New aspects of sphingosine 1-phosphate signaling in mammalian cells

Abstract

Sphingosine 1-phosphate (S1P) is a bioactive lipid that is formed by the phosphorylation of sphingosine by the enzyme, sphingosine kinase. S1P regulates cell function via a family of five closely related G-protein-coupled receptors (GPCR) termed S1P1-5 which bind S1P with high affinity (Chun et al., 2002). The S1P receptors relay the effects of S1P through signaling networks that regulate cell proliferation, survival, migration etc. A number of growth factors also activate sphingosine kinase to produce intracellular S1P which binds to putative intracellular proteins to produce cellular responses. There are two isoforms of sphingosine kinase termed SK1 and SK2. Sphingosine kinase 1 (SK1) was purified as a 49 kDa protein from rat kidney (Olivera et al., 1998) and subsequently two variants termed SK1a and SK1b were cloned from mouse (Kohama et al., 1998). The identification of SK2 was by BLAST searches of EST data using the mouse SK1 sequence. SK2 has regions of high homology with SK1, but contains an additional 240 amino acids located at the N-terminus and in the centre of the protein (Liu et al., 2000). Multiple spliced variant forms of SK1 and SK2 have subsequently been cloned (reviewed by Alemany et al., 2007). SK1 and SK2 are partially redundant since SK1−/− or SK2−/− mice are normal whereas elimination of both genes is embryonic lethal ([Allende et al., 2004] and [Mizugishi et al., 2005]). However, these enzymes may also have different sub-cellular localisations and antagonistic roles. For instance, SK1 enhances growth and survival whereas SK2 has been shown to be involved in the regulation of apoptosis (Spiegel and Milstien, 2003)