceramide, has been implicated as a secon d messenger in cellular proliferation and survival induced by platelet -derived growth factor, neuronal growth factor, and serum. SPP protect s cells from apoptosis resulting from elevations of ceramide. Inflamma tory cytokines stimulate sphingomyelinase, but not ceramidase, leading to accumulation of ceramide, whereas growth signals also stimulate ce ramidase and sphingosine kinase leading to increased SPP levels. We pr opose that the dynamic balance between levels of sphingolipid metaboli tes, ceramide, and SPP and consequent regulation of different members of the mitogen-activated protein kinases (JNK versus ERK) family is an important factor that determines whether a cell survives or dies.